EAU - EANM - ESTRO -

ESUR - ISUP - SIOG

Guidelines on
Prostate Cancer
P. Cornford (Chair), D. Tilki (Vice-chair), R.C.N. van den Bergh,
D. Eberli, G. De Meerleer, M. De Santis, S. Gillessen, A.M. Henry,
G.J.L.H. van Leenders, J. Oldenburg, D.E. Oprea-Lager,
M. Roberts, O. Rouvière, I.G. Schoots, J. Stranne, T. Wiegel
Patient Advocate: E. Briers
Guidelines Associates: P. Chiu, A. Farolfi, G. Gandaglia,
N. Grivas, E. Linares Espinós, A. Sachdeva
Guidelines Office: E.J. Smith, C. Bezuidenhout

© European Association of Urology 2025

TABLE OF CONTENTS PAGE
1.INTRODUCTION 11
1.1 Aims and scope 11
1.2 Panel composition 11
1.3 Available publications 11
1.4 Publication history and summary of changes 11
1.4.1 Publication history 11
1.4.2 Summary of changes 11

2. METHODS 12
2.1 Data identification 12
2.2 Review 12
2.3 Future goals 12

3.EPIDEMIOLOGY AND AETIOLOGY 13

3.1 Epidemiology 13
3.2 Aetiology and risk factors for prostate cancer 13
3.2.1 Hereditary risk factors for PCa 13
3.2.1.1 Ethnicity and Family history 13
3.2.1.2 Germline mutations 14
3.2.1.3 Genetic single nucleotide polymorphism (SNPs) 15
3.2.2 Non-hereditary risk factors for PCa 15
3.2.2.1 Metabolic syndrome 15
3.2.2.1.1 Obesity 15
3.2.2.1.2 Diabetes/metformin 15
3.2.2.1.3 Cholesterol/statins 16
3.2.2.2 Dietary factors 16
3.2.2.3 Hormonally active medication 16
3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs) 16
3.2.2.3.2 Testosterone 17
3.2.2.4 Other potential risk factors 17
3.2.3 Summary of evidence for epidemiology and aetiology 17

4. CLASSIFICATION AND STAGING SYSTEMS 18

4.1 Classification 18
4.2 Gleason score and International Society of Urological Pathology 2019 grade 19
4.3 Clinically significant prostate cancer 19
4.4 Prognostic relevance of stratification 20
4.5 Recommendations for classification and staging systems 21

5.DIAGNOSTIC EVALUATION 21
5.1 Screening and individual early detection 21
5.1.1 Prostate-specific antigen (PSA) 21
5.1.2 Clinical Symptoms 21
5.1.3 Individual early detection 21
5.1.4 Population-based screening 24
5.1.5 Screening in patients with BRCA mutations 25
5.1.6 Recommendations for individual early detection 25
5.1.7 Genetic testing for inherited prostate cancer 26
5.1.8 Recommendations for germline testing* 26
5.2 Diagnostic tools 26
5.2.1 Digital rectal examination 26
5.2.2 Prostate-specific antigen 26
5.2.3 Prostate-specific antigen density 28

2 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

 5.2.4 Imaging 28
5.2.4.1 Magnetic resonance imaging 28
5.2.4.2 Transrectal ultrasound and ultrasound-based techniques 28
5.2.4.3 Prostate-specific membrane antigen-Positron emission tomography/
Computed tomography (or Magnetic resonance imaging) 29
5.2.5 Blood and urine biomarkers 29
5.2.5.1 Blood based biomarkers: PHI/4K score/IsoPSA/Stockholm3/Proclarix 29
5.2.5.2 Urine biomarkers: PCA3/SelectMDX/MyProstateScore (MPS/MPS2)/
ExoDX 29
5.2.6 Recommendations for screening and individual early detection 30
5.3 Pathology of prostate needle biopsies 30
5.3.1 Processing 30
5.3.2 Microscopy and reporting 30
5.3.2.1 Recommended terminology for reporting prostate biopsies 31
5.3.2.2 Recommended item list for reporting prostate cancer biopsies 32
5.3.3 Tissue-based prognostic biomarker testing 32
5.3.4 Tissue samples for homologous recombination repair (HRR)-testing 32
5.3.5 Histopathology of radical prostatectomy specimens 32
5.3.5.1 Processing of radical prostatectomy specimens 32
5.3.5.2 Radical prostatectomy specimen report 33
5.3.5.3 ISUP GG in prostatectomy specimens 33
5.3.5.4 Definition of extra-prostatic extension 34
5.3.5.5 PCa volume 34
5.3.5.6 Surgical margin status 34
5.3.5.7 Intra-operative assessment of surgical margin status 34
5.4 Biopsy indication 34
5.4.1 Risk assessment before MRI and biopsy 34
5.4.1.1 Risk calculators assessing the risk of csPCa 35
5.4.1.2 Using risk-stratification to avoid Magnetic resonance imaging
scans and biopsy procedures 35
5.4.2 MRI based indication for biopsy 35
5.4.2.1 MRI as a triage test for biopsy (‘MRI pathway’) 35
5.4.2.2 Combining MRI and PSA Density 36
5.4.2.3 Risk calculators incorporating MRI findings 37
5.4.2.4 MRI in population-based screening protocols 37
5.5 Biopsy strategy 37
5.5.1 Systematic biopsy strategy 38
5.5.2 Targeted biopsy strategy 38
5.5.3 Targeted biopsy versus systematic biopsy 38
5.5.3.1 Increased detection of cancers labelled as clinically significant 38
5.5.3.2 Reduced detection of cancers labelled as ISUP GG 1 38
5.5.3.3 Added value of systematic biopsy and targeted biopsy 38
5.5.4 Perilesional biopsy 39
5.5.5 Prostate MRI and MRI-targeted biopsy reproducibility 40
5.5.6 Cancer grade shift 40
5.5.7 Recommendations for MRI imaging in biopsy indication and strategy 41
5.6 Biopsy approach 41
5.6.1 MRI-directed transrectal vs transperineal US-guided biopsy 42
5.6.2 Local anaesthesia prior to biopsy 42
5.6.3 Infection rate after transperineal and transrectal prostate biopsy 42
5.6.4 Summary of evidence and recommendations for performing prostate biopsy
(in line with the EAU Urological Infections Guidelines Panel) 43
5.6.5 Complications 45
5.7 What diagnostic pathway in clinical practice? 45
5.7.1 Repeat biopsy after negative biopsy 46
5.7.2 Saturation biopsy 46
5.7.3 Seminal vesicle biopsy 46
5.7.4 Transition zone biopsy 46

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 5.8 Diagnosis - Clinical Staging 46
5.8.1 T-staging 46
5.8.1.1 Ultrasound-based techniques and Computed Tomography 46
5.8.1.2 Magnetic Resonance Imaging 46
5.8.2 N-staging 47
5.8.2.1 Computed tomography and MRI 47
5.8.2.2 Risk calculators incorporating MRI findings and clinical data 47
5.8.2.3 Choline PET/CT 47
5.8.2.4 Prostate-specific membrane antigen-based PET/CT 47
5.8.2.5 Risk calculators incorporating MRI and PSMA findings 48
5.8.2.6 Surgical techniques 48
5.8.2.6.1 Pelvic lymph node dissection 48
5.8.2.6.2 Lymph-node-positive patients during radical
prostatectomy 48
5.8.2.6.3 Sentinel node biopsy analysis 48
5.8.2.6.4 Complications of extended pelvic lymph node dissection 49
5.8.3 M-staging 49
5.8.3.1 Bone scan 49
5.8.3.2 Fluoride PET/CT, choline PET/CT and MRI 49
5.8.3.3 PSMA PET/CT 50
5.8.4 Summary of evidence and practical considerations on initial N/M staging 50
5.8.5 Recommendations for staging of prostate cancer 50

6.TREATMENT 51
6.1 Estimating life expectancy and health status 51
6.1.1 Introduction 51
6.1.2 Life expectancy 51
6.1.3 Health status screening 52
6.1.3.1 Co-morbidity 52
6.1.3.2 Nutritional status 52
6.1.3.3 Cognitive function 52
6.1.3.4 Physical function 52
6.1.3.5 Shared decision-making 52
6.1.4 Conclusion 52
6.1.5 Guidelines for evaluating health status and life expectancy 56
6.2 Treatment modalities 56
6.2.1 Expectant management strategies 56
6.2.1.1 Watchful Waiting 57
6.2.1.2 Active surveillance 58
6.2.1.2.1 Active surveillance - inclusion criteria 59
6.2.1.2.2 Active surveillance – inclusion of intermediate risk
disease 59
6.2.1.2.3 Tissue-based prognostic biomarker testing for selection
for active surveillance 61
6.2.1.2.4 Magnetic resonance imaging for selection for active
surveillance 61
6.2.1.2.5 Active surveillance follow-up 61
6.2.1.2.6 Magnetic resonance imaging for follow-up during
active surveillance 62
6.2.1.2.7 Individualised repeat biopsy during active surveillance 62
6.2.1.2.8 Active Surveillance - change in treatment 62
6.2.1.2.9 Psychological factors during active surveillance 63
6.2.1.2.10 Interventions during active surveillance 63
6.2.1.3 Summary of evidence and recommendations for active surveillance
strategy 64
6.2.2 Radical prostatectomy 64
6.2.2.1 Introduction 64
6.2.2.2 Pre-operative preparation 65
6.2.2.2.1 Pre-operative patient education 65

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 6.2.2.3 Surgical techniques 65
6.2.2.3.1 Prostatic anterior fat pad dissection and histologic
analysis 65
6.2.2.3.2 Management of the dorsal venous complex 65
6.2.2.3.3 Nerve-sparing surgery 66
6.2.2.3.4 Removal of seminal vesicles 66
6.2.2.3.5 Bladder neck management 66
6.2.2.3.6 Urethral length preservation 67
6.2.2.3.7 Techniques of vesico-urethral anastomosis 67
6.2.2.3.8 Urinary catheter 68
6.2.2.3.9 Cystography prior to catheter removal 68
6.2.2.3.10 Use of a pelvic drain 68
6.2.2.3.11 Considerations during minimally-invasive radical
prostatectomy 68
6.2.2.3.11.1 Pneumoperitoneum pressure 68
6.2.2.4 Acute and chronic complications of radical prostatectomy 68
6.2.2.4.1 Effect of anterior and posterior reconstruction on
continence 70
6.2.2.4.2 Deep venous thrombosis prophylaxis 70
6.2.3 Radiotherapy 70
6.2.3.1 External beam radiation therapy 70
6.2.3.1.1 Technical aspects 70
6.2.3.1.2 Dose escalation 71
6.2.3.1.3 Hypofractionation 71
6.2.3.2 Proton beam therapy 73
6.2.3.3 Spacer during external beam radiation therapy 77
6.2.3.4 Brachytherapy 77
6.2.3.4.1 Low-dose rate brachytherapy 77
6.2.3.4.2 High-dose rate brachytherapy 78
6.2.3.5 Acute side effects of external beam radiotherapy and brachytherapy 79
6.2.4 Investigational therapies 79
6.2.4.1 Background 79
6.2.4.2 Whole-gland therapies 80
6.2.4.3 Focal therapy 80
6.3 Treatment by disease stages 81
6.3.1 Management of low-risk disease 81
6.3.1.1 Watchful waiting 81
6.3.1.2 Active surveillance 81
6.3.1.2.1 Androgen deprivation monotherapy 82
6.3.1.3 Other therapeutic options 82
6.3.1.4 Recommendations for the management of low-risk disease 82
6.3.2 Management of Intermediate-risk disease 82
6.3.2.1 Watchful waiting 82
6.3.2.2 Active Surveillance 82
6.3.2.3 Radical prostatectomy 82
6.3.2.4 Radiation therapy 82
6.3.2.4.1 Recommended IMRT/VMAT 82
6.3.2.4.2 Brachytherapy 83
6.3.2.5 Other therapeutic options 83
6.3.2.5.1 Focal therapy 83
6.3.2.5.2 Androgen deprivation therapy monotherapy 83
6.3.2.6 Recommendations for the management of intermediate-risk disease* 83
6.3.3 Management of high-risk localised disease 84
6.3.3.1 Radical prostatectomy 84
6.3.3.2 External beam radiation therapy 84
6.3.3.2.1 Lymph node irradiation in cN0 84
6.3.3.2.2 Brachytherapy boost 85
6.3.3.3 Recommendations for the management of high-risk localised
disease* 85

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 6.3.4 Treatment of locally-advanced PCa 85
6.3.4.1 Radical prostatectomy 85
6.3.4.2 Treatment of cN1 M0 PCa 86
6.3.4.2.1 Consideration of molecular imaging 86
6.3.4.2.2 Local treatment of cN1 M0 PCa 86
6.3.4.2.3 Systemic treatment of cN1 M0 PCa 86
6.3.4.3 Options other than surgery or radiotherapy for primary treatment 88
6.3.4.3.1 Investigational therapies 88
6.3.4.3.2 Androgen deprivation therapy monotherapy 88
6.3.4.4 Recommendation for management of locally-advanced disease* 88
6.3.5 Adjuvant treatment after radical prostatectomy 89
6.3.5.1 Introduction 89
6.3.5.2 Risk factors for relapse 89
6.3.5.2.1 Biomarker-based risk stratification after radical
prostatectomy 89
6.3.5.3 Immediate (adjuvant) post-operative external irradiation after RP
(cN0 or pN0) 89
6.3.5.4 Comparison of adjuvant and salvage radiotherapy 89
6.3.5.5 Adjuvant systemic therapy in N0 disease 92
6.3.5.6 Adjuvant treatment in pN1 disease 92
6.3.5.6.1 Adjuvant androgen ablation alone 92
6.3.5.6.2 Adjuvant radiotherapy combined with ADT in pN1 disease 92
6.3.5.6.3 Observation of pN1 patients after radical prostatectomy
and extended lymph node dissection 92
6.3.5.7 Recommendations for adjuvant treatment for pN0 and pN1 disease
after radical prostatectomy* 93
6.3.6 Persistent PSA after radical prostatectomy 93
6.3.6.1 Natural history of persistently elevated PSA after RP 93
6.3.6.2 Imaging in patients with persistently elevated PSA after RP 93
6.3.6.3 Management options for patients with persistent PSA 94
6.3.6.3.1 Comparison with biochemical recurrence (BCR) 94
6.3.6.3.2 Post-operative RT 94
6.3.6.3.3 Multimodal therapy (ADT with post-operative RT) 95
6.3.6.4 Conclusion 95
6.3.6.5 Recommendations for the management of persistent PSA after
radical prostatectomy 95
6.4 Management of PSA-only recurrence after treatment with curative intent 95
6.4.1 Background 95
6.4.1.1 PSA velocity and doubling time 95
6.4.2 Controversies in the definitions of clinically relevant PSA relapse 96
6.4.3 Natural history of biochemical recurrence 96
6.4.4 The role of imaging in PSA-only recurrence 97
6.4.4.1 Assessment of metastases (including nodal) 97
6.4.4.1.1 Bone scan and abdominopelvic CT 97
6.4.4.1.2 Choline PET/CT 97
6.4.4.1.3 Fluoride PET/CT 97
6.4.4.1.4 Fluciclovine PET/CT 97
6.4.4.1.5 Prostate-specific membrane antigen based PET/CT 98
6.4.4.1.6 Whole-body and axial MRI 99
6.4.4.2 Assessment of local recurrences 99
6.4.4.2.1 Local recurrence after radical prostatectomy 99
6.4.4.2.2 Local recurrence after radiation therapy 99
6.4.4.3 Summary of evidence of imaging in case of biochemical recurrence 99
6.4.4.4 Recommendations for imaging in patients with biochemical
recurrence 100
6.4.5 Treatment of PSA-only recurrences 100
6.4.5.1 Treatment of PSA-only recurrences after radical prostatectomy 100
6.4.5.1.1 Salvage radiotherapy for PSA-only recurrence after
radical prostatectomy (cTxcN0M0, without PET/CT) 100

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 6.4.5.1.2 Salvage radiotherapy combined with androgen
deprivation therapy (cTxcN0, without PET/CT) 101
6.4.5.1.2.1 Target volume, dose, toxicity 102
6.4.5.1.2.2 Salvage radiotherapy with or without ADT
(cTx cN0/1) with PET/CT 106
6.4.5.1.2.3 Nodal-directed therapy for rcN1
(with PET/CT) 107
6.4.5.1.3 Salvage lymph node dissection 107
6.4.5.2 Management of PSA failures after radiation therapy 108
6.4.5.2.1 Salvage radical prostatectomy 108
6.4.5.2.1.1 Oncological outcomes 108
6.4.5.2.1.2 Morbidity 108
6.4.5.2.1.3 Summary of salvage radical prostatectomy 108
6.4.5.2.2 Salvage cryoablation of the prostate 109
6.4.5.2.2.1 Oncological outcomes 109
6.4.5.2.3 Salvage re-irradiation 109
6.4.5.2.3.1 Salvage brachytherapy for radiotherapy
failure 109
6.4.5.2.3.2 Salvage stereotactic ablative body
radiotherapy for radiotherapy failure 110
6.4.5.2.3.2.1 Oncological outcomes and morbidity 110
6.4.5.2.3.2.2 Morbidity 110
6.4.5.2.3.2.3 Summary of salvage stereotactic
ablative body radiotherapy 111
6.4.5.2.4 Salvage high-intensity focused ultrasound 111
6.4.5.2.4.1 Oncological outcomes 111
6.4.5.2.4.2 Morbidity 111
6.4.5.2.4.3 Summary of salvage high-intensity
focused ultrasound 112
6.4.6 Hormonal therapy for relapsing patients 112
6.4.7 Observation 113
6.4.8 Recommendations for second-line therapy after treatment with curative intent 113
6.5 Systemic treatments for prostate cancer 114
6.5.1 Hormonal therapy 114
6.5.1.1 Castration level 114
6.5.1.2 Bilateral orchiectomy 114
6.5.1.3 Luteinising-hormone-releasing hormone agonists 114
6.5.1.4 Luteinising-hormone-releasing hormone antagonists 114
6.5.1.5 Anti-androgens 115
6.5.1.5.1 Steroidal anti-androgens 115
6.5.1.5.2 Non-steroidal anti-androgens 115
6.5.1.5.3 New androgen receptor pathway inhibitors (ARPIs) 115
6.5.1.5.3.1 Abiraterone acetate 115
6.5.1.5.3.2 Apalutamide, darolutamide, enzalutamide
and rezvilutamide (alphabetical order) 116
6.5.2 Cytotoxic drug treatment 116
6.5.2.1 Taxanes 116
6.5.3 Non-hormonal non-cytotoxic drug treatments 116
6.5.3.1 Poly (ADP-ribose) polymerase inhibitirs (PARPi) 116
6.5.3.2 Immune checkpoint inhibitors 116
6.5.3.3 Radiopharmaceutical therapy 116
6.6 Management of Metastatic prostate cancer 116
6.6.1 Introduction 116
6.6.2 Prognostic and predictive factors 117
6.6.3 First-line hormonal treatment 117
6.6.3.1 Non-steroidal anti-androgen monotherapy 117
6.6.3.2 Intermittent versus continuous androgen deprivation therapy 118
6.6.3.3 Early versus deferred androgen deprivation therapy 118

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 6.6.4 Combination therapies 118
6.6.4.1 ‘Combined’ androgen blockade with older generation NSAA
(bicalutamide, flutamide, nilutamide) 118
6.6.4.2 Androgen deprivation combined with other agents 118
6.6.4.2.1 Combination with an ARPI alone (abiraterone,
apalutamide, enzalutamide, rezvilutamide, darolutamide) 118
6.6.4.2.2 Androgen deprivation therapy combined with
chemotherapy 121
6.6.5 Treatment selection and patient selection 122
6.6.6 Treatment of the primary tumour in newly diagnosed metastatic disease 122
6.6.7 Metastasis-directed therapy in M1-patients 123
6.6.8 Recommendations for the first-line treatment of hormone-sensitive metastatic
disease* 124
6.7 Treatment: Castration-resistant PCa (CRPC) 125
6.7.1 Definition of CRPC 125
6.7.2 Management of mCRPC - general aspects 125
6.7.2.1 Molecular diagnostics 125
6.7.3 Treatment decisions and sequence of available options 125
6.7.4 Non-metastatic CRPC 126
6.7.5 Metastatic CRPC 126
6.7.5.1 Conventional androgen deprivation in CRPC 126
6.7.6 First-line treatment of metastatic CRPC 126
6.7.6.1 Abiraterone 126
6.7.6.2 Enzalutamide 126
6.7.6.3 Docetaxel 127
6.7.6.4 Sipuleucel-T 127
6.7.6.5 Combinations with PARP inhibitors 127
6.7.7 Second-line treatment for mCRPC 128
6.7.7.1 Cabazitaxel 128
6.7.7.2 Abiraterone acetate after docetaxel for mCRPC 129
6.7.7.3 Enzalutamide after docetaxel for mCRPC 129
6.7.7.4 Radium-223 after ARPI or both ARPI and docetaxel for mCRPC 129
6.7.7.5 Rucaparib after ARPI 130
6.7.7.6 Olaparib after ARPI 130
6.7.7.7 177Lu-PSMA-617 after ARPI 130
6.7.8 Treatment after docetaxel and one line of hormonal treatment for mCRPC 130
6.7.8.1 General considerations 130
6.7.8.2 Radiopharmaceuticals 130
6.7.8.2.1 Introduction 130
6.7.8.2.2 PSMA-based therapy 131
6.7.8.3 PARP inhibitors for mCRPC 132
6.7.8.4 Sequencing treatment 133
6.7.8.4.1 ARPI -> ARPI (chemotherapy-naïve mCRPC patients) 133
6.7.8.4.2 ARPI -> PARP inhibitor 133
6.7.8.4.3 Docetaxel for mHSPC -> docetaxel rechallenge 133
6.7.8.4.4 ARPI -> docetaxel or docetaxel -> ARPI followed by
PARP inhibitor 133
6.7.8.4.5 ARPI before or after docetaxel 133
6.7.8.4.6 ARPI –> docetaxel -> cabazitaxel or docetaxel –>
ARPI -> cabazitaxel 133
6.7.8.5 Platinum chemotherapy 133
6.7.9 Monitoring of treatment 138
6.7.10 When to change treatment 138
6.7.11 Symptomatic management in metastatic castration-resistant prostate cancer 138
6.7.11.1 Common complications due to bone metastases 139
6.7.11.2 Preventing skeletal-related events 139
6.7.11.2.1 Bisphosphonates 139
6.7.11.2.2 RANK ligand inhibitors 139

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 6.7.12 Summary of evidence and recommendations for life-prolonging
treatments of castrate-resistant disease 139
6.7.13 Recommendations for systemic treatments of castrate-resistant
disease 140
6.7.14 Guideline for non-metastatic castrate-resistant disease 141

7.FOLLOW-UP 143
7.1 Watchful waiting 143
7.2 Active surveillance strategy 143
7.3 Follow-up: After local treatment with curative intent 143
7.3.1 Definition 143
7.3.2 Why follow-up? 143
7.3.3 How to follow-up? 143
7.3.3.1 Prostate-specific antigen monitoring 143
7.3.3.1.1 Prostate-specific antigen monitoring after radical
prostatectomy 143
7.3.3.1.2 Prostate-specific antigen monitoring after radiotherapy 144
7.3.3.2 Digital rectal examination 144
7.3.3.3 Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT 144
7.3.3.4 Functional follow-up 144
7.3.4 How long to follow-up? 144
7.3.5 Summary of evidence and recommendations for follow-up after treatment
with curative intent 145
7.4 Follow-up: During first line hormonal treatment (androgen sensitive period) 145
7.4.1 Introduction 145
7.4.2 Purpose of follow-up 145
7.4.3 General follow-up of men on ADT 145
7.4.3.1 Testosterone monitoring 145
7.4.3.2 Liver function monitoring 146
7.4.3.3 Serum creatinine and haematological parameters 146
7.4.3.4 Monitoring of metabolic complications 146
7.4.3.5 Monitoring bone problems 146
7.4.3.6 Monitoring lifestyle, cognition, fatigue and sexual function 146
7.4.4 Methods of follow-up in men on ADT without metastases 147
7.4.4.1 Prostate-specific antigen monitoring 147
7.4.4.2 Imaging 147
7.4.5 Methods for follow-up in men under ADT for hormone-sensitive metastatic PCa 147
7.4.5.1 PSA monitoring 147
7.4.5.2 Imaging as a marker of response in metastatic PCa 147
7.4.6 Recommendations for follow-up during hormonal treatment 148

8.QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER 148

8.1 Introduction 148
8.2 Adverse effects of PCa therapies 149
8.2.1 Active surveillance 149
8.2.2 Surgery 149
8.2.3 Radiotherapy 149
8.2.3.1 Side effects of external beam radiotherapy 149
8.2.3.2 Side effects from brachytherapy 150
8.2.4 Local primary whole-gland treatments other than surgery or radiotherapy 150
8.2.4.1 Whole-gland treatments 150
8.2.4.2 Focal treatments 150
8.2.5 Androgen deprivaton therapy 150
8.2.5.1 Sexual function 151
8.2.5.2 Hot flushes 151
8.2.5.3 Non-metastatic bone fractures 152
8.2.5.4 Metabolic effects 152
8.2.5.5 Cardiovascular morbidity 153

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 9

 8.2.5.6 Fatigue 153
8.2.5.7 Neurological side effects 153
8.2.6 Osteonecrosis during bisphosphonates or denosumab 154
8.3 Overall quality of life in men with PCa 154
8.3.1 Long-term (> twelve months) quality of life outcomes in men with localised
disease 155
8.3.1.1 Men undergoing local treatments 155
8.3.1.2 Recommendations for quality of life in men undergoing local
treatments 156
8.3.2 Improving quality of life in men who have been diagnosed with PCa 156
8.3.2.1 Men undergoing local treatments 156
8.3.2.2 Men undergoing systemic treatments 157
8.3.2.3 Decision regret 158
8.3.2.4 Decision aids in prostate cancer 159
8.3.2.5 Recommendations for quality of life in men undergoing systemic
treatments 159

9. REFERENCES 160

10. CONFLICT OF INTEREST 251

11. CITATION INFORMATION 251

12. COPYRIGHT AND TERMS OF USE 251

10 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1. INTRODUCTION
1.1 Aims and scope
The Prostate Cancer (PCa) Guidelines Panel have prepared this guidelines document to assist medical
professionals in the evidence-based management of PCa.
It must be emphasised that clinical guidelines present the best evidence available to the experts
but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.

1.2 Panel composition

The PCa Guidelines Panel consists of an international multidisciplinary group of urologists, radiation
oncologists, medical oncologists, radiologists, pathologists and a patient representative.
All imaging sections in the text have been developed jointly with the European Society of Urogenital
Radiology (ESUR) and the European Association of Nuclear Medicine (EANM). Representatives of the ESUR
are Prof.Dr. O. Rouvière and Dr. I.G. Schoots and the EANM are Dr. A. Farolfi and Dr. D. Oprea-Lager. All
radiotherapy (RT) sections have been developed jointly with the European Society for Radiotherapy & Oncology
(ESTRO). Representatives of ESTRO are Prof.Dr. G. De Meerleer, Prof.Dr. A.M. Henry, and Prof.Dr. T. Wiegel. The
International Society of Urological Pathology (ISUP) is represented by Prof.Dr. A. van Leenders. Dr. E. Briers
represents the patient voice from the European Prostate Cancer Coalition and Europa UOMO.
All experts involved in the production of this document have submitted potential conflict of interest
statements which can be viewed on the EAU website Uroweb: https://uroweb.org/guideline/prostate-cancer/.

1.3 Available publications

A quick reference document, the Pocket guidelines, is available in print. This is an abridged version which may
require consultation together with the full text version. Several scientific publications are available, the latest
dating to 2024 [1, 2]. All documents can be accessed on the EAU website: http://uroweb.org/guideline/prostate-
cancer/. An EAU Guidelines App for iOS and Android devices is also available containing the Pocket Guidelines,
interactive algorithms and calculators, clinical decision support tools, guidelines cheat sheets and links to the
extended guidelines.

1.4 Publication history and summary of changes

1.4.1 Publication history
The EAU PCa Guidelines were first published in 2001. Standard procedure for EAU Guidelines includes an annual
assessment of newly published literature in the field to guide future updates. This 2025 PCa Guidelines present
a limited update of the 2024 publication.

1.4.2 Summary of changes

For the 2025 PCa Guidelines new and relevant evidence was identified, collated and appraised through a
structured assessment of the literature for all sections of the Guidelines. Key changes include:

• Addition of Table 3.1: Definition of familial and hereditary PCa.

• Update of the EAU risk groups for biochemical recurrence of localised and locally-advanced PCa
based on systematic biopsy. EAU intermediate-risk group has now been split into favourable and
unfavourable.
• Addition of Table 5.3: Sources of error in PSA value assessment
• Significant update to section 5.4.2.4 – MRI in population-based screening protocols.
• Adaption of the recommendation for transperineal biopsy in section 5.6.4.
• Restructure and update of section 5.5.2.6 Surgical techniques for N-staging.
• Updated recommendation for use of prostate-specific antigen-positron emission tomography/
computed tomography for staging of intermediate-risk PCa (see section 5.8.5).
• General recommendations for management of PCa have been removed. All recommendations are
now given per disease stage.
• Section 6.6.4 – Combination therapies for management of metastatic PCa has been restructured.
• New recommendation on use of darolutamide in section 6.6.8 - Recommendations for the first-line
treatment of hormone-sensitive metastatic disease.
• New recommendation on discussing all patients with hormone-sensitive metastatic disease in a
multidisciplinary team in section 6.6.9 - Recommendations for the first-line treatment of hormone-
sensitive metastatic disease.

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 11

 • New recommendation on offering bone protective agents to men on long-term androgen deprivation
therapy plus/minus ARPI in the supportive care recommendations in section 6.6.9 related to hormone-
sensitive metastatic disease.
• New recommendation in section 7.4.6 for follow-up during hormonal treatment.
• Expansion and update of section 8.2.5 – Androgen deprivation therapy with section 8 – Quality of life
outcomes in PCa.

2. METHODS
2.1 Data identification
For the 2025 PCa Guidelines, new and relevant evidence has been identified, collated and appraised through
a structured assessment of the literature. A number of comprehensive searches were performed, covering
all sections of the PCa Guidelines. The searches were limited to English language publications. Databases
searched included Medline, EMBASE and the Cochrane Libraries, covering a time frame between May 1st
2023 and May 1st 2024. A total of 3,060 unique records were identified, retrieved and screened for relevance.
Detailed search strategies are available online: https://uroweb.org/guideline/prostate-cancer/?type=appendices-
publications.

Changes in recommendations were generally only considered on the basis of high-level evidence (i.e. systematic
reviews (SR) with meta-analysis, randomised controlled trials (RCTs), and prospective comparative studies).

Recommendations within the Guidelines are developed by the panels to prioritise clinically important care
decisions. The strength of each recommendation is determined by the balance between desirable and
undesirable consequences of alternative management strategies, the quality of the evidence (including certainty
of estimates), and the nature and variability of patient values and preferences. This decision process, which can
be reviewed in the strength rating forms which accompany each guideline statement, addresses a number of
key elements:

1. the overall quality of the evidence which exists for the recommendation [3];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study
related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact and certainty of patient values and preferences on the intervention.

Strong recommendations typically indicate a high degree of evidence quality and/or a favourable balance
of benefit to harm and patient preference. Weak recommendations typically indicate availability of lower
quality evidence, and/or equivocal balance between benefit and harm, and uncertainty or variability of patient
preference [4].
Additional methodology information and a list of associations endorsing the EAU Guidelines can be
found online: https://uroweb.org/eau-guidelines/methodology-policies.

2.2 Review
Publications ensuing from SRs have all been peer-reviewed.

2.3 Future goals

Results of ongoing projects will be included in the 2026 update of the PCa Guidelines:
• A SR assessing the performance of risk stratification tools incorporating imaging, biomarkers, biopsy
involvement and/or magnetic resonance imaging (MRI)-targeted biopsies, compared to the classical risk
classifications (d’Amico, EAU, the Cancer of the Prostate Risk Assessment (CAPRA) and the National
Comprehensive Cancer Network (NCCN)) recommended in current guidelines for predicting biochemical
recurrence, metastasis or death after local treatment for prostate cancer. Are the new stratification tools
preferred above the classical risk classifications?
• Care pathways for the various stages of PCa management have been developed. These pathways will, in
due time, inform treatment flowcharts and a new EAU clinical decision support tool for PCa.

12 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

3. EPIDEMIOLOGY AND AETIOLOGY
3.1 Epidemiology
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, with an estimated 1.4 million
diagnoses and 375,000 deaths worldwide in 2020 [5, 6]. In more than half of the countries of the world it is the
most frequently diagnosed cancer in men and PCa is the leading cause of death among men in a quarter of all
countries [7]. In Europe, it is the most frequently diagnosed cancer in men and the third cancer-related cause of
death in men [8].
A SR of autopsy studies reported a prevalence of PCa at age < 30 years of 5% (95% confidence
interval [CI]: 3–8%), increasing with age, to a prevalence of 59% (48–71%) by age > 79 years [9]. There is
variation in the frequency of autopsy-detected PCa between men with different ethnical backgrounds and
geographical areas (e.g., 83% in white US males vs. 41% in Japan at age 71–80) [10].
Regarding incidence of PCa diagnosis, the variation is even more pronounced between different
geographical areas, partly driven by rate of prostate-specific antigen (PSA) testing and influenced by (inter)
national organisations recommendations on screening (see section 5.1) [11]. It is highest in Australia/New
Zealand and Northern America (age-standardised rates [ASR] per 100,000 of 111.6 and 97.2, respectively), and
in Western and Northern Europe (ASRs of 94.9 and 85, respectively) [12]. The incidence is low in Eastern and
South-Central Asia (ASRs of 10.5 and 4.5, respectively), but rising [13]. Rates in Eastern and Southern Europe
were low but have also shown a steady increase [6, 10]. Other reasons for variation in PCa incidence include the
age of the population, ethnicity and dietary factors [7].
There is relatively less variation in mortality rates worldwide, although rates are generally high in
populations of African descent (e.g., Caribbean: ASR of 29 and Sub-Saharan Africa: ASRs ranging between 14
and 19), intermediate in the USA and very low in Asia (South-Central Asia: ASR of 2.9) [6, 7]. Mortality due to PCa
has decreased in most Western nations but the magnitude of the reduction varies between countries [5].

3.2 Aetiology and risk factors for prostate cancer

A wide variety of endogenous and exogenous/environmental factors have been discussed as being associated
with the risk of developing PCa, or as being aetiologically important for the progression from latent to clinical
PCa [14]. As previously discussed, there is likely a racial factor involved, but Asians who immigrated to the
USA have approximately half the risk of PCa when compared to their US born Asian-descendant counterparts,
implying a role for environmental and/or dietary factors [15]. These guidelines divide the risk factors into
hereditary, such as ethnicity, family history and known genetic mutations, in which direct heritance of the risk
factor is more obvious and direct, and non-hereditary, such as dietary and medical factors as well as metabolic
syndrome and obesity, in which there may well be hereditary components, but they are more indirect.

3.2.1 Hereditary risk factors for PCa

There are basically three inherited risk factors that are consistently associated with PCa: ethnicity/family history,
rare germline mutations in several candidate genes, and common genetic single nucleotide polymorphism
(SNPs).

3.2.1.1 Ethnicity and Family history

Ethnic background and family history are both associated with varying PCa incidence, suggesting a genetic
predisposition [7]. Men of African ancestry in the Western world demonstrate more unfavourable outcomes
that may be due to biological, environmental, social, and/or health care factors [16]. They have been reported
to be at increased risk of being diagnosed with more advanced disease [17] and more likely to be upgraded
after prostatectomy than White men [18], but the question is more intricate than that. In a population, race is
categorised based on a combination of e.g. ancestry, skin colour and geographical origin, and within any race
there are hundreds of areas of geographical origins [7]. Indeed, a multi-ancestry polygenic risk score of 278
risk variants showed a strong association with PCa risk in men with African ancestry, especially sub-Saharan,
and might be used to identify susceptibility in this high-risk population [19]. There is also data suggesting no
difference in overall survival (OS) or prostate cancer specific mortality (PCSM) between White, Black or Hispanic
men with metastatic PCa [20]. Racial disparities in development of, prevention of, and therapies for PCa may
exist. It should be kept in mind that very few PCa treatment trials report on race, education and socioeconomics
[21]. Moreover, participation in a clinical trial is precluded by a selection process, whereby in itself, decrease
PCSM drastically and most PCa studies include either small percentages of non-White men, or focus on highly
specific other groups [22, 23]. A recent SR also found that Black men without PCa seem to have higher baseline
levels of PSA which could lead to over-detection, and further affect described differences [24].

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A small subpopulation of all men with PCa, regardless of ethnicity, have true hereditary PCa (HPCA), defined as
≥ 3 cases in the same family, PCa in three successive generations, or ≥ 2 cases in the same family diagnosed
< 55 yrs. In a Swedish population-based study, the probability of high-risk PCa at age 65 was 11.4% (vs. a
population risk of 1.4%), and for any PCa 43.9% (vs. 4.8%) if the father as well as two brothers were affected
[25]. HPCa was also, in a large USA population database, reported by 2.18% of participants, and showed a
relative risk (RR) of 2.30 for diagnosis of any PCa, 3.93 for early-onset PCa, 2.21 for lethal PCa, and 2.32 for
clinically significant PCa (csPCa) [26]. On the other hand, recent data from the UK even suggest an inverse
association between PCSM and a stronger family history, likely attributed to higher awareness of the risks
and adherence to screening [27]. For familial PCa, defined as ≥ 2 first- or second-degree relatives with PCa on
the same side of the pedigree, or familial syndromes such as hereditary breast and ovarian cancer and Lynch
syndrome, the risk is lower [25].

Table 3.1: Definition of familial and hereditary PCa

Type Definition
Familial 2 first-degree relatives diagnosed with PCa at any age or 1 first-degree relative and ≥ 2 second-
degree relatives diagnosed at any age.
Hereditary ≥ 3 cases in the same family, PCa in three successive generations, or ≥ 2 cases in the same
family diagnosed < 55 yrs.

3.2.1.2 Germline mutations

Pathogenic germline mutations in the BRCA2 and HOXB13 genes, but also in the genes CHEK2, BRCA1, ATM,
NBS1, and genes involved in Lynch syndrome, have been suggested to increase the risk of PCa [7]. Data from
UK, on over 21,000 men without a PCa diagnosis, suggest that 1.6 % carry a pathogenic mutation in at least
one of the genes BRCA2, HOXB13 or CHEK2. Even though germline mutations leading to PCa are relatively
rare (1/300), the impact on PCa risk is quite strong, and the prevalence in patients with advanced PCa is high
[28]. In a study on 3,607 unselected patients with PCa diagnosis as many as 17.2% contained a pathogenic
mutation [29]. In men with PCa undergoing multigene testing across the USA, it was found that 15.6% of men
with PCa have pathogenic variants identified in genes tested ([Breast Cancer genes] BRCA1, BRCA2, HOXB13,
MLH1, MSH2, PMS2, MSH6, EPCAM, ATM, CHEK2, NBN, and TP53), and 10.9% of men have germline pathogenic
variants in DNA repair genes (Table 3.2) [30]. Pathogenic variants were most commonly identified in BRCA2
(4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%) [30].
Among men with metastatic PCa, an incidence of 11.8% was found for germline mutations in
genes mediating DNA-repair processes [31], and for patients diagnosed with metastatic castrate-resistant PCa
(mCRPC) the incidence was 16.2% [32]. Targeted genomic analysis of genes associated with an increased risk
of PCa could offer options to identify families at high risk [33, 34].
A prospective cohort study of male BRCA1 and BRCA2 carriers confirmed BRCA2 association with
aggressive PCa [35]. An analysis of the outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2
carriers, and 1,940 non-carriers) showed that PCa with germline BRCA1/2 mutations were more frequently
associated with ISUP grade group (GG) ≥ 4, stage T3/T4, nodal involvement, and metastases at diagnosis,
than PCa in non-carriers [36]. BRCA-susceptibility gene mutation carriers were also reported to have worse
outcome when compared to non-carriers after local therapy [37]. In a retrospective study of 313 patients who
died of PCa and 486 patients with low-risk localised PCa, the combined BRCA1/2 and ATM mutation carrier
rate was significantly higher in lethal PCa patients (6.1%) than in localised PCa patients (1.4%) [38]. The rate of
PCa among BRCA1 carriers was more than twice as high (8.6% vs. 3.8%) compared to the general population,
in contrast to findings of the prospective IMPACT study (Identification of Men with a Genetic Predisposition to
Prostate Cancer) [39].

Table 3.2: Germline mutations in DNA repair genes associated with increased risk of PCa

Gene Location PCa risk Findings

BRCA2 13q12.3 RR 2.5 to 4.6 [40, 41] • Up to 12 % of men with metastatic PCa harbour germline
- PCa at 55 years or mutations in 16 genes (including BRCA2 [5.3%]) [31]
under: RR: 8–23 [42, 43] • 2% of men with early-onset PCa harbour germline
mutations in the BRCA2 gene [42]
• BRCA2 germline alteration is an independent predictor of
metastases and worse PCa-specific survival [36, 44]

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HOXB13 17q21.2 OR 3.4–7.9 [33, 45] • Significantly higher PSA at diagnosis, higher Gleason
score and higher incidence of positive surgical margins
in the RP specimen than non-carriers [46]
CHEK2 22q12.1 OR 3.3 [40, 41] • Up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including CHEK2 [1.9%]) [31]
BRCA1 17q21 RR: 1.8–3.8 at 65 years • Higher rates of lethal PCa among mutation carriers [38]
or under [47, 48] •U p to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including BRCA1 [0.9%]) [31]
ATM 11q22.3 RR: 6.3 for metastatic • Higher rates of lethal PCa among mutation carriers [38]
PCa [31] • Up to 12% of men with metastatic PCa harbour germline
mutations in 16 genes (including ATM [1.6%]) [31]
MMR genes 3p21.3 RR: 3.7 [49] • Mutations in MMR genes are responsible for Lynch
MLH1 2p21 syndrome [50]
MSH2 2p16 • MSH2 mutation carriers are more likely to develop PCa
MSH6 7p22.2 than other MMR gene mutation carriers [51]
PMS2
BBRCA2 = breast cancer gene 2; HOXB13 = homeobox B13; CHEK2 = checkpoint kinase 2; BRCA1 = breast
cancer gene 1; ATM = ataxia telangiectasia mutated; GS = Gleason score; MMR = mismatch repair; MLH1 = mutL
homolog 1; MSH2 = mutS homolog 2; MSH6 = mutS homolog 6; OR = odds ratio; PMS2 = post-meiotic segregation
increased 2; PCa = prostate cancer; RP = radical prostatectomy; RR = relative risk; PSA = prostate-specific antigen.

3.2.1.3 Genetic single nucleotide polymorphism (SNPs)

If germline genetic mutations are relatively rare, but with quite high impact on PCa risk, SNPs are very common,
but each SNP has low impact on the risk of developing PCa [7]. Two hundard and sixty nine individual SNPs
have been identified to be associated with PCa risk [52]. Although each individual SNP has a low impact on
PCa risk, the additive effects of multiple alleles can cause substantial increased risk of developing PCa and are
likely causative of a large proportion of hereditary PCa [53]. The additive effect of of the different SNPs can be
summed into polygenic risk scores (PRSs), which are directly associated with the absolute risk of developing
PCa [19, 54]. However, so far there seems to be no additive prognostic value in the PRSs when added to PSA and
PRSs can therefore not be used for risk stratification [53].

3.2.2 Non-hereditary risk factors for PCa

There are a number of risk factors for PCa, that are less determined by ethnicity and/or heredity, of which age is
the most obvious [9]. Despite this, currently there are no known effective preventative dietary or pharmacological
interventions.

3.2.2.1 Metabolic syndrome

The association between metabolic syndrome and PCa is not clear, with mixed results in various studies. There
seems to be a weak association overall, but a slightly stronger in the sub-group of men with more aggressive
disease [7]. The single components of metabolic syndrome (MetS) that have been strongest associated with a
significantly greater risk of PCa are hypertension (p = 0.035) and waist circumference ≥ 102 cm (p = 0.007) [55].

3.2.2.1.1 Obesity
Within the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, obesity was associated with
lower risk of low-grade PCa (OR: 0.79, p = 0.01), and a higher risk of high-grade PCa (OR: 1.28, p = 0.042), in
multivariable analyses [56]. This effect seems mainly explained by environmental determinants of height/body
mass index (BMI) rather than genetically elevated height or BMI [57]. A SR showed an association between
obesity and increased PC-specific mortality [58].

3.2.2.1.2 Diabetes/metformin
A SR from 2021 could not identify any association between diabetes type 2 and PCa [59]. The association
between metformin use and PCa is controversial. At population level, metformin users (but not other oral
hypoglycaemic agents) were found to be at a decreased risk of PCa diagnosis compared with never users
(adjusted OR: 0.84; 95% CI: 0.74–0.96) [60]. In 540 diabetic participants of the REDUCE study, metformin use
was not significantly associated with PCa and therefore not advised as a preventive measure (OR: 1.19, p =
0.50).

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3.2.2.1.3 Cholesterol/statins
A meta-analysis of fourteen large prospective studies did not show any association between blood total
cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol levels and the risk of
developing either overall PCa or high-grade PCa [51]. Two meta-analysis suggested a lower risk of PCa overall
(OR: 0.94) as well as advanced PCa in statin users [61, 62]. Pooled estimates indicated that the effect seemed to
be exclusive to lipophilic statins [61].

3.2.2.2 Dietary factors

The association between a wide variety of dietary factors and PCa have been studied, but there is a paucity of
quality evidence (Table 3.3). To date, the current body of evidence will not support a causal relationship between
specific (dietary and otherwise) factors and the development of PCa. Consequently, no effective preventative
strategies can be suggested.

Table 3.3: Main dietary factors that have been associated with PCa

Alcohol High alcohol intake, but also total abstention from alcohol has been associated with
a higher risk of PCa and PCa-specific mortality [63]. A meta-analysis suggests a weak
relationship with PCa [64].
Coffee/Tea Coffee consumption may be associated with a reduced risk of PCa; with a pooled RR
of 0.91 for the highest category of coffee consumption [65]. No clear association was
found between tea consumption and PCa risk [7].
Dairy/Calcium A SR suggests a correlation between high intake of protein from dairy products and
the risk of PCa was found, but many of the included studies were affected by PSA
screening bias [66].
Fat No association between intake of long-chain omega-3 poly-unsaturated fatty acids and
PCa was found [67]. A relation between intake of fried foods and risk of PCa may exist
[68].
Tomatoes A trend towards a favourable effect of tomato intake (mainly cooked) and lycopenes
(lycopenes/ on PCa incidence has been identified in meta-analyses [69, 70]. Randomised controlled
carotenes) trials comparing lycopene with placebo did not identify a significant decrease in the
incidence of PCa [71].
Plant-based diets A SR on the association between plant-based diets and PCa suggest a small beneficial
impact on PCa risk [72]. Another SR/meta-analysis, including a total of 16 studies and
> 1.2 million men, suggested a linear association between higher intake of cruciferous
vegetables and a lower risk of PCa [73].
Meat Meta-analyses show a potential association between red meat, total meat, and
processed meat consumption and PCa [74, 75].
Fish A SR/meta-analysis comparing men with high vs. low intake of fish over time could not
find an association between fish intake and risk of PCa. However, there was a strong
association with high intake of fish and PCSM (RR: 0.55), as well as PCa progression
(RR: 0.84) [76].
Soy (phytoestrogens Phytoestrogen intake was significantly associated with a reduced risk of PCa in a meta-
[isoflavones/ analysis [66]. Total soy food intake has been associated with a reduced risk of PCa [77].
coumestans])
Vitamin D A U-shaped association has been observed, with both low- and high vitamin-D
concentrations being associated with an increased risk of PCa, and more strongly for
high-grade disease [69, 70].
Vitamin E/Selenium An inverse association of blood, but mainly nail selenium levels (reflecting long-term
exposure) with aggressive PCa have been found [78, 79]. Selenium and Vitamin E
supplementation were, however, found not to affect PCa incidence [80].

3.2.2.3 Hormonally active medication

3.2.2.3.1 5-alpha-reductase inhibitors (5-ARIs)
Although it seems that 5-ARIs have the potential of preventing or delaying the development of PCa (decreasing
the risk by 25% but only for ISUP GG 1 cancer), this must be weighed against treatment-related side effects
as well as the potential small increased risk of high-grade PCas (although this does not seem to impact PCa

16 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

mortality) [81-83]. None of the available 5-ARIs have been approved by the European Medicines Agency (EMA)
for chemoprevention.

3.2.2.3.2 Testosterone
Hypogonadal men receiving testosterone supplements do not have an increased risk of developing PCa
[84]. A pooled analysis showed that men with very low concentrations of free testosterone (lowest 10%)
have a below average risk (OR: 0.77) of PCa [85]. Furthermore, although the evidence is limited, men who are
managed expectantly for PCa, or who received radical curative therapy, do not have worse outcomes when
receiving testosterone supplementation, despite a theoretical higher risk of progression after correction of the
hypogonadal situation [86].

3.2.2.4 Other potential risk factors

Taller height, potentially due to higher levels if insulin-like growth factor during puberty, and vertex pattern
baldness, has been reported to be associated with an increased risk of PCa [7, 87].
A significantly higher rate of ISUP GG ≥ 2 PCa (hazard ratio [HR]: 4.04) was found in men with
inflammatory bowel disease (IBD) when compared with the general population [88]. However, in a SR the results
on IBD overall were mixed, except for the sub-group of ulcerative colitis, where a clear association could be seen
[7].
Occupational exposure may also play a role. Increased occupational physical activity appears
to reduce PCa risk while occupational exposure to chemicals and pesticides increases the risk [7]. Plasma
concentration of the estrogenic insecticide chlordecone is associated with an increase in the risk of PCa (OR:
1.77 for highest tertile of values above the limit of detection) [89]. Meta-analyses indicate that night-shift work
is associated with an increased risk of PCa in a dose-dependent manner [7, 90]. There has been reports of an
increased risk among firefighters and policemen, but the studies showed great heterogeneity and the results
may be hampered by a high rate of PSA testing among the included men. A meta-analysis on Cadmium (Cd)
found a positive association (magnitude of risk unknown due to heterogeneity) between high Cd exposure and
risk of PCa for occupational exposure, but not for non-occupational exposure, potentially due to higher Cd levels
during occupational exposure [91].
Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24, 95% CI:
1.18–1.31) and with aggressive tumour features and worse prognosis, even after quitting smoking [92, 93].
Men positive for human papillomavirus-16 may be at increased risk [94], and gonorrhoea has been
significantly associated with an increased incidence of PCa (OR: 1.31; 95% CI: 1.14–1.52) [95].
The use of aspirin or nonsteroidal anti-inflammatory drugs seems to have a protective effect on the
risk of PCa [7]. Ultraviolet radiation exposure also decreased the risk of PCa (HR: 0.91, 95% CI: 0.88–0.95) [96],
and a review found a small but protective association of circumcision status with PCa [97]. Higher ejaculation
frequency (≥ 21 times a month vs. 4 to 7 times) has been associated with a 20% lower risk of PCa [98]. A
number of other factors previously linked to an increased risk of PCa have been disproved including vasectomy
[99], and self-reported acne [100].

3.2.3 Summary of evidence for epidemiology and aetiology

Summary of evidence LE
Prostate cancer is a major health concern in men, with incidence mainly dependent on age and extent 3
of PSA testing.
Genetic factors are associated with risk of (aggressive) PCa. 3
A variety of dietary/exogenous/environmental factors have been associated with PCa incidence and 3
prognosis.
In hypogonadal men, testosterone supplements do not increase the risk of PCa. 2a
No conclusive data exist which could support specific preventive or dietary measures aimed at 1a
reducing the risk of developing PCa.

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4. CLASSIFICATION AND STAGING SYSTEMS
4.1 Classification
The objective of a tumour classification system is to combine patients with a similar clinical outcome. This
allows for discussion about prognosis with patients, the design of clinical trials on relatively homogeneous
populations, the comparison of clinical and pathological data obtained from different hospitals across the world,
and the development of recommendations for the treatment of these patient populations. Throughout these
Guidelines the Union for International Cancer Control (UICC) 8th edition (2017), the Tumour, Node, Metastasis
(TNM) classification for staging of PCa (Table 4.1) [101] and the EAU risk group classification are used [102].
The latter classification is based on the grouping of patients with a similar risk of biochemical recurrence (BCR)
after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Changes in the diagnostic pathway, such
as imaging (e.g., MRI, Prostate-Specific Membrane Antigen [PSMA] Positron Emission Tomography Computed
Tomography [PET/CT] scan) and biopsy (e.g., increasing number of systematic biopsy cores, targeted biopsy)
may cause stage and grade shift altering the risk profile of any specific classification systems [103].

Although the 2017 American Joint Committee on Cancer (AJCC) staging 8th edition specifically states that
clinical staging should be based on digital rectal examination (DRE) only, such an explicit comment is not
made by the UICC. Since clinical stage as assessed by DRE only, is included in the EAU (D’Amico) risk group
classification, cT-stage should be based on DRE findings and not on imaging. Additional staging information
based on imaging should be reported separately. A non-palpable PCa with bilateral positive biopsies and extra-
prostatic extension (EPE) on MRI would therefore be categorised as cT1c with a separate report of MRI findings.

Table 4.1: Clinical Tumour Node Metastasis (TNM) classification of PCa [101]

T - Primary Tumour (stage based on digital rectal examination only)

TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Clinically inapparent tumour that is not palpable
T1a Tumour incidental histological finding in 5% or less of tissue resected
T1b Tumour incidental histological finding in more than 5% of tissue resected
T1c Tumour identified by needle biopsy (e.g. because of elevated prostate-specific antigen [PSA])
T2 Tumour that is palpable and confined within the prostate
T2a Tumour involves one half of one lobe or less
T2b Tumour involves more than half of one lobe, but not both lobes
T2c Tumour involves both lobes
T3 Tumour extends palpably through the prostatic capsule
T3a Extracapsular extension (unilateral or bilateral)
T3b Tumour invades seminal vesicle(s)
T4 Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum,
levator muscles, and/or pelvic wall
N - Regional (pelvic) Lymph Nodes1
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M - Distant Metastasis2
M0 No distant metastasis
M1 Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)
1 Nodal metastasis no larger than 0.2 cm can be designated pNmi.
2  hen more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most
W
advanced category.

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Pathological staging (pTNM) is based on histopathological tissue assessment and largely parallels the clinical
TNM, except for clinical T1 and T2 substages. Pathological stages pT1a/b/c do not exist and histopathologically
confirmed organ-confined PCas after RP are pathological stage pT2. The current UICC no longer recognises pT2
substages [101].

Of note, the EANM proposed a molecular imaging TNM (‘miTNM’) classification, taking into account PSMA PET/
CT findings [104]. The prognosis of the miT, miN and miM substages is likely to be better than their T, N and M
counterparts due to the ‘Will Rogers phenomenon’; the extent of this prognosis shift remains to be assessed as
well as its practical interest and impact [105]. This reclassification is not endorsed by the UICC or the AJCC.

4.2 Gleason score and International Society of Urological Pathology 2019 grade
In the original Gleason grading system, 5 Gleason grades (ranging from 1–5) based on histological tumour
architecture were distinguished, but in the 2005 and subsequent 2014 ISUP consensus meetings Gleason
grades 1 and 2 were eliminated [106, 107]. The 2005 ISUP modified Gleason score (GS) of biopsy-detected
PCa comprises the Gleason grade of the most extensive (primary) pattern, plus the second most common
(secondary) pattern, if two are present. If only one pattern is present, it needs to be doubled to yield the GS. For
three grades, the biopsy GS comprises the most common grade plus the highest grade, irrespective of its extent.
In case intraductal carcinoma (IDC) is present intermixed with invasive PCa, it should be incorporated in the GS
based on its underlying architectural pattern [108]. In addition to reporting of the carcinoma features for each
biopsy site, it is optional to provide an overall (or global) GS based on all carcinoma-positive biopsies. The global
GS takes into account the cumulative extent of each grade from all prostate biopsies. The 2014 and 2019 ISUP
endorsed a grading system limiting the number of PCa grades, ranging them from 1 to 5 (Table 4.2) [107, 109].

Table 4.2: International Society of Urological Pathology 2014 grade group system

Gleason score ISUP grade group

2-6 1
7 (3+4) 2
7 (4+3) 3
8 (4+4 or 3+5 or 5+3) 4
9-10 (4+5 or 5+4 or 5+5) 5

4.3 Clinically significant prostate cancer

The descriptor ‘clinically significant’ is widely used to differentiate PCa that may cause morbidity or death in a
specific patient from types of PCa that rarely do. This distinction is particularly important as insignificant PCa
is common [9]. Unless this distinction is made, such cancers are at high risk of being over-treated, with the
treatment itself risking harmful side effects to patients. The over-treatment of insignificant PCas has also been
criticised as a major drawback of population-based screening and individual early detection [110]. Although
pathological factors are often used to delineate insignificant PCa, the definition of significant vs. insignificant
is a balance between tumour and patient factors. High-risk PCa is significant in almost all men, except when life
expectancy is limited. Low-risk PCa is insignificant in almost all men.

From a pathological point of view, in large studies of RP specimens with only ISUP GG 1 disease, EPE (0.3%)
[111] and biochemical recurrence (3.5%) were rare, and seminal vesicle (SV) invasion or lymph node (LN)
metastasis did not occur at all [112, 113]. International Society of Urological Pathology GG 1 disease at RP
itself can therefore be considered clinically insignificant. Whilst ISUP GG 1 bears the hallmarks of cancer
histologically, ISUP GG 1 at RP itself does not behave in a clinically malignant fashion [114]. It is important
to note that the studies showing absence of metastasis in ISUP GG 1 were all done on RP specimens. Men
with biopsy ISUP GG 1 who are operated for their disease have a low risk of post-operative BCR, metastasis
and disease-specific death, particularly in case of high tumour biopsy volume and PSA levels, due to under-
sampling of a higher-grade component [115]. In a contemporary retrospective study of men with cT1-T2 cN0
ISUP GG 1 PCa at mpMRI-targeted biopsy, 72% had ISUP GG ≥ 2, 9% ISUP GG ≥ 3, 25% had pT3a and 4% pT3b
at subsequent RP [116]. In a Danish population-based registry study including men with localised biopsy ISUP
GG 1 PCa diagnosed after 2006, 15-year prostate cancer specific mortality (PCSM) was 1-4% for those initially
treated by RP or RT, 5.5% for those on AS, and 14% for those commenced on WW [117]. Finally, modifications in
PCa grading has led to a grade shift during the past ten to fifteen years; for instance the introduction of the ISUP
2005 led to 20% of pre-ISUP 2005 GS 6 tumours being upgraded to GS 7 or higher, which has to be taken into
account when interpreting older studies [118].

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The current standard practice of MRI-targeted and systematic template biopsies has improved diagnostic
accuracy [119], however sampling error may still occur such that higher grade cancer could be missed. This
should especially be considered in case of high PSA density, high pathological biopsy tumour volume and a
visible lesion at MRI, but only ISUP GG 1 at biopsy [120, 121]. Another complexity in defining insignificant cancer
is that ISUP GG 1 may progress to higher grades over time, becoming clinically significant at a later biopsy [122],
at a rate of approximately 1% per year.

Therefore, although ISUP GG 1 itself can be described as clinically insignificant, it is important to take into
account other factors, including age, imaging prior to biopsy and adequate sampling core number [115]. When
combined with low-risk clinical factors (Table 4.3), ISUP GG 1 represents low-risk PCa and recommended
management options are active surveillance (AS) or watchful waiting (WW) (see sections 6.2.1.1 & 6.2.1.2).

Epidemiological and autopsy data suggest that a proportion of ISUP GG 2 PCa would remain undetectable
during a man’s life [123] and therefore may be over-treated. In current guidelines deferred treatment may be
offered to select patients with intermediate-risk PCa [124], but clear evidence is lacking for appropriate selection
criteria [125].

Recent papers have defined clinically significant cancer differently, commonly using ISUP GG 2 and above and
even ISUP GG 3 and above, demonstrating the lack of consensus and evolution of its definition [126, 127]. Some
papers provide more than one definition within a single study [128, 129]. Since there is insufficient data to relate
modern histological grading to hard clinical endpoints, it is imperative that authors define and state in their own
studies what they believe csPCa is, including exactly how the disease was diagnosed.

Table 4.3: EAU risk groups for biochemical recurrence of localised and locally-advanced prostate cancer
(based on systematic biopsy)

Definition
Low-risk Intermediate-risk High-risk
Favourable Unfavourable
ISUP grade 1 and ISUP grade 2 and PSA < ISUP grade 2 and ISUP grade 4/5 cT3-4* and/or
PSA < 10 ng/mL 10 ng/ml and cT1-2b* PSA Or cN+**
and cT1-2a* Or 10 – 20 ng/ml PSA > 20 ng/ml any ISUP grade*
ISUP grade 1 and PSA 10 and cT1-2b* Or any PSA
– 20 ng/ml and cT1-2b* Or cT2c*
Or ISUP grade 3
ISUP grade 1 and PSA < and cT1-2b*
10 ng/ml and cT2b*
Localised Locally advanced

GS = Gleason score; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen.
* Based on digital rectal examination.
** Based on CT/bone scan.

4.4 Prognostic relevance of stratification

Tumour, Node, Metastasis (TNM) staging is a schematic representation of anatomic tumour extent and
pathological grade is reflective of intrinsic features of tumour aggressiveness. EAU risk group classification,
which is essentially based on D’Amico’s classification system for PCa, combines clinical information on
tumour extent, PSA and pathology from systematic biopsy (Table 4.3). A more precise stratification of the
clinically heterogeneous subset of intermediate-risk group patients could provide a better framework for their
management [130, 131]. Specifically, the NCCN Guidelines subdivide intermediate-risk disease into favourable
and unfavourable intermediate-risk, with unfavourable features including ISUP GG 3, and/or ≥ 50% positive
systematic biopsy cores and/or at least two intermediate-risk factors [124]. In 2016, Cambridge Prognostic
Groups representing a 5-tier model based on ISUP GG, PSA and cT-stage were shown to have significantly better
discriminative performance than current 3-tier EAU risk groups for prostate cancer specific mortality [132]. This
model separates both EAU intermediate- and high-risk groups in clinically relevant subgroups and has been
validated in several cohorts [132-134].

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 Increasing granularity, such as in NCCN and CPG, improves model performance in prediction PCSM
compared to the EAU risk classification [135, 136]. Although the optimal risk stratification system remains to
be defined, separation of the EAU intermediate-risk group into favourable and unfavourable intermediate-risk
based on PSA and ISUP GG is recommended. It should be noted that studies comparing model performance
are retrospective and prognostic, while initial risk stratification, inclusion criteria and therapeutic decisions were
mainly based on EAU risk groups.

4.5 Recommendations for classification and staging systems

Recommendations Strength rating

Use the Tumour, Node, Metastasis (TNM) classification for staging of PCa. Strong
Clinical stage should be based on digital rectal examination only; additional staging Strong
information based on imaging should be reported separately.
Use the International Society of Urological Pathology (ISUP) 2019 system for grading of PCa. Strong

5. DIAGNOSTIC EVALUATION
5.1 Screening and individual early detection
The diagnostic pathway for PCa aims for timely detection of significant PCa, while leaving insignificant PCa
undetected, balancing diagnostic accuracy with the burden on an individual and healthcare provider. Patient-
specific factors such as lower urinary tract symptoms (LUTS), family history, age, and comorbidity should
always be considered.
Men may enter the diagnostic pathway through different indications, including clinical symptoms,
opportunistic early detection (individual), or screening (population-based). The prevalence of PCa and
significant PCa is different dependent on the indication, resulting in different yields of the subsequent diagnostic
pathway.

5.1.1 Prostate-specific antigen (PSA)

Regardless of which pathway a patient goes through to his PCa diagnosis, a PSA test will be part of it. For more
info on PSA, its production, function and sources of error in PSA assessment see section 5.2.2.

5.1.2 Clinical Symptoms

Symptoms usually occur late in the natural history of PCa and localised PCa is therefore usually asymptomatic.
Local progression may cause symptoms such as LUTS, erectile dysfunction (ED), retention, pain, haematospermia,
or haematuria. Bone metastases may cause pain or spinal cord compression. Digital rectal examination (DRE)
and PSA are usually part of the initial diagnostic work-up in these cases, after which a further diagnostic algorithm
may be initiated. Definitive diagnosis normally depends on histopathological verification in prostate biopsy cores.
However, men with high suspicion of malignancy (e.g., malignant feeling prostate, PSA >100 ng/mL and a positive
bone scan might avoid a biopsy especially if pre-existing co-morbidities would exclude second-line treatments.

5.1.3 Individual early detection

Early detection may be initiated on an individual level, with or without concurring LUTS. As increasing age is a
major risk factor for PCa there is very little point in starting diagnostic evaluation too early. In men with no other
risk factors, the risk of having a clinically significant PCa (csPCa) under the age of 50 years, is extremely low;
therefore, early testing with PSA can be recommended from 50 years. For men with a family history of PCa and for
men of African descent the corresponding age for testing is 45 years (see section 3.2.1.1), and for men carrying
BRCA2 mutations 40 years [137, 138]. The risk of detecting clinically insignificant cancers, leading to possible
overtreatment, should be discussed along with the possibility of improved disease-specific mortality. It is difficult
to accurately estimate the individual benefit or harm due to early detection for the individual man, but the effect
may be larger as diluting effects from intention-to-treat analyses in screening trials are not applicable (i.e., non-
participation: no participation after screening invitation; contamination: screening occurring in control arm) [139].
Nevertheless, a comparison of systematic and opportunistic screening suggested over-diagnosis and mortality
reduction in the systematic screening group compared to a higher over-diagnosis with only a marginal survival
benefit, at best, in the opportunistic screening regimen [140].

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Even though the risk of having csPCa is low, a baseline PSA may be used to predict PCa mortality after 12-20 years
and can therefore be used to guide the frequency of follow-up. The risk of dying from PCa by age 85 is ≤ 0.2% for
60-year-old men with PSA concentration below the median of ≤ 1.0 ng/mL [141]. Follow-up intervals of 8-10 years
may be offered to a majority of men up to the age of 60, and 50% of the men may be reassured and exempted from
further screening after the age of 60 years. Follow-up intervals of two years may be offered to those initially at risk
(PSA > 1 ng/mL at 40 years; PSA > 1(-2) ng/mL at 60 years) [142-144].

The age at which attempts of an early diagnosis should be stopped remains controversial, but an individual’s life
expectancy must be taken into account. Asymptomatic men who have less than a fifteen-year life expectancy are
unlikely to benefit from an early diagnosis of prostate cancer, based on data from the Prostate Cancer Intervention
Versus Observation Trial (PIVOT) and the European Randomized Screening for Prostate Cancer (ERSPC) trials
[145]. However, a large proportion of them have prostate cancer that will not cause serious symptoms during
their lifetime, meaning the risk of overdiagnosis is high. An even larger proportion have elevated PSA levels due
to benign prostatic hyperplasia (BPH), leading to investigations and follow-ups. Therefore, men with a life span of
less than 10-15 years should not be PSA tested in the absence of symptoms or clinical signs of prostate cancer.
Nevertheless, there is no simple tool to evaluate individual life expectancy and co-morbidity is at least as important
as age. A detailed review can be found in section 6.1 ‘Estimating life expectancy and health status’ and in the
SIOG Guidelines [146]. Informed men with one of the risk factors above (including age), a life expectancy of > 15
years and requesting investigation should be given a PSA test and undergo a DRE, after which a further diagnostic
algorithm may be initiated [147].

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 * PSA >50, cT3-4
** If MRI not available/possible
Low risk
Life expectancy Individualised
Asymptomatic (>10-15 yrs) follow-up
Initial risk

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(individual early +
detection) assessment -ve
Shared decision
(PSA, DRE + Low risk
making
life Intermediate Pre-biopsy MRI
expectancy, Risk stratification High risk +ve Targeted +
risk (if not performed
family history, for biopsy Perilesional
at risk
Symptomatic ethnicity) (MRI, risk-calculator biopsy
stratification)
and/or serum/urine
Figure 5.1 Presents a flow diagram for deciding on prostate biopsy

biomarker test)
Direct biopsy **
Systematic
indications* biopsy
Diagnosis Treatment Follow-up

23
5.1.4 Population-based screening
Population or mass screening is defined as the ‘systematic examination of asymptomatic men to identify
individuals at risk for a specific disease’ and is usually initiated by health authorities. The co-primary objectives are:
• reduction in mortality due to PCa;
• a maintained quality of life (QoL) as expressed by QoL-adjusted gain in life years (QALYs).

Screening for PCa remains one of the most controversial topics in the urological literature [148]. A Cochrane review
of randomised PCa screening trials with PCa mortality as endpoint was published in 2013 [149] and updated in
2018 [150, 151]. The main findings of the updated publication from the results of five RCTs, randomising more than
721,718 men, are:
• Screening is associated with an increased diagnosis of PCa (Incidence ratio [IR]: 1.23, 95% CI: 1.03 - 1.48).
• Screening is associated with detection of more localised disease (RR: 1.39, [1.09–1.79]) and less advanced
PCa (T3–4, N1, M1; RR: 0.85 [0.72–0.99]).
• No PCa-specific survival benefit was observed (IR: 0.96 [0.85–1.08]). This was the main endpoint in all trials.
• No overall survival (OS) benefit was observed (IR: 0.99, 95% CI: 0.98–1.01). None of the trials were designed/
powered for this endpoint.

The included studies are different regarding multiple aspects including trial size, time periods, age groups,
participation/compliance rates, previous screening rates (opportunistic testing in control arm, ‘contamination’),
one-time screening (i.e., prevalence screening, where patients are invited for PSA test at one time only) vs.
repeat screening (where patients are repeatedly invited for PSA-testing over time), and the applied diagnostic
pathway. These differences account for discrepancies in results between single studies and the Cochrane review
aggregated findings.

Two studies showed a favourable impact of screening: ERSPC and CAP. The latter, after 15 years follow-up,
showed a small, but significant, reduction in PCSM, despite being only a one-time PSA screening [152].

The ERSPC study started in the early 90s, which included > 182,000 European men, found a significant reduction
in PCa mortality due to screening. ERSPC applied a mainly PSA-based screening protocol (cut-off 3.0–4.0 ng/
mL followed by systematic sextant prostate biopsy, every two to four years in men aged 50–74) [145]. The
contamination rate was relatively low when compared to other large studies such as the Prostate Lung Colorectal
and Ovarian (PLCO) screening trial [145]. A limitation is the heterogeneity in patient groups and the applied
screening protocols. Since 2013, data have been updated with sixteen years of follow-up [145]. With extended
follow-up, the mortality reduction (21% and 29% after non-compliance adjustment) remains unchanged. However,
the number needed to screen (NNS) and to treat is decreasing and is now below the NNS observed in breast
cancer trials [145, 153] (Table 5.1).

Table 5.1: Follow-up data from the ERSPC study [145]

Years of follow-up Number needed to screen Number needed to treat

9 1,410 48
11 979 35
13 781 27
16 570 18

In the Rotterdam section of the ERSPC, with 21 years follow-up, the risk ratio of death due to PCa was 0.73 in
the screening group, with number needed to invite of 246 and number needed to diagnose (NND) of fourteen to
prevent one death due to PCa [154]. To prevent one metastasized case NNS was 121 and NND seven.

In the Goteborg screening trial, with eighteen years of follow-up, the ratio of death from PCa for the screening
group compared with the control group was 0.65 (95% CI: 0.49–0.87) and for men commencing screening at
age 55–59 it was 0.47 (95% CI: 0.29–0.78) [155]. The number needed to invite was 231; the NND ten. After 22
years of follow-up the corresponding NNS was 221 and NND was nine, and the highest risk of PCSM was for
men who started screening at the age of 60 years, and for non-attenders [156].

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The benefit of screening in reducing PCa-specific mortality (PCSM) and the even more favourable impact on
metastases rates, is counter-balanced by the side effects of screening such as increased diagnosis rates, which
has led to over-treatment of low-risk PCa, and subsequent treatment-related side-effects [157]. Regarding QoL,
the beneficial effects of screening and the side effects seem to balance out, resulting in limited overall impact
on the invited population [157, 158].

Recognition of the harms of over-diagnosis and over-treatment had led to a redesign in the pathway for early
detection of PCa including identification of specific risk groups, individualised re-testing interval, improved
indication for biopsy using risk calculators and/or MRI, targeted biopsies, and the application of AS for low-risk
disease.

After a negative screening, PSA measurement and DRE need to be repeated [159], but the optimal intervals for
PSA testing and DRE follow-up are unknown as they varied between several prospective screening trials. A risk-
adapted strategy might be a consideration, based on the initial PSA level. Men with a baseline PSA < 1 ng/mL at
40 years or < 2 ng/mL at 60 years are at decreased risk of PCa metastasis or death from PCa several decades
later [50, 143]. The retesting interval can therefore be every two years for those initially at increased risk or
postponed up to eight years for those at low-risk [143, 160].

An analysis of ERSPC data supports a recommendation for an eight-year screening interval in men with an initial
PSA concentration < 1 ng/mL; fewer than 1% of men with an initial PSA concentration < 1 ng/mL were found to
have a concentration above the biopsy threshold of 3 ng/mL at four-year follow-up; the cancer detection rate by
eight years was close to 1% [161]. The long-term survival and QoL benefits of extended PSA re-testing (every
eight years) remain to be proven at a population level.

5.1.5 Screening in patients with BRCA mutations

The IMPACT study evaluates targeted PCa screening using PSA in men aged 40–69 years with germline
BRCA1/2 mutations (annually, biopsy recommended if PSA > 3.0 ng/mL). After three years of screening, BRCA2
mutation carriers were associated with a higher incidence of PCa, a younger age of diagnosis, and more
clinically significant tumours compared with non-carriers [138, 162]. The influence of BRCA1 mutations on PCa
remained unclear. No differences in age or tumour characteristics were detected between BRCA1 carriers and
BRCA1 non-carriers. The mismatch repair cohort of IMPACT in men with MSH2 and MSH6 pathogenic variants
found a higher incidence of significant PCa vs. non-carriers [163].

5.1.6 Recommendations for individual early detection

Recommendations Strength rating

Do not subject men to prostate-specific antigen (PSA) testing without counselling them on Strong
the potential risks and benefits.
Offer an individualised risk-adapted strategy for early detection to a well-informed man with Weak
a life-expectancy of at least fifteen years.
Offer early PSA testing to well-informed men at elevated risk of having PCa: Strong
• men from 50 years of age;
• men from 45 years of age and a family history of PCa;
• men of African descent from 45 years of age;
• men carrying breast cancer gene 2 (BRCA2) mutations from 40 years of age.
Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of two years Weak
for those initially at risk:
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age;
Postpone follow-up up to eight years in those not at risk.
Stop early diagnosis of PCa based on life expectancy and performance status; men who Strong
have a life-expectancy of less than fifteen years are unlikely to benefit.

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5.1.7 Genetic testing for inherited prostate cancer
Increasing evidence supports the implementation of genetic counselling and germline testing in early detection
and PCa management [164]. Several commercial screening panels are now available to assess the main
PCa risk genes [165]. However, it remains unclear when germline testing should be considered and how this
may impact localised and metastatic disease management. Germline BRCA1 and BRCA2 mutations occur in
approximately 0.2% to 0.3% of the general population [28, 166]. It is important to understand the difference
between somatic testing, which is performed on the tumour, and germline testing, which is performed on
blood or saliva and identifies inherited mutations. Genetic counselling is required prior to and after undergoing
germline testing.

Germline mutations can drive the development of aggressive PCa. Therefore, the consensus is the following
men, with a personal or family history of PCa or other cancer types arising from DNA repair gene mutations
should be considered for germline testing:

• Men with metastatic PCa who are candidates for targeted treatment;
• Men with BRCA mutations on somatic testing;
• Men with multiple family members diagnosed with csPCa at age < 60 years or a family member who died
from PCa;
• Men with a family history of high-risk germline mutations or a family history of multiple cancers on the
same side of the family.

Further research in this field (including not so well-known germline mutations) is needed to develop screening,
early detection and treatment paradigms for mutation carriers and family members.

5.1.8 Recommendations for germline testing*

Recommendations Strength rating

Consider germline testing in men with multiple family members diagnosed with PCa at age Weak
< 60 years or a family member who died from PCa.
Offer germline testing in men with a family history of high-risk germline mutations or a family Strong
history of multiple cancers on the same side of the family.
Offer germline testing to patients with BRCA mutations on somatic testing. Strong
*Genetic counselling is required prior to germline testing.

5.2 Diagnostic tools

Different diagnostic tools are available for the diagnosis of prostate cancer (PCa). These can be used
separately, or in multiple-tier combinations and/or sequences. Usually, diagnosis is confirmed
histopathologically using prostate biopsy.

5.2.1 Digital rectal examination

In ~18% of cases, PCa is detected by suspect DRE alone, irrespective of PSA level [167]. A suspect DRE in
patients with a PSA level ≤ 4 ng/mL has a positive predictive value (PPV) of 5–30% [167]. In the ERSPC trial,
an abnormal DRE in conjunction with an elevated PSA more than doubled the risk of a positive biopsy (48.6%
vs. 22.4%) [168]. Abnormal DRE is an indication for MRI, or direct biopsy in case of suspicion of extracapsular
disease (cT3-4) [168, 169]. An abnormal DRE is associated with an increased risk of a higher ISUP GG (GG),
predicts clinically significant PCa in men under active surveillance (AS) [170] and remains a strong predictor
of advanced PCa (OR: 11.12 for cT3 and OR: 5.28 for cT4) [171]. Clinical T staging, as well as current EAU risk
group stratification depends on DRE.

5.2.2 Prostate-specific antigen

Prostate-specific antigen is a glycoprotein enzyme secreted by prostate epithelial cells with a small portion
present in the blood stream. It is the primary test in the suspicion of PCa. Its use as a serum marker has
revolutionised PCa diagnosis [172]. Prostate-specific antigen is organ- but not cancer specific; therefore, it
may also be elevated in BPH, prostatitis and other non-malignant conditions. There are no agreed standards
for defining abnormal PSA thresholds [173]. It is a continuous parameter, with higher levels indicating greater
likelihood of PCa. Some men may harbour PCa despite having low serum PSA [174]. Table 5.2 demonstrates the
occurrence of any PCa and ISUP GG ≥ 2 PCa in systematic biopsies at low PSA levels.

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Table 5.2: Risk of PCa identified by systemic PCa biopsy in relation to low prostate-specific antigen values
[174]

PSA level (ng/mL) Risk of PCa (%) Risk of ISUP grade > 2 PCa (%)
0.0–0.5 6.6 0.8
0.6–1.0 10.1 1.0
1.1–2.0 17.0 2.0
2.1–3.0 23.9 4.6
3.1–4.0 26.9 6.7

In a screening situation, the most frequently applied threshold for PSA is ≥ 3.0 ng/ml, resulting in 16.5% of
invited men returning a positive test [175]. The risk of finding PCa at a specific PSA threshold in a clinical cohort
may be different than in a screening situation, due to differences in cancer prevalence, protocol for referral, and
diagnostic algorithm. Prostate-specific antigen retains its diagnostic value for cancer detection in symptomatic/
referred patients. A review and meta-analysis on the diagnostic accuracy of PSA (≥ 4.0 ng/ml) for the detection
of PCa in clinically referred men found an estimated combined sensitivity of 0.93 and specificity of 0.20 [176].
Prostate-specific antigen production is androgen dependent and 5a-reductase inhibitors (e.g.,
finasteride, dutasteride), used for benign prostatic enlargement of the prostate, reduce PSA levels by 50% [177].
In such cases, PSA level should be corrected to decide about further investigation, although PSA-density is less
impacted as prostate volume decreases concomitantly.
In case of a moderately elevated PSA, a repeat test after a few weeks should be considered
to confirm the indication for further diagnostic analysis, as one-third of men with a PSA < 10 ng/ml had a
difference of greater than +/- 1.0 ng/ml at the second measurement [178]. Within 1-2 months PSA drops to
below 3 ng/mL in about one-fifth of men,
A repeat PSA test before prostate biopsies in men with an initial PSA 3–10 ng/mL reduced the
indication for biopsies in 16.8% of men while missing 5.4% ISUP GG > 1 in the Stockholm3 trial [179]. Similarly,
in the Prostate Testing for Cancer and Treatment (ProtecT) trial men with a more than 20% lower repeat-PSA
analysis within seven weeks had a lower risk of PCa (OR: 0.43, 95% CI: 0.35–0.52) as well as a lower risk of ISUP
GG ≥ 2 (OR: 0.29, 95% CI: 0.19–0.44) [180]. Based on the above, a PSA of 3-10 ng/mL, in men without suspicious
palpation findings, should prompt a second PSA test after 4 weeks. If the PSA has normalised, a new PSA test
can be performed after one year.
Repeat PSA should be performed in the same laboratory using the same assay under standardised
conditions (i.e., no ejaculation, manipulations, and urinary tract infections [UTIs]) [181, 182]. The type of PSA
assay used may impact PSA values and rates of PSA above certain fixed thresholds [183]. Table 5.3 presents
sources of error in PSA value assessment.

Table 5.3: Sources of error in PSA value assessment

Sources of error in PSA value assessment

• Intra-individual variation: PSA values can vary by +/- 15% [184].
• Measurement method: Variations exist between laboratories (up to approximately 5%).
• Sample handling: Proper handling is crucial, with specific stability timelines for centrifuged samples.
• (Febrile) urinary tract infection: Infections can cause very high PSA values (> 100 ng/mL), taking up to a
year to normalise [185, 186].
• Acute urinary retention: This condition moderately increases PSA values [187].
• Biopsy: PSA tests should be delayed for at least a month after biopsies [188].
• Hypogonadism: PSA production depends on testosterone levels, affecting PSA values in men with low
testosterone [189, 190].
• Prostate-specific antigen production is androgen dependent and 5a-reductase inhibitors (e.g., finasteride,
dutasteride), used for benign prostatic enlargement of the prostate, reduce PSA levels by 50% [177].
• DRE does not affect PSA value [191].

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5.2.3 Prostate-specific antigen density
Prostate-specific antigen density (PSA-D) is the level of serum PSA divided by the prostate volume. The higher
the PSA-D, the more likely clinically significant PCa is present; in particular in smaller prostates when a PSA-D
cut-off of 0.15 ng/mL/cc was applied [195]. Several studies found a PSA-D over 0.1-0.15 ng/mL/cc predictive
of PCa [192, 193]. Patients with a PSA-D below 0.09 ng/mL/cc were found unlikely (4%) to be diagnosed with
csPCa [194]. PSA-D is also one of the strongest predictors incorporated in risk calculators for biopsy decisions
[195].
PSA-D based on volume estimation assessed by DRE is imperfect due to an underestimation of
prostate volume [196]. Using imaging, a lack of standardisation of prostate volume estimation exists as TRUS
or MRI use various techniques such as ellipsoid formula or planimetry. Nonetheless, one study involving
seven radiologists who assessed prostate volume on 40 MRI scans using two different ellipsoid methods
and a manual planimetry method suggested that intra and inter-reader reproducibility of the three methods
were excellent with intraclass correlation coefficient > 0.90 [197]. In a series of 640 men, TRUS found prostate
volumes on average 8% smaller than MRI; in the 109 men who underwent RP, MRI-derived prostate volume was
better correlated to the volume of the surgical specimen than TRUS-derived volume [198].
Transabdominal ultrasound evaluation of prostate volume is discouraged due to an overestimation
of the prostate volume by 9.9 ml [199].
PSA-D remains predictive for csPCa when combined with MRI PIRADS scores [200, 201].

5.2.4 Imaging
5.2.4.1 Magnetic resonance imaging
Prostate MRI combines different imaging sequences to identify PCa accurately. MRI is initiated after suspicion
of PCa, based on PSA and/or DRE. Besides suggesting the presence of PCa, imaging also allows guidance in
targeted prostate biopsy and provides staging information.
Prostate cancer appears as areas with low signal intensity on T2-weighted imaging, restriction of
diffusion on diffusion-weighted imaging, and early and intense enhancement on dynamic contract enhanced
imaging. However, there is substantial overlap between the appearances of PCa and some prostate benign
conditions. The Prostate Imaging-Reporting and Data System (PI-RADS) standardises interpretation and
stratifies men with suspected PCa on a 1- to 5- risk scale of having csPCa [202, 203].
Correlation with RP specimens shows good sensitivity for MRI in the detection and localising
of ISUP GG ≥ 2 cancers, especially when their diameter is larger than 10 mm [182]. MRI is less sensitive
in identifying ISUP grade 1 PCa [204-207]. The good sensitivity of MRI for ISUP GG ≥ 2 cancer was further
confirmed in patients who underwent template biopsies. In a Cochrane meta-analysis which compared MRI to
template biopsies (≥ 20 cores) in biopsy-naïve and repeat-biopsy settings, MRI had a pooled sensitivity of 0.91
(95% CI: 0.83–0.95) and a pooled specificity of 0.37 (95% CI: 0.29–0.46) for ISUP grade ≥ 2 cancers. For ISUP
grade ≥ 3 cancers, MRI pooled sensitivity and specificity were 0.95 (95% CI: 0.87–0.99) and 0.35 (95% CI: 0.26-
0.46), respectively [208].

5.2.4.2 Transrectal ultrasound and ultrasound-based techniques

Standard TRUS is not reliable at detecting PCa [209] and the diagnostic yield of additional biopsies performed
on hypoechoic lesions is negligible [210]. New sonographic modalities such as micro-Doppler, sonoelastography
or contrast-enhanced US provided promising preliminary findings, either alone, or combined into the so-called
‘multi-parametric US’ [211, 212]. In the multi-parametric US vs. multi-parametric MRI to diagnose PCa (CADMUS)
trial, 306 patients underwent both multi-parametric MRI and multi-parametric US composed of B-mode, Colour
Doppler, real-time elastography, and contrast-enhanced US. Patients with at least one positive test underwent
targeted biopsy. Multi-parametric US detected 4.3% fewer csPCa while submitting 11.1% more patients to
biopsy than MRI [213].
High-resolution micro-US shows improved spatial resolution but struggles to assess the anterior part
of large prostates. Two prospective trials assessed MRI and micro-US interpreted in a blinded manner before
combined targeted and systematic biopsy. In one, MRI and micro-US detected respectively 60 (76%) and 58
(73%) of the 79 csPCas, while systematic sampling detected 45/79 cases (57%). MRI-targeted biopsy detected
seven csPCas missed by micro-US; of these three were anterior lesions. Micro-US-guided biopsy detected five
csPCas missed by MRI; of these, three were at the apex [214]. In the other study, MRI- and micro-US-targeted
biopsy depicted csPCa in 37 (39%) and 33 (35%) of the 94 men, respectively while the MRI- plus micro-US-
targeted pathway detected 38 csPCa [215]. These findings suggest that MRI and micro-US could complement
each other. Micro-US could also be an interesting alternative to MRI/fusion since biopsy operators who are
aware of MRI findings can localise most MRI lesions on micro-US and, thus, target them with direct US image
guidance [216]. Of note, evaluation of micro-US inter-operator variability is currently lacking.

28 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

5.2.4.3 Prostate-specific membrane antigen-Positron emission tomography/Computed tomography
(or Magnetic resonance imaging)
Though mainly used for staging purposes, PSMA-PET/CT (or -PET/MRI) prostate expression may be used to
indicate and target biopsies. For csPCa detection, a pooled sensitivity of 0.89 and a pooled specificity of 0.56
have been reported [217]. In a prospective trial of 291 patients, combined PSMA + MRI improved negative
predictive value (NPV) compared with MRI alone (91% vs. 72%, test ratio = 1.27 [1.11–1.39], p < 0.001).
Sensitivity also improved (97% vs. 83%, p < 0.001), but specificity was reduced (40% vs. 53%, p = 0.011) [127].

5.2.5 Blood and urine biomarkers

Urine and serum biomarkers as well as tissue-based biomarkers have been proposed for improving detection
and risk stratification of PCa patients, potentially avoiding unnecessary biopsies. However, further studies
are necessary to validate their efficacy [218]. It may be noted that most of the tests are validated against only
a few of the available clinical parameters and risk factors used in the risk assessment of a patient, such as
family history, previous biopsy results and PSA-tests, results of DRE, ratio of free PSA to total PSA (f/t PSA)
and other biomarkers, and PSA density. Furthermore, it has been shown that f/t PSA does not add any value in
discriminating for csPCa if you know the PSA density [219].

5.2.5.1 Blood based biomarkers: PHI/4K score/IsoPSA/Stockholm3/Proclarix

The use of biomarkers (included in a nomogram) may help in predicting indolent PCa [220, 221]. Several assays
measuring a panel of kallikreins in serum or plasma are now commercially available, including the U.S. Food
and Drug Administration (FDA) approved Prostate Health Index (PHI) test (combining free and total PSA and
the [-2]pro-PSA isoform [p2PSA]), and the four kallikrein (4K) score test (measuring free, intact and total PSA
and kallikrein-like peptidase 2 [hK2] in addition to other parameters age, DRE and prior biopsy status). Both tests
are intended to reduce the number of unnecessary prostate biopsies in PSA-tested men. A few prospective
multi-centre studies demonstrated that both the PHI and 4K score test out-performed f/t PSA for PCa detection,
with an improved prediction of csPCa in men with a PSA between 2–10 ng/mL [222, 223]. In a head-to-head
comparison both tests performed equally [224].

In contrast to the 4K score and PHI, which focus on the concentration of PSA isoforms, IsoPSA utilises a
technology which focuses on the structure of PSA. In a multi-centre prospective validation in 271 men the assay
area under curve (AUC) was 0.784 for high-grade vs. low-grade cancer/benign histology, which was superior to
the AUCs of total PSA and percent free PSA [208]. In men with a negative mpMRI, PSA-D, 4K score and family
history predicted the risk of csPCa on biopsy and using a nomogram reduced the number of negative biopsies
and indolent cancers by 47% and 15%, respectively, while missing 10% of csPCa [225].
The Stockholm3 test is a prediction model that is based on several clinical variables (age, first-
degree family history of PCa, and previous biopsy), blood biomarkers (total PSA, f/t PSA, human kallikrein 2,
macrophage inhibitory cytokine-1, and microseminoprotein-β [MSMB]), and a polygenic risk score for predicting
the risk of PCa with ISUP GG ≥ 2, and was shown to reduce the percent of clinically insignificant cancers when
used in combination with MRI in a PSA screening population [226]. It also has the potential to decrease the
number of mpMRI scans required in prostate cancer screening [227].
The Proclarix® test is a blood-based test that estimates the likelihood of csPCa according to
measurement results for thrombospondin-1, cathepsin D, total PSA, percentage free PSA and patient age. This
test has been correlated with the detection of csPCa, notably in case of equivocal MRI (PI-RADS 3 lesions) [228].

5.2.5.2 Urine biomarkers: PCA3/SelectMDX/MyProstateScore (MPS/MPS2)/ExoDX

Prostate cancer gene 3 (PCA3) is an overexpressed long non-coding RNA (lncRNA) biomarker that is detectable
in urine sediments obtained after three strokes of prostatic massage during DRE. However, the clinical utility of
the commercially available Progensa urine test for PCA3 for biopsy decision-making remains uncertain. Still,
combining MRI findings with the PCA3 score may improve risk stratification [229].
The SelectMDX test is similarly based on mRNA biomarker isolation from urine. The presence of
HOXC6 and DLX1 mRNA levels is assessed to provide an estimate of the risk of both presence of PCa on biopsy
as well as presence of high-risk cancer [230]. A multi-centre trial evaluated SelectMDX in men with an MRI
PI-RADS score < 4 or PI-RADS score < 3, and the percentage of missed csPCas was 6.5% and 3.2%, respectively,
whereas 45.8% and 40% of biopsies were avoided [231]. Hendriks et al., found more biopsies were avoided and
more high-grade PCas detected in an MRI-based biopsy strategy compared to a SelectMDX strategy. When
both tests were combined, more Gleason grade > 1 lesions were found, but the number of negative or low-grade
cancer biopsies more than doubled [221]. Combining SelectMDX and MRI in men with a PSA between 3–10
ng/mL had a NPV of 93% [232]. The clinically added value of SelectMDX in the era of upfront MRI and targeted
biopsies remains unclear [233].

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 TMPRSS2-ERG fusion, a fusion of the trans-membrane protease serine 2 (TMPRSS2) and the ERG
gene can be detected in 50% of PCas [234]. When detection of TMPRSS2-ERG in urine was added to PCA3
expression and serum PSA (MyProstate Score [MPS]), cancer prediction improved [235]. An update of the test,
MyProstateScore 2.0 (MPS2), where an 18-gene score was used, outscored the original MPS model significantly
[236]. Exosomes secreted by cancer cells may contain mRNA diagnostic for high-grade PCa [237, 238]. Use of
the ExoDx Prostate IntelliScore urine exosome assay resulted in avoiding 27% of unnecessary biopsies when
compared to standard of care (SOC). However, currently, both the MiPS-score and ExoDx assay are considered
investigational.
In the screening population of the ERSPC study the use of both PCA3 and 4K panel when added to
the risk calculator led to an improvement in AUC of less than 0.03 [239]. Based on the available evidence, some
biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional
value compared to the prognostic parameters currently used by clinicians [240]. However, upfront MRI is also
likely to affect the utility of the above-mentioned biomarkers.

5.2.6 Recommendations for screening and individual early detection

Recommendations Strength rating

In asymptomatic men with a prostate-specific antigen (PSA) level between 3 and 10 ng/mL and Weak
a normal digital rectal examination (DRE), repeat the PSA test prior to further investigations.
In asymptomatic men with a PSA level between 3 and 20 ng/mL and a normal DRE, use one Strong
of the following tools for biopsy indication:
• magnetic resonance imaging of the prostate;
• risk-calculator, provided it is correctly calibrated to the population prevalence; Weak
• an additional serum, urine biomarker test.

5.3 Pathology of prostate needle biopsies

5.3.1 Processing
Prostate core biopsies from different sites are processed separately, as delivered by the biopsy operator. Before
processing, the number and length of the cores are recorded. The length of biopsy tissue significantly correlates
with the PCa detection rate [241]. In case individual cores can clearly be identified in submitted jars, a maximum
of three cores should be embedded per tissue cassette, and sponges or paper should be used to keep the
cores stretched and flat to achieve optimal flattening and alignment [242, 243]. To optimise detection of small
lesions and improve accuracy of grading, paraffin blocks should be cut at three levels and intervening unstained
sections may be kept for immunohistochemistry (IHC) [244].

5.3.2 Microscopy and reporting

Diagnosis of PCa is based on histology. The diagnostic criteria include features pathognomonic of cancer,
major and minor features favouring cancer and features against cancer. Ancillary staining and additional
(deeper) sections should be considered if a suspect lesion is identified [244]. Diagnostic uncertainty is
resolved by intradepartmental or external consultation [244]. Sections 5.3.2.1 and 5.3.2.2 list the recommended
terminology and item list for reporting prostate biopsies [243]. Type and subtype of PCa should be reported
such as, for instance, acinar adenocarcinoma, ductal adenocarcinoma and small or large cell neuroendocrine
carcinoma, even if representing a small proportion of the PCa. The distinct aggressive nature of small/large
cell neuroendocrine carcinoma should be commented upon in the pathology report [243]. Apart from grading
acinar and ductal adenocarcinoma, the percentage of Gleason grade 4 components should be reported in
Gleason score 7 (3+4 and 4+3) PCa biopsies. Percentage Gleason grade 4 has additional prognostic value and
is considered in some AS protocols [245, 246]. Considerable evidence has been accumulated in recent years
supporting the idea that among the Gleason grade 4 patterns, cribriform pattern carries an increased risk of
biochemical recurrence, metastatic disease and death from disease [247-250]. Reporting of this sub-pattern
based on established criteria is recommended [108, 251]. Intraductal carcinoma, defined as an extension
of cancer cells into pre-existing prostatic ducts and acini, distending them, with preservation of basal cells
[108], should be distinguished from high-grade prostatic intraepithelial neoplasia (PIN) [252] as it conveys
unfavourable prognosis in terms of biochemical recurrence and cancer-specific survival (CSS) [253, 254]. Its
presence should be reported whether occurring in isolation or associated with adenocarcinoma [108]. Some
intra-epithelial lesions have architectural complexity and/or cytological atypia exceeding those of high-grade
PIN but fall short for a definitive diagnosis of IDC. These lesions have been referred to as Atypical Intraductal
Proliferation (AIP) and, amongst others, encompass lesions that were previously classified as cribriform high-
grade PIN. Small retrospective series suggest that AIP at biopsy is associated with unsampled IDC [255, 256].

30 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Therefore, the presence of AIP should be reported and commented on in non-malignant biopsies and biopsies
with ISUP GG 1 and 2 cancers in the absence of overt invasive cribriform and IDC.

5.3.2.1 Recommended terminology for reporting prostate biopsies [257]

Heading
Benign/negative for malignancy; if appropriate, include a description
Active inflammation
Granulomatous inflammation
High-grade prostatic intraepithelial neoplasia (PIN)
High-grade PIN with atypical glands, suspicious for adenocarcinoma
Focus of atypical glands/lesion suspicious for adenocarcinoma/atypical small acinar proliferation, suspicious
for cancer
Adenocarcinoma, provide type and subtype, and presence or absence of cribriform pattern
Atypical intraductal proliferation (AIP)
Intraductal carcinoma

Each biopsy site should be reported individually, including its location (in accordance with the sampling site)
and histopathological findings, which include the histological type and the ISUP 2019 GG [108, 258, 259]. For
MRI targeted biopsies consisting of multiple cores per target the aggregated (or composite) ISUP GG should be
reported per targeted lesion [108]. If the targeted biopsies are negative, presence of specific benign pathology
should be mentioned, such as dense inflammation, fibromuscular hyperplasia or granulomatous inflammation
[108, 260]. It is optional to report a global ISUP GG comprising all systematic (non-targeted) and targeted biopsies
in conjunction to the GG per biopsy site. A global ISUP GG comprising all systematic (non-targeted) and targeted
biopsies is also reported (see section 4.2). The global ISUP GG takes into account all biopsies positive for
carcinoma, by estimating the total extent of each Gleason grade present. For instance, if three biopsy sites are
entirely composed of Gleason grade 3 and one biopsy site of Gleason grade 4 only, the global ISUP GG would
be 2 (i.e., GS 7[3+4]) or 3 (i.e., GS 7[4+3]), dependent on whether the extent of Gleason grade 3 exceeds that of
Gleason grade 4, whereas the worst grade would be ISUP GG 4 (i.e., GS 8[4+4]). In case biopsy sites have different
GS, it is recommended to take clinical, pathological and radiological characteristics into account for patient risk
stratification and management. Neither global nor worst ISUP GG is clearly superior over the other [261]. The
majority of clinical studies have not specified whether global or worst biopsy grade was taken into account. In
addition to GS/ISUP GG, the presence/absence of intraductal/invasive cribriform pattern should be reported [108,
258, 259]. Furthermore, in biopsy GS 7 (ISUP GG 2 and 3) percentage Gleason grade 4 should be monitored at
the case and/or biopsy level [108, 259]. Lymphovascular invasion (LVI), EPE and ejaculatory duct/seminal vesicle
involvement must each be reported, if identified, since they carry unfavourable prognostic information [262-264].
Studies on biopsy perineural invasion (PNI) have shown variable outcome. Two systematic reviews and meta-
analyses of biopsy PNI showed independent association with PSM and BCR in men who went RP [265, 266].

Recently, a series of studies have demonstrated that computer-assisted PCa grading artificial intelligence
algorithms can perform grading at the level of experienced genito-urinary pathologists. These algorithms have
potential in supporting grading of less experienced pathologists, by reducing inter-observer variability, and
in quantitative analyses. However, more extensive and prospective validation of these algorithms is needed
for implementation in daily clinical practise [108, 258, 259, 267]. The proportion of systematic (non-targeted)
carcinoma-positive cores as well as the extent of tumour involvement per biopsy core correlate with the
ISUP GG, tumour volume, surgical margins and pathological stage in RP specimens and predict BCR, post-
prostatectomy progression and RT failure. These parameters are included in nomograms created to predict
pathological stage and SV invasion after RP and RT failure [268, 269]. A pathology report should therefore
provide both the number of carcinoma positive cores and the extent of cancer involvement for each core. The
length in mm and percentage of carcinoma in the biopsy have equal prognostic impact [270].

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5.3.2.2 Recommended item list for reporting prostate cancer biopsies [108, 258, 259]

Type of carcinoma
Primary and secondary Gleason grade, per biopsy site and global International Society of Urological Pathology
(ISUP) GG
Percentage of global Gleason grade 4 in Gleason Score (GS) 7 biopsies
Presence/absence of intraductal/invasive cribriform carcinoma
Presence of Atypical Intraductal Proliferation (AIP) in intraductal/invasive cribriform-negative cases
Number of cancer-positive biopsy cores
Extent of cancer (in mm or percentage)
For Magnetic resonance imaging (MRI)-targeted biopsies with multiple cores aggregate (or composite) ISUP
GG per lesion For carcinoma-negative MRI-targeted biopsy, specific benign pathology, e.g., fibromuscular
hyperplasia or granulomatous inflammation
If present, lymphovascular invasion (LVI), extraprostatic extension and ejaculatory duct/seminal vesicle
involvement

5.3.3 Tissue-based prognostic biomarker testing

After a comprehensive literature review and several panel discussions an American Society of Clinical Oncology
(ASCO)-EAU-American Urological Association (AUA) multi-disciplinary expert panel made recommendations
regarding the use of tissue-based PCa biomarkers. The recommendations were limited to five commercially
available tests (Oncotype Dx, Prolaris, Decipher, Decipher PORTOS and ProMark) with extensive validation in
large retrospective studies and evidence that their test results might actually impact clinical decision-taking. The
selected commercially available tests significantly improved the prognostic accuracy of clinical multi-variable
models for identifying men who would benefit from AS and those with csPCa requiring curative treatment, as
well as for guidance of patient management after RP. Few studies showed that tissue biomarker tests and
MRI findings independently improved the detection of csPCa in an AS setting, but it remains unclear which
men would benefit from both tests. Decipher® test outcome has been associated with presence of intraductal/
invasive cribriform carcinoma but retains independent value in multi-variable analysis. Since the long-term
impact of the use of these commercially available tests on oncological outcome remains unproven and
prospective trials are largely lacking, the Panel concluded that these tests should not be offered routinely but
only in subsets of patients where the test result provides clinically actionable information, such as, for instance,
in men with favourable intermediate-risk PCa who might opt for AS or men with unfavourable intermediate-risk
PCa scheduled for RT to decide on treatment intensification with hormone therapy (HT) [271]. Since then, data
from a RCT including 215 patients with intermediate risk PCa randomised to two different radiotherapy doses,
and with a median follow-up of 12.8 years, showed that a Decipher® test indicating high risk showed to be
prognostic for disease progression (HR: 1.12), biochemical failure (HR: 1.22), distant metastasis (HR: 1.28) and
PCSM (HR: 1.45) [272]. However, as the endpoint was secondary, and the study was designed for a completely
different purpose, the recommendations remain unchanged until the findings have been confirmed.

5.3.4 Tissue samples for homologous recombination repair (HRR)-testing

Homologous recombination repair-testing in the PROfound trial was conducted on archival or recent biopsy
tissue from primary or metastatic disease with successful sequencing in 69% [273]. Alterations in HRR genes
are relatively unchanged comparing matched treatment-naïve diagnostic and mCRPC biopsies [274, 275].
Whereas there is no preference for use of archival or new metastatic biopsies for HRR-testing, bone biopsies
might be associated with lower success rates related to decalcification of tissue [276]. Testing of circulating
tumour DNA might be a good alternative if tumour tissue is not available [275, 277]. With tissue as reference,
ctDNA showed 81% positive and 92% negative percentage agreement [278].

5.3.5 Histopathology of radical prostatectomy specimens

5.3.5.1 Processing of radical prostatectomy specimens
Histopathological examination of RP specimens describes the pathological stage, histopathological type, grade
and surgical margins of PCa. It is recommended that RP specimens are totally embedded to enable assessment
of cancer location, multi-focality and heterogeneity. For cost-effectiveness, partial embedding may also be
considered, particularly for prostates > 60 g. The most widely accepted method includes complete embedding
of the posterior prostate and a single mid-anterior left and right section. Compared with total embedding, partial
embedding with this method missed 5% of positive margins and 7% of EPE [279].

32 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

The entire RP specimen should be inked upon receipt in the laboratory to demonstrate the surgical margins.
Specimens are fixed by immersion in buffered formalin for at least 24 hours, preferably before slicing. After
fixation, the apex and the base (bladder neck) are removed and cut into (para)sagittal or radial sections; the
shave method is not recommended [106]. The remainder of the specimen is cut in transverse, 3-4 mm sections,
perpendicular to the long axis of the urethra. The resultant tissue slices can be embedded and processed as
whole-mounts or after quadrant sectioning. Whole-mounts provide better topographic visualisation, faster
histopathological examination and better correlation with pre-operative imaging, although they are more time-
consuming and require specialist handling. For routine sectioning, the advantages of whole mounts do not
outweigh their disadvantages.

5.3.5.2 Radical prostatectomy specimen report

The pathology report provides essential information on the prognostic characteristics relevant for clinical
decision-making (Table 5.4). As a result of the complex information to be provided for each RP specimen, the
use of synoptic(-like) or checklist reporting is recommended. Synoptic reporting results in more transparent and
complete pathology reporting [280].

Table 5.4: Mandatory elements provided by the pathology report

Histopathological (sub)type
Type of carcinoma, e.g., conventional acinar adenocarcinoma, (small cell) neuroendocrine cell carcinoma or
ductal carcinoma
Subtype and unusual variants, e.g., pleomorphic giant cell or mucinous
Histological grade
Primary (predominant) Gleason grade
Secondary Gleason grade
Tertiary Gleason grade (if applicable)
Global ISUP GG
Approximate percentage of Gleason grade 4 or 5
Tumour quantitation (optional)
Percentage of prostate involved
Size/volume of dominant tumour nodule
Pathological staging (pTNM)
If extraprostatic extension is present:
• indicate whether it is focal or extensive;
• specify sites;
• indicate whether there is seminal vesicle invasion.
If applicable, regional lymph nodes:
• location;
• number of nodes retrieved;
• number of nodes involved.
Surgical margins
If carcinoma is present at the margin:
• specify sites;
• extent: focal or extensive;
• (highest) grade at margin.
Other
Presence of lymphovascular invasion
Location of dominant tumour
Presence of intraductal carcinoma/cribriform architecture

5.3.5.3 ISUP GG in prostatectomy specimens

Grading of conventional prostatic adenocarcinoma using the Gleason system is the strongest prognostic factor
for clinical behaviour and treatment response [107]. The GS is incorporated in nomograms that predict disease-
specific survival (DSS) after prostatectomy [281, 282]. The ISUP GG in prostatectomy specimens is determined
mostly in a similar way as in biopsies, with a minor exception, i.e., the exclusion of minor (< 5%) high-grade
components from the ISUP GG. For instance, in a carcinoma almost entirely composed of Gleason grade 3

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the presence of a minor (< 5%) Gleason grade 4 or 5 component is not included in the GS (ISUP GG 1), but its
presence is commented upon [108]. In case of multi-focality the ISUP GG of the index lesion i.e., the tumour
having the highest grade, stage or volume, is given.

5.3.5.4 Definition of extra-prostatic extension

Extra-prostatic extension is defined as carcinoma mixed with peri-prostatic adipose tissue, or tissue that
extends beyond the prostate gland boundaries (e.g., neurovascular bundle, anterior prostate). Microscopic
bladder neck invasion is considered EPE. It is useful to report the location and extent of EPE for surgical and
radiological quality assurance. While extent of EPE has been associated with recurrence risk in some studies
[283], a systematic review and meta-analysis did not find a statistically significant difference between focal
and extensive EPE for BCR-free survival [284]. There are no internationally accepted definitions of focal or
microscopic, vs. non-focal or extensive EPE. Some describe focal as a few glands [285] or < 1 high-power field in
one or at most two sections whereas others measure the depth of extent in millimetres [285]. At the apex of the
prostate, tumour mixed with skeletal muscle does not constitute EPE. In the bladder neck, microscopic invasion
of smooth muscle fibres is not equated to bladder wall invasion, i.e., not as pT4, because it does not carry
independent prognostic significance for PCa recurrence and should be recorded as EPE (pT3a) [286, 287]. Stage
pT4 is assigned when the tumour invades the bladder muscle wall as determined macroscopically [101].

5.3.5.5 PCa volume

Although PCa volume at RP correlates with tumour grade, stage and surgical margin status, the independent
prognostic value of PCa volume has not been established [285, 288, 289]. Improvement in prostatic radio-
imaging allows more accurate pre-operative measurement of cancer volume. Since the independent value of
pathological tumour volume at RP has not been established, reporting of the diameter/volume of the dominant
tumour nodule, or a rough estimate of the percentage of cancer tissue, is optional [290].

5.3.5.6 Surgical margin status

Surgical margin status is an independent risk factor for BCR. Margin status is positive if tumour cells are in
contact with the ink on the specimen surface. Margin status is negative if tumour cells are close to the inked
surface [291] or at the surface of the tissue lacking ink. In tissues that have severe crush artefacts, it may
not be possible to determine margin status [292]. Surgical margin is separate from pathological stage, and a
positive margin is not evidence of EPE [293]. There is evidence for a relationship between margin extent and
recurrence risk [294, 295]. A systematic review including sixteen retrospective studies showed that positive
surgical margin length measured either as continuous or dichotomized (< 3 mm vs. > 3 mm, < 1 mm vs. > 1 mm)
variable was an independent prognostic parameter for BCR-free survival [296]. Some indication must be given of
the multi-focality and extent of margin positivity, such as the linear extent in mm of involvement: focal, ≤ 1 mm
vs. extensive, > 1 mm [297], or number of blocks with positive margin involvement. Gleason score at the positive
margin was found to correlate independently with outcome and should be reported [280, 294, 298].

5.3.5.7 Intra-operative assessment of surgical margin status

Intra-operative surgical margin assessment can be performed during RP to reduce positive margins and
increase neurovascular bundle preservation. A SR reported a 1-15% decrease of positive surgical margins in
eight out of ten studies [299]. Intra-operative evaluation of the posterolateral prostatic margin according to
the neurovascular structure-adjacent frozen section examination (NeuroSAFE) technique is a systematic way
of intra-operative surgical margin evaluation [300]. Non-randomised studies showed that men subjected to
NeuroSAFE had lower positive surgical margin rates and more frequently underwent uni- or bilateral nerve-
sparing surgery [300-303]. Pending the results on long-term oncological and functional outcome as well as
the outcome of the randomised NeuroSAFE PROOF trial, intra-operative frozen section analysis should not be
considered standard of care [304].

5.4 Biopsy indication

5.4.1 Risk assessment before MRI and biopsy
An elevated risk of significant PCa is established based on one or more of the primary diagnostic tools applied,
such as PSA level, DRE, or primary imaging. While in the classic diagnostic algorithm the indication for biopsy
was generally solely based on a PSA-threshold or abnormal DRE, different two- or three-tier sequential/
conditional pathways are now available to indicate prostate biopsy, such as imaging and/or biomarkers. These
can be combined and/or sequenced into two or multiple-tier conditional diagnostic pathways (e.g., PSA -> MRI,
PSA -> risk calculator, PSA -> risk calculator -> MRI, etc). Age, co-morbidity, life expectancy, and therapeutic
consequences should also be considered and discussed beforehand [305].

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 The chosen diagnostic algorithm may be elected based on availability, expertise, and resources. The
different approaches impact cancer detection rates, number of (un)necessary biopsies, number of patient visits,
and option of targeted biopsies. The elected strategy may also be decided based on prevalence of disease in
men entering the pathway (e.g., screening versus clinical symptoms).
Different sequences and combinations of these tools, lead to different rates of biopsy indications,
detection rates of insignificant PCa, and significant PCa, but also on the burden and costs of the diagnostic
algorithm [306].
For re-evaluation of the initial PSA value and the use of PSA-D in risk assessment before MRI, see
chapter 5.2.2 and 5.2.3.

5.4.1.1 Risk calculators assessing the risk of csPCa

At different steps during the diagnostic process, available parameters may be combined into risk calculators
to optimise risk-assessment of csPCa. Validation and adaption to the target population are important issues
before use. Risk calculators, combining clinical data (age, DRE findings, PSA level, prostate volume, etc.) may
be useful in helping to determine (on an individual basis) what the potential risk of cancer may be, thereby
improving the balance of the cancer detection rates and number of biopsies [307].

Several tools developed from cohort studies are available including (among others) the calculator derived
from the ERSPC cohort (http://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-
calculators) that has been updated by incorporating the 2014 ISUP Pathology Gleason Grading and Cribriform
growth [161], and the one derived from the Prostate Cancer Prevention Trial (PCPT) cohort (PCPTRC 2.0
http://myprostatecancerrisk.com). However, calculators are limited by their dependency on disease prevalence.
All calculators show miscalibration when tested in populations with a different prevalence than that of the
training population of the model. Recalibrations taking into account the local prevalence are possible, but this
approach is difficult in routine as the local prevalence is difficult to estimate and may change over time.

5.4.1.2 Using risk-stratification to avoid Magnetic resonance imaging scans and biopsy procedures
Use repeated PSA, if the initial PSA is between 3 and 10 ng/mL, and PSA-D in risk-stratification (see sections
5.2.2 and 5.2.3).
A retrospective analysis including 200 men from a prospective database of patients who underwent
MRI and combined systematic and targeted biopsy showed that upfront use of the Rotterdam Prostate Cancer
Risk Calculator would have avoided MRI and biopsy in 73 men (37%). Of these 73 men, ten had ISUP GG 1
cancer and four had ISUP GG ≥ 2 cancer [308]. A prospective multi-centre study evaluated several diagnostic
pathways in 545 biopsy-naive men who underwent MRI and systematic and targeted biopsy. Using a PHI
threshold of > 30 to perform MRI and biopsy would have avoided MRI and biopsy in 25% of men at the cost of
missing 8% of the ISUP GG ≥ 2 cancers [309]. Another prospective multi-centre trial including 532 men (with or
without history of prostate biopsy) showed that using a threshold of ≥ 10% for the Stockholm3 test to perform
MRI and biopsy would have avoided MRI and biopsy in 38% of men at the cost of missing 8% of ISUP GG ≥ 2
cancers [226]. Finally, a risk calculator developed on 1,486 men who underwent MRI and biopsy was externally
validated on a cohort of 946 men from two institutions; using a risk threshold that provided 95% sensitivity in
the development cohort could have avoided 22% of the MRI scans in the validation cohort while missing 5% of
csPCa [310].
In conclusion, as long as patients with a low risk-score on the risk calculator are offered repeat
testing and follow-up until they have a life expectancy of < 15 years it seems unlikely that any preliminary missed
case would cause increased morbidity or lead to PCSM.

5.4.2 MRI based indication for biopsy

5.4.2.1 MRI as a triage test for biopsy (‘MRI pathway’)
Owing to its high sensitivity, MRI showed an excellent NPV for ruling out the presence of csPCa not only at
subsequent biopsy [311], but also after four years of follow-up [312].
The diagnostic yield and number of biopsy procedures potentially avoided by the ‘MR pathway’ (in
which only patients with positive MRI undergo biopsy) depends on the Likert/PI-RADS threshold used to define
a positive MRI. In a meta-analysis on PI-RADS v2.1 data [313], PI-RADS ≥ 3 thresholding showed MRI sensitivity/
specificity for significant disease of 96%/43% on a patient level for ISUP GG ≥ 2 cancer (fifteen reports, 4,484
men); PI-RADS ≥ 4 thresholding showed sensitivity/specificity of 88%/64% (21 reports, 5,745 men). ISUP GG
≥ 2 cancer detection rates on a patient level were PI-RADS 1: 6% [95% CI: 3-12%], PI-RADS 2: 6% [3-11%], PI-RADS
3: 20% [15-26%], PI-RADS 4: 55% [45-65%], and PI-RADS 5: 83% [78-88%]. On a patient level, the distribution of
PI-RADS categories was PI-RADS 1: 9%, PI-RADS 2: 29%, PI-RADS 3: 19%, PI-RADS 4: 22%, and PI-RADS 5: 19%.

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 35

 In pooled studies on biopsy-naive patients and patients with prior negative biopsies, a Likert/
PI-RADS threshold of ≥ 3 would have avoided 30% (95% CI: 23–38) of all biopsy procedures while missing 11%
(95% CI: 6–18) of all detected ISUP GG ≥ 2 cancers (relative percentage) [208]. Increasing the threshold to
≥ 4 would have avoided 59% (95% CI: 43–78) of all biopsy procedures while missing 28% (95% CI: 14–48) of all
detected ISUP GG ≥ 2 cancers [208]. Of note, the percentages of negative MRI (Likert/PI-RADS score ≤ 2) may
show substantial variability among series. In the PRECISION, MRI-FIRST and 4M trials percentages of negative
MRI were 21.1%, 28.9% and 49%, with related ISUP GG ≥ 2 cancer prevalence of 27.7% (23.7–32.6), 37.5% (31.4–
43.8), and 30% (ND) respectively [126, 210, 314].
In the MR PROPER trial, a prospective, multi-centre, non-randomised opportunistic early detection
setting (PSA > 3 ng/mL), comparable rates of ISUP GG ≥ 2 cancer detection (24% vs. 25%) were obtained by
the MRI pathway and by a strategy indicating systematic biopsy based on a risk calculator. However, the MRI
pathway avoided biopsy in more men as compared to the diagnostic pathway using a risk calculator (559/1015,
55% vs. 403/950, 42%; difference -13%, 95% 27 CI: -17% to -8.3%; p < 0.01); it also detected less ISUP GG 1
cancers (84/1015, 8.3% vs. 121/950, 13%; difference 4.5%, 95% CI: 1.8–7.2%; p < 0.01) [315].

5.4.2.2 Combining MRI and PSA Density

Prostate-specific antigen density (PSA-D) may help refine the risk of csPCa in patients undergoing MRI as PSA-D
and the PI-RADS score are significant independent predictors of csPCa at biopsy [316, 317]. Combinations of
PSA-D and MRI have been explored [318, 319], showing guidance in biopsy-decisions whilst safely avoiding
redundant biopsy testing and detection of insignificant PCa. In a meta-analysis of eight studies, pooled MRI
NPV for ISUP GG ≥ 2 cancer was 84% (95% CI: 81–87) in the whole cohort, 83% (95% CI: 80–84) in biopsy-naive
men and 88% (95% CI: 85–91) in men with prior negative biopsies. In the subgroup of patients with PSA-D < 0.15
ng/mL/cc, NPV increased to respectively 90% (95% CI: 87–93), 89% (95% CI: 83–93) and 94% (95% CI: 91–97)
[320]. In contrast, the risk of ISUP GG ≥ 2 cancer is as high as 27–40% in patients with negative MRI and PSA-D
> 0.15–0.20 ng/mL/cc [314, 317, 321-323].

Based on a meta-analysis of > 3,000 biopsy-naive men, a risk-adapted data table of csPCa was developed,
linking PI-RADS score (1-2, 3, and 4-5) to PSA-D categories (< 0.10, 0.10–0.15, 0.15–0.20 and > 0.20 ng/mL)
(Table 5.5) [318]. This risk-adapted matrix table may guide the decision to perform a biopsy.
In a multi-centre retrospective cohort of 1,476 men with PIRADS 3 lesions and a prevalence of 18.5%
of ISUP GG ≥ 2 cancer, age, prior negative biopsy and PSA-D were significant independent predictors of the
presence of ISUP GG ≥ 2 cancer at subsequent systematic and targeted biopsy. Applying a PSA-D cut-off of
0.15 ng/mL/cc, 817 biopsy procedures (58.4%) would have been avoided at the cost of missing ISUP GG ≥ 2
cancer in 91 men (6.5%); ISUP GG 1 cancer would not have been detected in 115 men (8.2%) [324]. Two studies
provided follow-up data for patients with PI-RADS scores of 1-3 and PSA-D < 0.15 ng/ml/cc for whom biopsy
was omitted. The cumulative incidence of ISUP GG ≥ 2 cancer detection was 1.3% at two years [325] and 3.2% at
36 months [326].

Table 5.5: Risk data table of clinically significant prostate cancer, related to PI-RADS score and PSA-D
categories in biopsy-naive men, clinically suspected of having significant disease [318]*

Detection of clinically significant prostate cancer (ISUP GG 2 and higher)

PSA-density risk groups
PI-RADS risk Prevalence ISUP Low Intermediate-low Intermediate-high High
categories > 2 PCa < 0.10 0.10–015 0.15–0.20 > 0.20
31% 28% 16% 25%
(678/2199) (612/2199) (360/2199) (553/2199)
Compiled totals of csPCa risk
PI-RADS 1–2 6% 3% 7% 8% 18%
(48/839) (11/411) (17/256) (8/104) (12/68)
PI-RADS 3 16% 4% 13% 29% 29%
(41/254) (3/74) (11/88) (12/41) (15/51)
PI-RADS 4–5 62% 31% 54% 69% 77%
(687/1106) (59/189) (144/286) (148/215) (336/434)
All PI-RADS 35% 11% 28% 47% 66%
(776/2199) (73/674) (172/612) (168/360) (363/553)

36 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

 Risk-adapted matrix table for biopsy decision management
PI-RADS 1–2 No biopsy No biopsy No biopsy Consider biopsy
PI-RADS 3 No biopsy Consider biopsy Highly consider Perform biopsy
biopsy
PI-RADS 4–5 Perform biopsy Perform biopsy Perform biopsy Perform biopsy

Very low 0–5% csPCa (below population risk) #

Low 5–10% csPCa (acceptable risk)
Intermediate-low 10–20% csPCa
Intermediate-high 20–30% csPCa
High 30–40% csPCa
Very high > 40% csPCa
# T
 hompson IM et al. N Engl J Med. 2004 May 27;350(22):2239-46. Prevalence of prostate cancer among men
with a prostate-specific antigen level < or = 4.0 ng/mL [174].

*Table adapted from: Schoots, IG and Padhani AR. BJU Int 2021 127(2):175. Risk-adapted biopsy decision based
on prostate magnetic resonance imaging and prostate-specific antigen density for enhanced biopsy avoidance in
first prostate cancer diagnostic evaluation, with permission from Wiley.

5.4.2.3 Risk calculators incorporating MRI findings

Several groups have developed comprehensive risk calculators which combine MRI findings with simple clinical
data as a tool to predict subsequent biopsy results [327]. Some calculators underwent external validation with
good results both in terms of discrimination and clinical utility and tended to outperform risk calculators not
incorporating MRI findings [328-331]. However, their use is hindered by their miscalibration due to prevalence
dependency (see section 5.4.1.1).

5.4.2.4 MRI in population-based screening protocols

MRI as a sequential screening tool following PSA
A meta-analysis comparing the use of PSA followed by MRI (sequential) with PSA-only screening methods in
terms of clinically significant CDR did not show any significant difference when thresholding at PI-RADS ≥ 3
(OR: 1.02 [0.75-1.37]; p = 0.86) [332]. However, the MRI pathway was associated with lower odds of insignificant
PCa detection (OR: 0.34 [0.23-0.49]; p = 0.002). Furthermore, MRI-(sequential) screening methods had a higher
PPV for detecting significant PCa (OR: 4.15 [2.93-5.88]; p = 0.001) and a lower biopsy rate (OR: 0.28 [0.22- 0.36];
p < 0.001) than PSA-only-based methods. Thresholding at PI-RADS ≥ 4 showed even lower odds of insignificant
PCa detection (OR: 0.23; 95% CI: 0.05-0.97; p = 0.048) and biopsy (OR: 0.19; 95% CI: 0.09-0.38; p = 0.01), with a
higher PPV (OR: 7.01; 95% CI: 1.76- 27.98; p = 0.03) and similar clinically significant CDR (OR: 0.85; 95% CI: 0.49-
1.45; p = 0.23), compared with standard PSA-only screening [332].
Therefore, in a population-based screening setting, the ‘MRI pathway’ may reduce the risk of over-
diagnosis by two-thirds, without substantially compromising clinically significant tumours. However, these
results were obtained at single academic centres with double reading of the MRI, which may limit their
generalisability in less experienced centres (see section 5.5.5).

MRI as a first-line screening Tool

Thresholding at a PI-RADS ≥ 4 in MRI as the primary screening tool, clinically significant and insignificant CDRs
were 6% [0.6-39%] and 1.2% [0.2-7%], respectively [333-335]. The PPV of up-front MRI to detect significant PCa
was 42% [16-73%]. The IP1-PROSTAGRAM study (PSA > 3 ng/mL; thresholding at PIRADS ≥ 3), proposed a
pathway that combines PSA ≥ 1 ng/ml and MRI-score ≥ 4, maintaining the detection of ISUP GG ≥ 2 cancers
while recommending fewer men for biopsies, as the preferred strategy to evaluate in future studies at the first
screening round [333].

5.5 Biopsy strategy

Prostate biopsy can be performed using different strategies (systematic, targeted etc.,) and approaches
(i.e., transperineal vs. transrectal).

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 37

5.5.1 Systematic biopsy strategy
For systematic biopsies, where no prior imaging is used for targeting, the sample sites should be bilateral from
apex to base, as far posterior and lateral as possible in the peripheral gland regardless of the approach used.
A 2006 SR showed that twelve is the minimum number of cores for systematic biopsies, with > 12 cores not
increasing cancer detection rate significantly [336].

5.5.2 Targeted biopsy strategy

Where MRI has shown a suspicious lesion, MR-targeted biopsy can be obtained through cognitive guidance, US/
MR fusion software or direct in-bore guidance. Current literature, including SRs and meta-analyses, does not
show a clear superiority of one image-guided technique over another [337-339]. The Target Biopsy Techniques
Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative
Biopsies (FUTURE) randomised trial compared three techniques (cognitive fusion, software fusion, in-bore MRI)
of MRI-targeted biopsy in the repeat-biopsy setting and found no differences in cancer detection [338].

5.5.3 Targeted biopsy versus systematic biopsy

5.5.3.1 Increased detection of cancers labelled as clinically significant
The PRECISION (Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or
Not?) [126] and PRECISE (Prostate Evaluation for Clinically Important Disease: MRI vs. Standard Evaluation
Procedures) [340] prospective trials randomised biopsy naïve patients to either ten to twelve core systematic
biopsy or to MRI with subsequent MRI-targeted biopsy (up to four cores) in case of positive MRI. They found
that MRI-targeted biopsy significantly out-performed [126] or was not inferior to [340] systematic biopsy for
the detection of ISUP GG ≥ 2 cancers. In pooled data of 25 reports on agreement analysis (head-to-head
comparisons) between systematic biopsy (median number of cores: 8–15) and MRI-targeted biopsies (median
number of cores: 2–7), the detection ratio (i.e., the ratio of the detection rates obtained by MRI-targeted biopsy
alone and by systematic biopsy alone) was 1.12 (95% CI: 1.02–1.23) for ISUP GG ≥ 2 cancers and 1.20 (95%
CI: 1.06–1.36) for ISUP GG ≥ 3 cancers, and therefore in favour of MRI-targeted biopsy [168]. Another meta-
analysis of studies limited to biopsy-naive patients with a positive MRI also found that MRI-targeted biopsy
detected significantly more ISUP GG ≥ 2 cancers than systematic biopsy (risk difference, -0.11 [95% CI: -0.2 to
0.0]; p = 0.05) [341]. This data was further confirmed in another prospective multi-centre trial [342].
In a subgroup of 152 patients from the FUTURE trial who underwent both MRI-targeted biopsy and
systematic biopsy in a repeat biopsy setting, MRI-targeted biopsy detected significantly more ISUP GG ≥ 2
cancers than systematic biopsy (34% vs. 16%; p < 0.001, detection ratio of 2.1) [343]. These findings support
that MRI-targeted biopsy significantly out-performs systematic biopsy for the detection of ISUP GG ≥ 2 also in
the repeat-biopsy setting.

5.5.3.2 Reduced detection of cancers labelled as ISUP GG 1

In pooled data of 25 head-to-head comparisons between systematic biopsy and MRI-targeted biopsy, the
detection ratio for ISUP GG 1 cancers was 0.62 (95% CI: 0.44–0.88) in patients with prior negative biopsy and
0.63 (95% CI: 0.54–0.74) in biopsy-naive patients [208]. In the PRECISION and 4M trials, the detection rate of
ISUP GG 1 patients was significantly lower in the MRI-targeted biopsy group as compared to systematic biopsy
(9% vs. 22%, p < 0.001, detection ratio of 0.41 for PRECISION; 14% vs. 25%, p < 0.001, detection ratio of 0.56 for
4M) [126, 314]. In the MRI-FIRST trial, MRI-targeted biopsy detected significantly fewer patients with clinically
insignificant PCa (defined as ISUP GG 1 and maximum cancer core length < 6 mm) than systematic biopsy
(5.6% vs. 19.5%, p < 0.0001, detection ratio of 0.29) [210]. Consequently, MRI-targeted biopsy without systematic
biopsy significantly reduces over-diagnosis of low-risk disease, as compared to systematic biopsy. This seems
true even when systematic biopsies are indicated after risk stratification with the Rotterdam Prostate Cancer
Risk Calculator) [315].

5.5.3.3 Added value of systematic biopsy and targeted biopsy

From head-to-head comparisons between the two biopsy techniques, it is possible to compute their added value,
i.e., the percentage of additional patients with csPCa they help to diagnose. Table 5.6 shows the added value of
systematic and MRI-targeted biopsy for ISUP GG ≥ 2 and ≥ 3 cancer detection. The absolute added values in the
table refer to the percentage of patients in the entire cohort; if the cancer prevalence is considered, the ‘relative’
percentage of additional detected csPCa can be computed. Adding MRI-targeted biopsy to systematic biopsy
in biopsy-naive patients increases the number of detected ISUP grade ≥ 2 and grade ≥ 3 PCa by approximately
20% and 30%, respectively. In the repeat-biopsy setting, adding MRI-targeted biopsy increases detection of ISUP
GG ≥ 2 and GG ≥ 3 PCa by approximately 40% and 50%, respectively. Omitting systematic biopsy in biopsy-naive
patients would miss approximately 16% of all detected ISUP GG ≥ 2 PCa and 18% of all ISUP grade ≥ 3 PCa. In
the repeat-biopsy setting, it would miss approximately 10% of ISUP GG ≥ 2 PCa and 9% of ISUP GG ≥ 3 Pca. The
low added value of systematic biopsy in the repeat biopsy setting has been further confirmed by other studies

38 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

that reported absolute added values of 1.2-3.9% for the detection of ISUP GG ≥ 2 cancers and of 1.2-1.6% for
ISUP GG ≥ 3 cancers [343-345].

Table 5.6: Absolute added values of targeted and systematic biopsies for ISUP grade ≥ 2 and ≥ 3
Cancer Detection

ISUP GG ≥ 2 ISUP GG ≥ 3
ISUP grade Cochrane MRI-FIRST 4M trial Cochrane MRI-FIRST 4M trial
meta- trial* [314] meta- trial* [314]
analysis* [210] analysis* [210]
[208] [208]
Added value of 6.3% 7.6% 7.0% (ND) 4.7% 6.0% 3.2% (ND)
MRI-TBx (4.8–8.2) (4.6–11.6) (3.5–6.3) (3.4–9.7)
Added value 4.3% 5.2% 5.0% (ND) 2.8% 1.2% 4.1% (ND)
of systematic (2.6–6.9) (2.8–8.7) (1.7–4.8) (0.2–3.5)
Biopsy-naïve
biopsy
Overall 27.7% 37.5% 30% (ND) 15.5% 21.1% 15% (ND)
prevalence (23.7– (31.4–43.8) (12.6– (16.2–26.7)
32.6) 19.5)
Added value of 9.6% - - 6.3% - -
MRI-TBx (7.7–11.8) (5.2–7.7)
Added value of 2.3% - - 1.1% - -
Prior negative
systematic biopsy (1.2–4.5) (0.5–2.6)
biopsy
Overall 22.8% - - 12.6% - -
prevalence (20.0– (10.5–
26.2) 15.6)
*Intervals in parenthesis are 95% CI. The absolute added value of a given biopsy technique is defined by the
percentage of patients of the entire cohort diagnosed only by this biopsy technique.
ISUP = International Society of Urological Pathology (grade); MRI-TBx = magnetic resonance imaging-targeted
biopsies; ND = not defined.

Table 5.7: Detection rates of ISUP GG 1 cancers by targeted and systematic biopsies

Study Targeted biopsy Systematic biopsy p-value

PRECISION [126] 9% 22% <0.001
PRECISE [340] 10.1 21.7 <0.001
MRI-FIRST [210]* 5.6% 19.5% <0.0001
4M [314] 14% 24.7% <0.0001
Cochrane meta-analysis 13.5% 22.4% <0.01
[208]
* In the MRI-FIRST trial, the percentages refer to the detection rates of ISUP 1 cancers with a maximum cancer
core length < 6 mm.

5.5.4 Perilesional biopsy

A minimum of three to five cores is required for proper sampling of an MRI detected lesion [345-347]. Several
concordant studies showed that, in case of a unilateral MRI lesion, contralateral systematic biopsy (i.e., from
the MRI-negative lobe) has little added value for diagnosing csPCa (0.3-4%). Paradoxically, the added value of
ipsilateral systematic biopsy is higher (4.9-18.4%) and comes mostly from the systematic cores obtained in
the sextant containing the MR lesion, or the sextant immediately adjacent [348-352]. Consequently, including
additional peri-lesional/regional systematic biopsies, rather than standard sextant-based systematic biopsies
may decrease the total number of cores taken (by avoiding systematic biopsies in MRI-negative lobes) and
improve the detection of csPCa (by compensating for guiding imprecision). In addition, the MRI-targeted and
regional biopsy approach could avoid detecting 12-17% of the insignificant cancers detected by the classical
combined approach [353-355].

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 39

 A meta-analysis of eight studies showed a non-significant difference in detection of ISUP GG ≥ 2
cancer in the MRI-directed targeted and regional biopsy approach, compared to the recommended practice of
MRI-directed targeted- and systematic biopsy approach (RR: 0.95; 95% CI: 0.90–1.01; p = 0.09). However, the
MRI-directed targeted- and regional biopsy approach detected significantly more ISUP GG ≥ 2 cancers than MRI-
targeted biopsy alone (RR: 1.18; 95% CI: 1.10–1.25; p < 0.001) [356]. Other prospective [357] and retrospective
[355, 358] studies not included in the meta-analysis provided similar evidence (Table 5.8).
Two studies retrospectively used the location of biopsy cores registered by MRI/US fusion systems
to assess the added value of systematic cores based on their distance from the nearest MRI lesion. The
diagnostic yield of these systematic cores decreased with increasing distance. Combining the targeted and
systematic cores located within a 10 mm and a 15 mm radius from the MR lesions detected 90-92% and 94-97%
of the csPCa respectively [353, 354]. The width of the distance from the MRI lesion which enclosed 90% of
csPCa may also depend on the PI-RADS score of the lesion; in one series it was found to be 5.5 mm, 12 mm
and 16 mm for lesions with PI-RADS scores of 5, 4 and 3 respectively [353]. As a consequence, in men with a
PI-RADS 5 index lesion, the absolute added value of additional biopsy has been repeatedly found to be less than
4% for ISUP GG ≥ 2 cancers and less than 2% for ISUP GG ≥ 3 cancers [345, 359-361].

5.5.5 Prostate MRI and MRI-targeted biopsy reproducibility

Despite the use of the PI-RADS scoring systems, MRI inter-reader reproducibility remains moderate at best. MRI
performance is better with experienced radiologists and at high-volume centres. This currently limits its broad
use by non-dedicated radiologists [346, 362].
The accuracy of MRI-targeted biopsy is also substantially impacted by the experience of the biopsy
operator [346]. The PRECISE trial, that reproduced the design of the PRECISION trial obtained quite different
results. In both trials, the detection rate for ISUP GG ≥ 2 PCa was higher for the MRI pathway than for the
classical systematic biopsy pathway. Yet, the difference was much lower in the PRECISE trial (+5.2% vs. +12.1%
for ISUP GG ≥ 2 cancers; +2.1% vs. +5.5% for ISUP GG ≥ 3 cancers). In addition, there was major intersite
variability in the PRECISE trial: the centre with the highest csPCa detection rate on MRI-targeted biopsy had the
lowest on systematic biopsy and vice versa [340].
These factors of variability give rise to concerns about the reproducibility of the good results of
the MRI-directed diagnostic pathways. Efforts towards standardisation of the whole diagnostic pathway (MRI
acquisition and interpretation, biopsy planning and acquisition) through quality assurance and quality control
are currently undertaken [346, 363]. However, significant improvement in the accuracy of MRI and MRI-targeted
biopsy can be observed over time through simple measures such as training and participation to MDT meeting
with pathological correlation and feedback [346, 364]. Artificial intelligence (AI)-based algorithms have recently
provided excellent results in detecting ISUP GG ≥2 PCa on MRI and can even outperform experienced human
readers [365]. However, whether these good results will be reproducible on routine multi-scanner, multi-vendor
MRI cohorts remains uncertain. Studies comparing unassisted and AI-assisted human reading have reported
conflicting results so far [366].

5.5.6 Cancer grade shift

MRI findings are significant predictors of adverse pathology features on prostatectomy specimens, and of
survival-free BCR after RP or RT [103, 367, 368]. In addition, tumours visible on MRI are enriched in molecular
hallmarks of aggressivity, as compared to invisible lesions [369]. Thus, MRI does identify aggressive tumours.
Nonetheless, as MRI-targeted biopsy is more sensitive than systematic biopsy in detecting areas of
high-grade cancer, ISUP GG ≥ 2 cancers detected by MRI-targeted biopsy are, on average, of better prognosis
than those detected by the classical diagnostic especially if the biopsy core with the highest grade is taken
into consideration [105]. This is illustrated in a retrospective series of 1,345 patients treated by RP which
showed that, in all risk groups, patients diagnosed by MRI-targeted biopsy had better BCR-free survival than
those diagnosed by systematic biopsy only [103]. Preliminary findings suggest that, when the grade is different
between systematic biopsy and MRI-targeted biopsy [370] or between systematic biopsy and prostatectomy
specimens [371], the prognosis is intermediate between grades. This is in line with the 2019 ISUP consensus
conference recommended using an aggregated ISUP GG summarising the results of all biopsy cores from the
same MR lesion, rather than using the result from the core with the highest ISUP GG [108] (see section 4.2).
When long term follow-up of patients who underwent MRI-targeted biopsy is available, a revision of the risk-
groups definition will become necessary. In the meantime, results of MRI-targeted biopsy must be interpreted in
the context of this potential grade shift [372].

40 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Table 5.8: Detection rates for ISUP GG ≥2 prostate cancer achieved by targeted biopsy, combined systematic
and targeted biopsy and targeted biopsy with perilesional sampling

Study Type of study N Targeted biopsy with Targeted biopsy with

perilesional sampling perilesional sampling
vs. vs.
Combined systematic and Targeted biopsy
targeted biopsy
Ratio of Median Ratio of Median
detection number of detection number of
rates cores rates cores
Hagens MJ Meta-analysis 2603 0.95 (0.90 - 9.5 [7.5-12.3] 1.18 9.5 [7.5 - 12.3]
[356] 1.01), p=0.09 vs. 16.5 [15.3 (1.1 - 1.25), vs. 3.5 [3 - 4]
– 12.3] p < 0.001
Hagens MJ Retrospective, 235 0.968 (0.91 - 7 [6 - 9] vs. 12 - -
[355] single centre 0.993) [10 - 15]
Hsieh PF [357] Prospective, 100 1 15 [12.8 - 18] 1.20, p = 0.008 15 [12.8 - 18]
single centre vs. 26 [23 - 28] vs. 6 [4 - 7]

5.5.7 Recommendations for MRI imaging in biopsy indication and strategy

Recommendations Strength rating

Do not use magnetic resonance imaging (MRI) as an initial screening tool. Strong
Adhere to PI-RADS guidelines for MRI acquisition and interpretation and evaluate MRI results Strong
in multidisciplinary meetings with pathological feedback.
Where MRI has shown a suspicious lesion, MR-targeted biopsy can be obtained through Weak
cognitive guidance, US/MR fusion software or direct in-bore guidance.
Perform MRI before prostate biopsy in men with suspected organ confined disease. Strong
In men with suspicion of locally advanced disease on digital rectal examination (DRE) and/ Weak
or prostate-specific antigen (PSA) > 50 ng/mL, or those not for curative treatments, consider
limited biopsy without MRI.
When MRI is positive (i.e., PI-RADS ≥ 4), combine targeted biopsy with perilesional sampling. Weak
When MRI is negative (i.e., PI-RADS ≤ 2), and clinical suspicion of PCa is low (PSA density Weak
< 0.20 ng/mL/cc, negative DRE findings, no family history), omit biopsy and offer PSA
monitoring; otherwise consider systematic biopsy.
When MRI is indeterminate (PI-RADS = 3), and clinical suspicion of PCa is very low (PSA Weak
density < 0.10 ng/mL/cc, negative DRE findings, no family history), omit biopsy and offer PSA
monitoring; otherwise consider targeted biopsy with perilesional sampling.
If MRI is not available, use a risk calculator and systematic biopsies if indicated. Strong
When performing systematic biopsy only, at least twelve cores are recommended. Strong

5.6 Biopsy approach

MRI-directed US-guided prostate biopsy is now the standard of care although MRI in-bore biopsy is offered
in a few centres. MRI-directed US-guided prostate biopsy can be performed by either the transperineal or the
transrectal approach. Both can be performed under local anaesthesia [373]. A meta-analysis of nine RCTs
including 2,230 patients found that extended biopsy templates (20 vs. 8) showed comparable infectious
complications to standard templates (RR: 95% CI: 0.80 [0.53–1.22]) [374]. Additional meta-analyses found
no difference in infectious complications regarding needle guide type (disposable vs. reusable), needle type
(coaxial vs. non-coaxial), needle size (large vs. small), and number of injections for peri-prostatic nerve block
(standard vs. extended) [374].

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 41

5.6.1 MRI-directed transrectal vs transperineal US-guided biopsy
A systematic review and meta-analysis comparing MRI-targeted transrectal (TR) biopsy to MRI-targeted
transperineal (TP) biopsy, including eight studies, showed a higher sensitivity for detection of csPCa when
the transperineal approach was used (86% vs. 73%) [375]. However, in two subsequent RCTs, csPCa detection
was not superior for the TP route compared to TR biopsy [376, 377]. The PREVENT trial showed similar csPCa
detection for TP (53%) and TR (50%) routes, while the PERFECT trial showed non-inferior csPCa rates for TP
(47%) and TR (54%) [376]. Clinically significant PCa detection was different for anterior and posterior tumours
[375, 378]. The PERFECT trial showed higher significant cancer detection rates for anterior tumours with the TP
approach (41% in TP and 27% in TR), while the TR approach favoured posterior tumours (44% in TP and 59% in
TR) [378].

5.6.2 Local anaesthesia prior to biopsy

Ultrasound-guided peri-prostatic block is recommended [379]. Intra-rectal instillation of local anaesthetic cream
is inferior to peri-prostatic infiltration by injection [380]. Local anaesthesia can also be used effectively for MRI-
targeted and systematic transperineal biopsy [381]. Patients are placed in the lithotomy position. Around twenty
mL of lignocaine or bupivacaine with or without adrenaline (1 in 200,000) is injected into the perineal skin and
subcutaneous tissues anterior to the anus, followed by a peri-prostatic block also via transperineal route. A SR
evaluating pain in three studies comparing transperineal vs. transrectal biopsies found that the transperineal
approach significantly increased patient pain (RR: 1.83 [1.27–2.65]) [382]. In a randomised comparison a
combination of peri-prostatic and pudendal block anaesthesia reduced pain during transperineal biopsies
compared to peri-prostatic anaesthesia only [383]. A novel perineal nerve-block was shown in an RCT to be
superior for the relief of pain during transperineal biopsy procedure vs. conventional peri-prostatic block (2.80
vs. 3.98; on 1-10 scale) [384]. Targeted biopsies can then be taken via a brachytherapy grid or a freehand needle-
guiding device under local infiltration anaesthesia [381, 385]. An updated meta-analysis of 28 RCTs with 4,027
patients found no evidence that use of peri-prostatic injection of local anaesthesia resulted in more infectious
complications than no injection (RR: 95% CI: 1.08 [0.79–1.48]) [374, 386, 387].

5.6.3 Infection rate after transperineal and transrectal prostate biopsy

A total of eight randomised studies including 1,596 patients compared the impact of biopsy route on infectious
complications. Infectious complications were significantly higher following transrectal biopsy (48 events among
789 men) compared to transperineal biopsy (22 events among 807 men) (RR: 95% CI: 2.48 [1.47–4.2]) [374,
386]. In addition, a SR including 165 studies with 162,577 patients described sepsis rates of 0.1% and 0.9%
for transperineal and transrectal biopsies, respectively [388]. Finally, a population-based study from the UK
(n = 73,630) showed lower re-admission rates for sepsis in patients who had transperineal vs. transrectal
biopsies (1.0% vs. 1.4%, respectively) [389]. However, two subsequent RCTs comparing infectious complications
after TP and TR biopsies did not show significant differences in infection rates. The PREVENT trial compared
TP without antibiotic prophylaxis with TR biopsy using rectal culture and targeted antibiotic prophylaxis, and
showed that infection rates were 0% in TP and 1.4% in TR (p = 0.059) [376]. In the ProBE-PC trial, TP without
routine antibiotic was compared with TR with antibiotic prophylaxis, and composite infection rates were 2.7%
and 2.6%, respectively [377].

A systematic review and meta-analysis of eight non-RCTs reported no significant differences between patients
receiving or not receiving antibiotic prophylaxis before transperineal biopsy in terms of post-biopsy infection
(0.11% vs. 0.31%) and sepsis (0.13% vs. 0.09%), [390]. This is in line with another systematic review and meta-
analysis of 112 individual patient cohorts which also showed no significant difference in the number of patients
experiencing post-transperineal-biopsy infection (1.35% of 29,880 patients receiving antibiotic prophylaxis
and 1.22% of 4,772 men not receiving antibiotic prophylaxis [p = 0.8]) [391]. In addition, two published RCTs
have reported comparably low post-biopsy infection rates for transperineal biopsy regardless of whether
antibiotic prophylaxis was administered or not [392, 393]. A SR and meta-analysis comparing transperineal
with and without antibiotic prophylaxis showed very low percentages of septic complications (0.05% vs. 0.08%;
p = 0.2) and overall infections (1.35% vs. 1.22%; p = 0.8) Thus, there is a growing body of evidence to suggest
that antibiotic prophylaxis may not be routinely required for transperineal biopsy.

An updated meta-analysis of eleven RCTs including 2,237 men showed that use of a rectal povidone-iodine
preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly lower
rate of infectious complications (RR: 0.47; 95% CI [0.36–0.61]) [374, 387, 394]. Single RCTs showed reported an
advantage for rectal povidone-iodine preparation before transrectal biopsy compared to after biopsy [395].
A meta-analysis of four RCTs including 671 men evaluated the use of rectal preparation by enema
before transrectal biopsy. No significant advantage was found regarding infectious complications (RR: 95%
CI: 0.96 [0.64–1.54]) [374].

42 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

A meta-analysis of eleven studies with 1,753 patients showed significantly reduced infections after transrectal
prostate biopsy when using antimicrobial prophylaxis as compared to placebo/control (RR: 95% CI: 0.56 [0.40–
0.77]) [396].
For transrectal biopsies Fluoroquinolones have been traditionally used for antibiotic prophylaxis;
however, in recent years there has been an increase in fluoroquinolone resistance. In addition, the European
Commission has implemented stringent regulatory conditions regarding the use of fluoroquinolones resulting in
the suspension of the indication for peri-operative antibiotic prophylaxis including prostate biopsy [397].
A SR and meta-analysis on antibiotic prophylaxis for the prevention of infectious complications
following prostate biopsy concluded that in countries where fluoroquinolones are allowed as antibiotic
prophylaxis, a minimum of a full one-day administration, as well as targeted therapy in case of fluoroquinolone
resistance, or augmented prophylaxis (combination of two or more different classes of antibiotics)
is recommended [396]. In countries where use of fluoroquinolones are suspended, cephalosporins or
aminoglycosides can be used as individual agents with comparable infectious complications based on meta-
analysis of two RCTs [396]. A meta-analysis of three RCTs reported that fosfomycin trometamol was superior
to fluoroquinolones (RR: 95% CI: 0.49 [0.27–0.87]) [396], but routine general use should be critically assessed
due to the relevant infectious complications reported in non-randomised studies [398]. Of note the indication
of fosfomycin trometamol for prostate biopsy has been withdrawn in Germany as the manufacturers did not
submit the necessary pharmacokinetic data in support of this indication. Urologists are advised to check their
local guidance in relation to the use of fosfomycin trometamol for prostate biopsy. Another possibility is the use
of augmented prophylaxis without fluoroquinolones, although no standard combination has been established to
date. Finally, targeted prophylaxis based on rectal swap/stool culture is plausible, but no RCTs are available on
non-fluoroquinolones. See figure 5.1 for prostate biopsy workflow to reduce infections complications.

Taking into account the feasibility of TP and TR biopsies under local anaesthesia, comparable csPCa detection
rates, and growing importance of antibiotic stewardship, transperineal biopsy route is preferred over transrectal
route despite potential logistical challenges.

5.6.4 Summary of evidence and recommendations for performing prostate biopsy

(in line with the EAU Urological Infections Guidelines Panel)

Summary of evidence LE
A meta-analysis of eleven studies including 3,306 patients showed significantly reduced infectious 1a
complications in patients undergoing transperineal biopsy as compared to transrectal biopsy.
One randomised controlled trial showed comparable low rates of infectious complication for 1a
transperitoneal biopsy without antibiotics and transrectal biopsy with targeted antibiotic prophylaxis.
A meta-analysis of eight non-RCTS reported comparable rates of post-biopsy infections in patients 1a
undergoing transperineal biopsy irrespective of whether antibiotic prophylaxis was given or not.
A meta-analysis of eleven RCTs including 2,237 men showed that use of a rectal povidone-iodine 1a
preparation before transrectal biopsy, in addition to antimicrobial prophylaxis, resulted in a significantly
lower rate of infectious complications.
A meta-analysis on eleven studies with 1,753 patients showed significantly reduced infections after 1a
transrectal biopsy when using antimicrobial prophylaxis as compared to placebo/control.

Recommendations Strength rating*

Perform prostate biopsy using the transperineal approach due to the low risk of infectious Strong
complications and better antibiotic stewardship.
Use routine surgical disinfection of the perineal skin for transperineal biopsy. Strong
Use rectal cleansing with povidone-iodine prior to transrectal prostate biopsy. Strong
Use either target prophylaxis based on rectal swab or stool culture; or augmented Weak
prophylaxis (two or more different classes of antibiotics); for transrectal biopsy.
Ensure that prostate core biopsies from different sites are submitted separately for Strong
processing and pathology reporting.
* Note on strength ratings: The above strength ratings are explained here due to the major clinical implications of
these recommendations. Although data showing the lower risk of infection via the transperineal approach is low in
certainty, its statistical and clinical significance warrants its strong rating. Strong ratings are also given for routine
surgical disinfection of skin in transperineal biopsy and povidone-iodine rectal cleansing in transrectal biopsy as,
although quality of data is low, the clinical benefit is high and practical application simple. A ‘Strong’ rating is given
for avoiding fluoroquinolones in prostate biopsy due to its legal implications in Europe.

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 43

Figure 5.2: Prostate biopsy workflow to reduce infectious complications*

Indication for prostate biopsy?

Transperineal biopsy feasible?

Yes No

Transperineal biopsy - 1st choice (⊕⊕⊝⊝) Transrectal biopsy – 2nd choice (⊕⊕⊝⊝)
with: with:
• perineal cleansing1 • povidone-iodine rectal preparation
• antibiotic prophylaxis1 • antibiotic prophylaxis2

Fluoroquinolones licensed? 3

No Yes

1. Targeted prophylaxis1,7: based on rectal Duration of antibiotic prophylaxis ≥ 24 hrs

swab or stool cultures (⊕⊕⊝⊝)
2. Augmented prophylaxis1,2,4: two or 1. Targeted prophylaxis6,7 (⊕⊕⊝⊝):
more different classes of antibiotics based on rectal swab or stool cultures
3. Alternative antibiotics 5 (⊕⊝⊝⊝): 2. Augmented prophylaxis 2,4,6,8 (⊕⊝⊝⊝):
• fosfomycin trometamol (e.g. 3 g before • Fluoroquinolone plus aminoglycoside
and 3 g 24-48 hrs after biopsy)* • Fluoroquinolone plus cephalosporin
• cephalosporin (e.g. ceftriaxone 1 g i.m.;
cefixime 400 mg p.o. for 3 days starting 3. Fluoroquinolone prophylaxis 5
24 hrs before biopsy) (⊕⊝⊝⊝; ⊕⊕⊝⊝)
• aminoglycoside (e.g. gentamicin 6-7 mg/kg
i.v.; amikacin 25-30 mg/kg i.m.)

Diagnosis Treatment Follow-up

Suggested workflow on how to reduce post biopsy infections.

1. Two systematic reviews including non-RCTs and two RCTs describe comparable rates of post-biopsy infection in
patients with and without antibiotic prophylaxis.
2. Be informed about local antimicrobial resistance.
3. Banned by European Commission due to side effects.
4. Contradicts principles of Antimicrobial Stewardship.
5. Fosfomycin trometamol (4 RCTs), cephalosporins (2 RCTs), aminoglycosides (2 RCTs).
6. Only one RCT comparing targeted and augmented prophylaxis.
7. Originally introduced to use alternative antibiotics in case of fluoroquinolone resistance.
8. Various schemes: fluoroquinolone plus aminoglycoside (4 RCTs); and fluoroquinolone plus cephalosporin
(1 RCT).

High certainty: ( ) very confident that the true effect lies close to that of the estimate of the effect. Moderate
certainty: ( ) moderately confident in the effect estimate: the true effect is likely to be close to the estimate
of the effect, but there is a possibility that it is substantially different. Low certainty: ( ) confidence in the
effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low
certainty: ( ) very little confidence in the effect estimate: the true effect is likely to be substantially different
from the estimate of effect. Figure adapted from Pilatz et al., [396] with permission from Elsevier.

* The indication of fosfomycin trometamol for prostate biopsy has been withdrawn in Germany as the
manufacturers did not submit the necessary pharmacokinetic data in support of this indication. Urologists are
advised to check their local guidance in relation to the use of fosfomycin trometamol for prostate biopsy.

44 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

5.6.5 Complications
Complications of TRUS biopsy are listed in Table 5.9 [399]. Mortality after prostate biopsy is extremely rare
and most are consequences of sepsis [400]. Low-dose aspirin is not an absolute contra-indication [401]. A SR
found favourable infection rates for transperineal compared to TRUS biopsies with similar rates of haematuria,
haematospermia and urinary retention [402]. A meta-analysis of 4,280 men randomised between transperineal
vs. TRUS biopsies in thirteen studies found no significant differences in complication rates; however, data on
sepsis compared only 497 men undergoing TRUS biopsy to 474 having transperineal biopsy. The transperineal
approach required more (local) anaesthesia [403].

Table 5.9: Adverse events of three groups of targeted biopsy [399] *

Overall Transrectal Transperineal Transrectal p value

(n = 234) MRI-TB (n = 77) FUS-TB (n = 79) COG-TB (n = 78)
Clavien-Dindo grade - - - - < 0.001
No adverse events 30.3 (71) 47.4 (36) 29.1 (23) 15.4 (12) -
Grade 1 63.2 (148) 50.0 (38) 65.8 (52) 74.4 (58) -
Grade 2 6.0 (14) 2.6 (2) 5.1 (4) 10.3 (8) -
Grades 3, 4, 5 - - - - -
Haematuria 53.4 (125) 35.5 (27) 50.6 (40) 74.4 (58) < 0.001
Haematospermia 37.2 (87) 26.3 (20) 35.4 (28) 50.0 (39) < 0.01
Rectal bleeding 3.4 (8) 2.6 (2) 2.5 (2) 5.1 (4) 0.59
UTI 3.4 (8) 2.6 (2) 1.3 (1) 6.4 (5) 0.21
Fever 3 (7) 1.3 (1) 2.5 (2) 5.1 (4) 0.46
Urinary retention 3 (7) - 3.8 (3) - 0.15
Haematoma 1.3 (3) - 3.8 (3) - 0.29
Other - - - - 0.56
Lower back pain 0.9 (2) 1.3 (1) 1.3 (1) - -
Atrial fibrilation 0.4 (1) - 1.3 (1) - -
COG-TB = cognitive registration TRUS targeted biopsy; FUS-TB = MRI-TRUS fusion targeted biopsy; MRI = magnetic
resonance imaging; MRI-TB = in-bore MRI targeted biopsy; TB = targeted biopsy; TRUS = transrectal ultrasound; UTI
= urinary tract infection. Data are presented as % (n).
*With permission by Elsevier.

5.7 What diagnostic pathway in clinical practice?

The ‘combined pathway’, in which patients with a positive MRI undergo combined systematic and targeted
biopsy, and patients with a negative MRI undergo systematic biopsy, maximises the detection of ISUP GG
≥ 2 cancers. However, it has the disadvantage of leading to a greater detection of ISUP GG 1 cancers and of
referring all patients with a clinical suspicion of cancer to biopsy. Given the growing concerns about over-
detection of insignificant PCa, the development of AS protocols in patients with ISUP GG 2 cancers (see section
6.2.1.2) and the grade shift induced by MRI-targeted biopsy (see section 5.5.6) the clinical relevance of a
diagnostic strategy aimed only at maximising the detection of ISUP GG ≥ 2 cancers, disregarding its negative
effects, is questionable [404, 405].
The ‘MRI pathway’, in which patients with a positive MRI undergo only MRI-targeted biopsy and
patients with a negative MRI are not biopsied at all, could avoid biopsy in 21-49% of the patients if a PI-RADS
threshold of ≥ 3 is used to trigger biopsy [126, 208, 210, 314], at the cost of missing some significant cancers,
especially in biopsy-naïve patients or in highly selected populations with high prevalence of csPCa (in which the
MRI NPV decreases) [311, 406].
Adding perilesional sampling to targeted biopsy could mitigate the drawbacks of the ‘MRI pathway’
by maintaining good detection of csPCa while decreasing the over-diagnosis of insignificant cancer (see section
5.5.4). Due to the low NPV of MRI in high risk populations, systematic biopsies are still necessary in patients
with negative MRI and high clinical suspicion of PCa e.g., high PSA density.
MRI-directed pathways were compared to the classical combined pathway in a retrospective cohort
of 499 men. The highest clinical utility above a risk threshold of 6.25% was obtained by a risk-based pathway
in which patients with a PI-RADS score of 1-3 and a low-risk profile (PSA-D < 0.15 ng/ml/cc, negative DRE,
no family history, no ASAP or ISUP1 cancer at prior biopsy) could forgo biopsy while the others underwent

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 45

combined systematic and MRI-targeted biopsy. In this pathway, biopsy could have been avoided in 99 men
(19%) while missing ISUP GG ≥ 2 cancers in only six men (1.2%) [407].

5.7.1 Repeat biopsy after negative biopsy

During follow-up after a negative systematic biopsy, the incidence of PCa is higher, but the risk of PCa death is
lower than the population average [408]. Men with prior negative systematic biopsy and persistent suspicion of
PCa should have an MRI if not already performed.
Significant PCa may still be present in men with abnormal MRI and negative targeted biopsy [409].
Therefore, follow-up or direct repeat biopsy should be considered depending on risk factors (e.g., PSA density,
PI-RADS score).
In a contemporary series of biopsies the likelihood of finding a csPCa after follow-up biopsy after
a diagnosis of atypical small acinar proliferation and high-grade PIN was only 6-8%, not significantly different
from follow-up biopsies after a negative biopsy [410, 411]. Therefore, routine re-biopsies in this setting are not
needed.
The added value of other biomarkers remains unclear (see sections 5.2.5.1 and 5.2.5.2).

5.7.2 Saturation biopsy

The incidence of PCa detected by saturation repeat biopsy (> 20 cores) is 30–43% and depends on the number
of cores sampled during earlier biopsies [412]. Saturation biopsy may be performed with the transperineal
technique, which detects an additional 38% of PCa. The rate of urinary retention varies substantially from 1.2%
to 10% [257, 413].
However, given the very low risk of subsequent csPCa after a negative biopsy and/or in case of
negative MRI, the clinical utility of saturation biopsy in the repeat biopsy setting remains uncertain in the current
MRI-driven diagnostic pathway and such schemes should not be routinely used [414].

5.7.3 Seminal vesicle biopsy

Indications for SV (staging) biopsies are poorly defined. At a PSA of > 15 ng/mL, the odds of tumour
involvement are 20–25% [415]. A SV staging biopsy is only useful if it has a decisive impact on treatment, such
as ruling out radical tumour resection or for potential subsequent RT. Its added value compared with MRI is
questionable.

5.7.4 Transition zone biopsy

Transition zone sampling during baseline biopsies has a low detection rate and should be limited to MRI
detected lesions or repeat template biopsies [416].

5.8 Diagnosis - Clinical Staging

5.8.1 T-staging
The cT category listed in Table 4.1 (TNM Classification) only relies on DRE findings. Imaging parameters and
biopsy results for local staging are, so far, not part of the T staging (within TNM) and the EAU risk category
stratification [417].

5.8.1.1 Ultrasound-based techniques and Computed Tomography

Transrectal US has limited accuracy for PCa local staging [418]. More advanced US-based techniques have not
yet been tested in large-scale studies. In case of locally-advanced cancers, abdominopelvic US or CT may show
rectal or bladder invasion and dilatation of the upper collecting systems [418].

5.8.1.2 Magnetic Resonance Imaging

T2-weighted imaging remains the most useful method for local staging on MRI. Pooled data from a meta-
analysis showed a sensitivity and specificity of 0.57 (95% CI: 0.49–0.64) and 0.91 (95% CI: 0.88–0.93), 0.58
(95% CI: 0.47–0.68) and 0.96 (95% CI: 0.95–0.97), and 0.61 (95% CI: 0.54–0.67) and 0.88 (95% CI: 0.85–0.91),
for EPE, SVI, and overall stage T3 assessment, respectively [419]. Similar results, with low sensitivity and good
specificity have also been found in more recent large series [420, 421].

In 552 men treated by RP at seven different Dutch centres, MRI showed significantly higher sensitivity (51% vs.
12%; p < 0.001), and lower specificity (82% vs. 97%; p < 0.001) than DRE for non-organ confined disease. All risk
groups redefined using MRI findings rather than DRE findings showed better BCR-free survival due to improved
discrimination and the Will Roger’s phenomenon [422].

46 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Traditionally, EPE/SVI is assessed visually using qualitative signs (e.g., capsular disruption, visible tumour
within peri-prostatic fat). Inter-reader agreement with such subjective reading is moderate, with kappa (k) values
ranging from 0.41 to 0.68 [423]. The length of tumour capsule contact (LCC) is also a significant predictor of
EPE; it has the advantage of being quantitative, although the ideal cut-off value remains debated [424, 425].

Several grading systems combining subjective qualitative signs and/or LCC into a score have shown good
sensitivity (0.64 - 0.82) and specificity (0.64 - 0.93) for EPE, with substantial inter-reader agreement (κ = 0.56 -
0.74). None of these scores has shown definitive superiority over the others [426, 427].

Magnetic resonance imaging findings can improve the prediction of the pathological stage when combined with
clinical and biopsy data. As a result, several groups developed multi-variate risk calculators for predicting EPE/
SVI or positive surgical margins [428]. In external validation cohorts, these risk calculators showed significantly
better discrimination than nomograms without MRI-based features [429-431]. In one study of 604 patients who
underwent RP at a single centre, the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) model
obtained similar results in predicting BCR after RP when the pathological EPE or SVI data were replaced by MRI-
based EPE or SVI assessment. Additionally, among the patients with pathological T3 disease, RFS was better for
those without T3 disease on MRI than for those with T3 disease [421].

Given its low sensitivity for focal (microscopic) EPE, MRI is not recommended for local staging in low-risk
patients. However, MRI can still be useful for treatment planning.

5.8.2 N-staging
5.8.2.1 Computed tomography and MRI
Abdominal CT and T1-T2-weighted MRI indirectly assess nodal invasion by using LN diameter and morphology.
However, the size of non-metastatic LNs varies widely and may overlap the size of LN metastases. Usually, LNs
with a short axis > 8 mm in the pelvis and > 10 mm outside the pelvis are considered malignant. Decreasing
these thresholds improves sensitivity but decreases specificity. As a result, the ideal size threshold remains
unclear [432, 433]. Computed tomography and MRI sensitivity is less than 40% [434, 435]. Detection of
microscopic LN invasion by CT is < 1% in patients with ISUP grade group < 4 cancer, PSA < 20 ng/mL, or
localised disease [432, 436].

Diffusion-weighted MRI (DW-MRI) may detect metastases in normal-sized nodes, but a negative DW-MRI cannot
rule out the presence of LN metastases, and DW-MRI provides only modest improvement for LN staging over
conventional imaging [437].

5.8.2.2 Risk calculators incorporating MRI findings and clinical data

Computed tomography and MRI lack sensitivity for direct detection of positive LNs, and as a consequence,
nomograms combining clinical data, systematic or MRI-targeted biopsy results and, for some of them, MRI
findings have been used to estimate the risk of patients harbouring positive LNs. Several underwent external
validation [438-442]. However, they tend to show limited specificity, and a substantial proportion of patients may
still be submitted to unnecessary LND, especially when the LNI prevalence is low.

5.8.2.3 Choline PET/CT

In a meta-analysis of 609 patients, pooled sensitivity and specificity of choline PET/CT for pelvic LN metastases
were 62% (95% CI: 51–66%) and 92% (95% CI: 89–94%), respectively [443]. In a prospective trial of 75 patients
at intermediate risk of nodal involvement (10–35%), the sensitivity was only 8.2% at region-based analysis and
18.9% at patient-based analysis, which is too low to be of clinical value [444]. The sensitivity of choline PET/CT
increases to 50% in patients at high risk and to 71% in patients at very high risk [445]. The ability of choline PET/
CT to identify LN (and distant) metastases at initial staging was recently assessed, in a prospective controlled,
open, 1:1 randomised multicentre phase III trial, including 236 patients [446]. In the experimental arm (i.e.,
conventional imaging and choline PET/CT), the sensitivity for LN metastases, confirmed by pathology and serial
PSA evaluations, was higher than in the control (conventional imaging only) arm, 77.78% vs. 28.57% and 65.62%
vs. 17.65%, respectively.

5.8.2.4 Prostate-specific membrane antigen-based PET/CT

Prostate-specific membrane antigen PET/CT, radiolabelled with 68Ga or 18F ligands, is an attractive target
because of its specificity for prostate tissue, even if the expression in other non-prostatic malignancies or
benign conditions may cause incidental false-positive findings [447, 448].

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A multi-centre prospective phase III imaging trial, investigating men with intermediate- and high-risk PCa who
underwent RP and PLND, showed a sensitivity and specificity of 68Ga-PSMA-11 PET of 0.40 (95% CI: 0.34-0.46),
and 0.95 (95% CI: 0.92-0.97), respectively [449]. This is line with previous results from prospective, multi-centre
studies addressing the accuracy of 68Ga-PSMA and 18F-DCFPyL PET/CT for LN staging in patients with newly
diagnosed PCa [450-452]. Prostate-specific antigen may be a predictor of a positive PSMA PET/CT. In the
primary staging cohort from a meta-analysis, however, no robust estimates of positivity were found [453].

Comparison between PSMA PET/CT and MRI was performed in a SR and meta-analysis including thirteen
studies (n = 1,597) [454]. 68Ga-PSMA was found to have a higher sensitivity and a comparable specificity for
staging pre-operative LN metastases in intermediate- and high-risk PCa [455].
Prostate specific membrane antigen PET/CT has a good sensitivity and specificity for LN
involvement, possibly impacting clinical decision-making. In a review and meta-analysis including 37 articles, a
subgroup analysis was performed in patients undergoing PSMA PET/CT for primary staging. On a per-patient-
based analysis, the sensitivity and specificity of 68Ga-PSMA PET were 77% and 97%, respectively, after eLND at
the time of RP. On a per-lesion based analysis, sensitivity and specificity were 75% and 99%, respectively [453].
In summary, PSMA PET/CT is more sensitive in N-staging as compared to MRI, abdominal contrast-
enhanced CT or choline PET/CT. However, small LN metastases, under the spatial resolution of PET, may still be
missed.

5.8.2.5 Risk calculators incorporating MRI and PSMA findings

An international, multi-centre study incorporated PSMA PET into existing nomograms in order to predict
pelvic LN metastatic disease in PCa patients. Performance of three nomograms was assessed in 757
patients undergoing RARP and ePLND. Addition of PSMA PET to the nomograms substantially improved the
discriminative ability of the models yielding cross-validated AUCs of 0.76 (95% CI: 0.70–0.82), 0.77 (95%
CI: 0.72–0.83), and 0.82 (95% CI: 0.76–0.87), respectively [456]. The same group developed a nomogram
incorporating staging MRI and PSMA PET findings to predict LN metastases in a contemporary cohort of 700
patients from the Netherlands, who underwent RP and ePLND. The nomogram was then tested in 305 patients
who underwent RP and ePLND at two centres in Australia. On this external cohort, the nomogram performed
significantly better than the Briganti 2017 and the MSKCC nomograms. Its performance was similar to that of
the Briganti 2019 nomogram [457]. However, given the excellent specificity of PSMA PET, it remains unclear
whether a nomogram is required in PSMA PET positive patients.

5.8.2.6 Surgical techniques

5.8.2.6.1 Pelvic lymph node dissection
Extended PLND includes removal of the nodes overlying the external iliac artery and vein, the nodes within the
obturator fossa located cranially and caudally to the obturator nerve, and the nodes medial and lateral to the
internal iliac artery. As such, ePLND provides accurate information for staging and prognosis [458]. However,
a SR has demonstrated that performing PLND during RP failed to improve oncological outcomes, including
survival [536]. Moreover, two RCTs have failed to show a benefit of an extended approach vs. a limited PLND on
early oncologic outcomes [459-461].

5.8.2.6.2 Lymph-node-positive patients during radical prostatectomy

Although no RCTs are available, data from prospective cohort studies comparing survival of pN+ patients
(as defined following pathological examination after RP) support that RP may have a survival benefit over
abandonment of RP in node-positive cases [462]. As a consequence, there is no role for performing frozen
section of suspicious LNs.

5.8.2.6.3 Sentinel node biopsy analysis

The rationale for a sentinel node biopsy (SNB) is based on the concept that a sentinel node is the first to be
involved by migrating tumour cells. Therefore, when this node is negative it is possible to avoid an ePLND [463].
Intraprostatic injections of indocyanine green (ICG) have been used to visualise prostate-related LNs for SNB.
A randomised comparison found more cancer-containing LNs in men who underwent a PLND guided by ICG
but no difference in BCR at 22.9-month follow-up [464]. A SR of 21 studies showed a sensitivity of 95.2% and
NPV of 98.0% for SNB, in detecting men with metastases at ePLND [465]. However, this review was hampered
by widespread heterogeneity of both definitions and how SNB is performed. This prompted the development of
an expert consensus report to guide further research [463]. A randomised trial reported on ICG-only PLND (ICG-
stained lymph nodes only, following pre-operative injection of ICG into bilateral transition zones) compared to
ePLND in 108 patients undergoing RP following staging with conventional imaging [466]. Operative time, lymph
node counts (median 24 vs. 7) and post-operative lymphoedema (RR: 4.75, p < 0.05) were higher in the ePLND
group but pN1 (ePLND 22% vs. ICG-PLND 28%, p = 0.7) and 24-month BCR-free survival (ePLND 83% vs. ICG-
PLND 75%, p = 0.58) rates were similar between the groups.

48 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

The prospective SENTINELLE study investigated the diagnostic accuracy of sentinel lymph node biopsy-guided
lymph node dissection (following intraprostatic injection of (99m)Tc-nanocolloid) compared to extended pelvic
LN dissection in patients with intermediate- or high-risk prostate cancer. Sensitivity, specificity, NPV, and PPV
of SNB method in detecting patients with at least one LN metastasis were 95.4% (95% CI: 75.1-99.7), 100%
(95% CI: 96.6-100), 99.2% (95% CI: 95.5-99.9), and 100% (95% CI: 80.7-100), respectively [545].

An emerging alternative to sentinel node removal following intraprostatic injections is PSMA-guided lymph node
dissection following intravenous radioisotope injection and intraoperative radio guidance or optical guidance
[467]. Initial studies report high specificity approaching 100% although limited sensitivity and associated poor
negative predictive value restrict the functional value at this point.

5.8.2.6.4 Complications of extended pelvic lymph node dissection

Extended PLND increases morbidity in the treatment of PCa [458]. Overall complication rates of 19.8% vs.
8.2% were noted for ePLND vs. limited PLND, respectively, with lymphoceles (10.3% vs. 4.6%) being the most
common adverse event (AE). Other authors have reported lower complication rates [468]. Another study [469]
also showed more complications after extended compared to limited PLND. Twenty percent of men suffer a
complication of some sort after ePLND. Thromboembolic events occur in less than 1% of cases overall, but the
RR of DVT and PE associated with PLND has been found to be 7.8 and 6.3, respectively [470].

Lymphocoele complicating ePLND may be reduced by incorporation of peritoneal interposition flap, with a SR
of RCTs reporting reduced symptomatic lymphocoele (OR: 0.46), overall lymphocoele (OR: 0.51) and Clavien-
Dindo ≥ 3 complications (OR: 0.41) without major function impairment [471]. The PELYCAN trial (n = 551) further
confirmed the benefits of bilateral peritoneal interposition flaps compared to no flap in reducing symptomatic
lymphocoele (3.7% vs. 9.1%, p = 0.005) and asymptomatic lymphocoele (10.3% vs. 27.2%, p < 0.001) without
compromise in postoperative complications at the expense of longer operating time (11 minutes, p < 0.001)
[472].

5.8.3 M-staging
5.8.3.1 Bone scan
99mTc-Bone scan is a highly sensitive conventional imaging technique, evaluating the distribution of active

bone formation in the skeleton related to malignant and benign disease. A meta-analysis showed combined
sensitivity and specificity of 79% (95% CI: 73–83%) and 82% (95% CI: 78–85%) at patient level [473]. Bone
scan diagnostic yield is significantly influenced by the PSA level, the clinical stage and the tumour ISUP
grade group [432, 474]. A retrospective study investigated the association between age, PSA and GS in 703
newly diagnosed PCa patients who were referred for bone scintigraphy. The incidence of bone metastases
increased substantially with rising PSA and upgrading GS [475]. In two studies, a dominant Gleason pattern
of 4 was found to be a significant predictor of positive bone scan [476, 477]. Bone scanning should be
performed in symptomatic patients, independent of PSA level, ISUP GG or clinical stage [432]. Nevertheless,
bone scintigraphy reveals lower specificity (64.5%) and positive predictive value (55.4%), with a relatively low
interobserver agreement [478]. Additional single-photon emission computed tomography (SPECT) using 99mTc-
diphosphonates may overcome these limitations, by improved discrimination of benign and equivocal findings.
In a multicentre phase 3 trial in patients with high-risk prostate or breast cancer, SPECT exhibited a sensitivity,
specificity, and PPV of 63.3%, 87.5%, and 78.4%, respectively [479].

5.8.3.2 Fluoride PET/CT, choline PET/CT and MRI

18F-sodium fluoride (18F-NaF) PET or PET/CT, similarly to bone scintigraphy, only assesses the presence of bone

metastases. The tracer was reported to have similar specificity and superior sensitivity to bone scintigraphy for
detecting bone metastases in patients with newly diagnosed high-risk PCa [480, 481]. Interobserver agreement
for the detection of bone metastases was excellent, demonstrating that 18F-NaF PET/CT is a robust tool for the
detection of osteoblastic lesions in patients with PCa [482]. Results of a prospective randomised multicentre
study showed that Choline PET/CT has a superior per-patient diagnostic accuracy, compared to conventional
imaging alone, in men with intermediate- and high-risk PCa [446]. This is in line with previous data [483-485].
Choline PET/CT has also the advantage of detecting visceral and nodal metastases.
Diffusion-weighted whole-body and axial skeleton MRI are more sensitive than bone scan and
targeted conventional radiography in detecting bone metastases in high-risk PCa. Whole-body MRI can also
detect visceral and nodal metastases; it was shown to be more sensitive and specific than combined bone
scan, targeted radiography and abdominopelvic CT [486]. A meta-analysis found that whole-body MRI is more
sensitive than choline PET/CT and bone scan for detecting bone metastases on a per-patient basis, although
choline PET/CT had the highest specificity [473].

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 49

5.8.3.3 PSMA PET/CT
A SR including twelve studies (n = 322) reported high variation in 68Ga-PSMA PET/CT sensitivity for initial
staging (range 33–99%; median sensitivity on per-lesion analysis 33–92%, and on per-patient analysis 66–91%),
with good specificity (per-lesion 82–100%, and per-patient 67–99%), with most studies demonstrating
increased detection rates with respect to conventional imaging modalities (bone scan and CT) [487].

In a prospective multi-centre study in patients with high-risk PCa before curative surgery or RT (proPSMA),
302 patients were randomly assigned to conventional imaging or 68Ga-PSMA-11 PET/CT [488]. The primary
outcome focused on the accuracy of first-line imaging for the identification of pelvic LN or distant metastases.
Accuracy of 68Ga-PSMA PET/CT was 27% (95% CI: 23–31) higher than that of CT and bone scintigraphy (92%
[95% CI: 88–95] vs. 65% [95% CI: 60–69]; p < 0.0001). Conventional imaging had a lower sensitivity (38% [95%
CI: 24–52] vs. 85% [95% CI: 74–96]) and specificity (91% [95% CI: 85–97] vs. 98% [95% CI: 95–100]) than PSMA
PET/CT. Furthermore, 68Ga-PSMA PET/CT scan prompted management change more frequently as compared
to conventional imaging (41 [28%] men [95% CI: 21–36] vs. 23 [15%] men [95% CI: 10–22], p = 0.08), with less
equivocal findings (7% [95% CI: 4–13] vs. 23% [95% CI: 17–31]) and lower radiation exposure (8.4 mSv vs. 19.2
mSv; p < 0.001) [488].The comparison of whole body MRI and PSMA PET/CT in detecting bone metastases has
led to inconclusive opposite results in two small cohorts [455, 489].

The added prognostic value of presurgical PSMA-PET for BCR-Free Survival (FS), compared with the presurgical
Cancer of the Prostate Risk Assessment (CAPRA) and postsurgical CAPRA-Surgery (CAPRA-S) scores, in
patients with intermediate- to high risk PCa treated with RP and PLND has been investigated [490]. During a
32 mo (interquartile range 23.3–42.9) follow-up, 91/240 (38%) BCR events were observed. The addition of
PSMA-PET N1/M1 status to the presurgical CAPRA score improved the risk assessment for BCR significantly, in
comparison with the presurgical CAPRA score alone (c-statistic 0.70 [0.64–0.75] vs 0.63 [0.57–0.69]; p < 0.001).

5.8.4 Summary of evidence and practical considerations on initial N/M staging

The field of non-invasive N- and M-staging of PCa patients is evolving very rapidly. Evidence shows that choline
PET/CT, PSMA PET/CT and whole-body MRI provide a more sensitive detection of LN- and bone metastases
than the classical work-up with bone scan and abdominopelvic CT. First results of a follow-up study of the
surgical cohort in the multicentre prospective phase 3 imaging trial demonstrate that presurgical PSMA-PET
is a strong prognostic biomarker, improving BCR-FS risk assessment [490]. However, the ideal management of
patients diagnosed as metastatic by these more sensitive tests is yet unknown [492].

5.8.5 Recommendations for staging of prostate cancer

Recommendations Strength rating

Any risk group staging
Use pre-biopsy magnetic resonance imaging (MRI) for local staging information. Weak
Low-risk localised disease
Do not use additional imaging for staging purposes. Strong
Intermediate-risk disease
For patients with International Society of Urological Pathology (ISUP) grade group 3 disease Weak
perform prostate-specific antigen-positron emission tomography/computed tomography
(PSMA-PET/CT) if available to increase accuracy or at least cross-sectional abdominopelvic
imaging and a bone-scan.
High-risk localised disease/locally advanced disease
Perform metastatic screening using PSMA-PET/CT if available or at least cross-sectional Strong
abdominopelvic imaging and a bone-scan.

50 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

6. TREATMENT
This chapter reviews the available treatment modalities, followed by separate sections addressing treatment for
the various disease stages.

6.1 Estimating life expectancy and health status

6.1.1 Introduction
Evaluation of life expectancy and health status is important in clinical decision-making for early detection,
diagnosis, and treatment of PCa. Prostate cancer is common in older men (median age 68 years) and diagnoses in
men > 65 years will result in a 70% increase in annual diagnosis by 2030 in Europe and the USA [493, 494].
Active treatment mostly benefits patients with intermediate- or high-risk PCa and longest expected
survival. In localised disease, over ten years life expectancy is considered mandatory for any benefit from local
treatment and an improvement in CSS may take longer to become apparent. Older age and worse baseline health
status have been associated with a smaller benefit in PCSM and life expectancy of surgery vs. AS [495]. Although
in a RCT the benefit of surgery with respect to death from PCa was largest in men < 65 years of age (RR: 0.45), RP
was associated with a reduced risk of metastases and use of androgen deprivation therapy (ADT) also among
older men (RR: 0.68 and 0.60, respectively) [496]. External beam RT shows similar cancer control regardless of age,
assuming a dose of > 72 Gy when using intensity-modulated or image-guided RT [497].
Older men have a higher incidence of PCa and may be under-treated despite the high overall mortality
rates [498, 499]. Of all PCa-related deaths 71% occur in men aged > 75 years [500], probably due to the higher
incidence of advanced disease and death from PCa despite higher death rates from competing causes [501-
503]. In the USA, only 41% of patients aged > 75 years with intermediate- and high-risk disease received curative
treatment compared to 88% aged 65–74 [504].

6.1.2 Life expectancy

Life expectancy tables for European men are available online: https://ec.europa.eu/eurostat/. Survival may
be variable and therefore estimates of survival must be individualised. Gait speed is a good single predictive
method of life expectancy (from a standing start, at usual pace, generally over 6 meters). For men at age 75, ten-
year survival ranged from 19% < 0.4 m/s to 87%, for ≥ 1.4 m/s [505].

Figure 6.1: Predicted Median Life Expectancy by Age and Gait Speed for males* [505]

*Figure reproduced with permission of the publisher, from Studenski S, et al. JAMA 2011 305(1)50.

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 51

6.1.3 Health status screening
Heterogeneity in performance increases with advancing age, so it is important to use measures other than
just age or performance status (PS) when considering treatment options. The International SIOG PCa Working
Group recommends that treatment for adults over 70 years of age should be based on a systematic evaluation
of health status using the G8 (Geriatric 8) screening tool (Table 6.1.1) [146]. This tool helps to discriminate
between those who are fit and those with frailty, a syndrome of reduced ability to respond to stressors.
Patients with frailty have a higher risk of mortality and negative side effects of cancer treatment [506]. Healthy
patients with a G8 score > 14 or vulnerable patients with reversible impairment after resolution of their geriatric
problems should receive the same treatment as younger patients. Frail patients with irreversible impairment
should receive adapted treatment. Patients who are too ill should receive only palliative treatment (see Figure
5.3) [146]. Patients with a G8 score ≤ 14 should undergo a comprehensive geriatric assessment (CGA) as this
score is associated with three-year mortality. A CGA is a multi-domain assessment that includes co-morbidity,
nutritional status, cognitive and physical function, and social supports to determine if impairments are reversible
[507]. A SR of the effect of geriatric evaluation for older cancer patients showed improved treatment tolerance
and completion [508].
The Clinical Frailty Scale (CFS) is another screening tool for frailty (see Figure 5.4) [509]. Although
not frequently used in the cancer setting, it is considered to be a common language for expressing degree of
frailty. The scale runs from one to nine, with higher scores indicating increasing frailty. Patients with a higher
CFS score have a higher 30-day mortality after surgery and are less likely to be discharged home [510].
It is important to use a validated tool to identify frailty, such as the G8 or CFS, as clinical judgement
has been shown to be poorly predictive of frailty in older patients with cancer [511].

6.1.3.1 Co-morbidity
Co-morbidity is a major predictor of non-cancer-specific death in localised PCa treated with RP and is more
important than age [512, 513]. Ten years after watchful waiting for PCa, most men with a high co-morbidity
score had died from competing causes, irrespective of age or tumour aggressiveness [512]. Measures for
co-morbidity include: Cumulative Illness Score Rating-Geriatrics (CISR-G) [514, 515] (Table 6.1.2) and Charlson
Co-morbidity Index (CCI) [516].

6.1.3.2 Nutritional status

Malnutrition can be estimated from body weight during the previous three months (good nutritional status < 5%
weight loss; risk of malnutrition: 5–10% weight loss; severe malnutrition: > 10% weight loss) [517].

6.1.3.3 Cognitive function

Cognitive impairment can be screened for using the mini-COG (https://mini-cog.com/) which consists of three-
word recall and a clock-drawing test and can be completed within five minutes. A score of ≤ 3/5 indicates
the need to refer the patient for full cognitive assessment. Patients with any form of cognitive impairment
(e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability to make an informed
decision, which is an increasingly important factor in health status assessment [518-520]. Cognitive impairment
also predicts risk of delirium, which is important for patients undergoing surgery [521].

6.1.3.4 Physical function

Measures for overall physical functioning include: Karnofsky score and ECOG scores [522]. Measures for
dependence in daily activities include Activities of Daily Living (ADL; basic activities) and Instrumental Activities
of Daily Living (IADL; activities requiring higher cognition and judgement) [523-525].

6.1.3.5 Shared decision-making

The patient’s own values and preferences should be considered as well as the above factors. A shared decision-
making process also involves anticipated changes to QoL, functional ability, and a patient’s hopes, worries and
expectations about the future [526]. Particularly in older and frail patients, these aspects should be given equal
importance to disease characteristics during the decision-making process [527]. Older patients may also wish to
involve family members, and this is particularly important where cognitive impairment exists.

6.1.4 Conclusion
Individual life expectancy, health status, frailty, and co-morbidity, not only age, should be central in clinical
decisions on screening, diagnostics, and treatment for PCa. A life expectancy of ten years is most commonly
used as a threshold for benefit of local treatment. Older men may be undertreated. Patients aged 70 years of
age or older who have frailty should receive a comprehensive geriatric assessment. Resolution of impairments
in vulnerable men allows a similar urological approach as in fit patients.

52 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Table 6.1.1: G8 screening tool (adapted from [528])

Items Possible responses (score)

A Has food intake declined over the past three 0 = severe decrease in food intake
months due to loss of appetite, digestive 1 = moderate decrease in food intake
problems, chewing, or swallowing difficulties?
2 = no decrease in food intake
B Weight loss during the last three months? 0 = weight loss > 3 kg
1 = does not know
2 = weight loss between 1 and 3 kg
3 = no weight loss
C Mobility? 0 = bed or chair bound
1 = able to get out of bed/chair but does not go out
2 = goes out
D Neuropsychological problems? 0 = severe dementia or depression
1 = mild dementia
2 = no psychological problems
E BMI? (weight in kg)/(height in m2) 0 = BMI < 19
1 = BMI 19 to < 21
2 = BMI 21 to < 23
3 = BMI > 23
F Takes more than three prescription drugs per day? 0 = yes
1 = no
G In comparison with other people of the same 0.0 = not as good
age, how does the patient consider his/her health 0.5 = does not know
status?
1.0 = as good
2.0 = better
H Age 0 = > 85
1 = 80-85
2 = < 80
Total score 0-17

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 53

Figure 6.2: Decision tree for health status screening (men > 70 years)** [146]

Screening with G8 and mini-COGTM

G8 score > 14/17 G8 score ≤ 14/17

no geriatric a full geriatric
evaluation is evaluation is
needed mandatory

- Abnormal ADL: 1 or 2 - Abnormal ADL: ≥ 2

- Weight loss 5-10% - Weight loss > 10%
- Comorbidities CISR-G - Comorbidities CISR-G
grades 1-2 grades 3-4

Geriatric assessment
then geriatric intervention

Group 1 Group 2 Group 3

Fit Vulnerable Frail
Diagnosis Treatment Follow-up

Mini-COGTM = Mini-COGTM cognitive test; ADLs = activities of daily living; CIRS-G = Cumulative Illness
Rating Score - Geriatrics; CGA = comprehensive geriatric assessment.
* For Mini-COGTM, a cut-off points of ≤ 3/5 indicates a need to refer the patient for full evaluation of potential
dementia.
**Reproduced with permission of Elsevier, from Boyle H.J., et al. Eur J Cancer 2019:116; 116 [146].

54 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Figure 6.3: The Clinical Frailty Scale version 2.0 [509]*

CLINICAL FRAILTY SCALE 6 LIVING

WITH
People who need help with all outside
activities and with keeping house.
MODERATE Inside, they often have problems with
stairs and need help with bathing and
1 VERY People who are robust, active, energetic
FIT and motivated. They tend to exercise
FRAILTY might need minimal assistance (cuing,
standby) with dressing.
regularly and are among the fittest for
their age.
7 LIVING
WITH
Completely dependent for personal
care, from whatever cause (physical or
2 FIT People who have no active disease
symptoms but are less fit than category
SEVERE
FRAILTY
cognitive). Even so, they seem stable
and not at high risk of dying (within ~6
1. Often, they exercise or are very active months).
occasionally, e.g., seasonally.
8 LIVING Completely dependent for personal care

3 MANAGING People whose medical problems are

WELL well controlled, even if occasionally
WITH VERY
SEVERE
and approaching end of life. Typically,
they could not recover even from a
symptomatic, but often are not FRAILTY minor illness.
regularly active beyond routine walking.
9 TERMINALLY Approaching the end of life. This
4 LIVING
WITH
Previously “vulnerable,” this category
marks early transition from complete
ILL category applies to people with a life
expectancy <6 months, who are not
VERY MILD independence. While not dependent on otherwise living with severe frailty.
(Many terminally ill people can still
FRAILTY others for daily help, often symptoms
exercise until very close to death.)
limit activities. A common complaint
is being “slowed up” and/or being tired
during the day. SCORING FRAILTY IN PEOPLE WITH DEMENTIA
The degree of frailty generally In moderate dementia, recent memory is
5 LIVING
WITH
People who often have more evident
slowing, and need help with high
corresponds to the degree of
dementia. Common symptoms in
very impaired, even though they seemingly
can remember their past life events well.
mild dementia include forgetting They can do personal care with prompting.
MILD order instrumental activities of daily
the details of a recent event, though In severe dementia, they cannot do
FRAILTY living (finances, transportation, heavy still remembering the event itself, personal care without help.
housework). Typically, mild frailty repeating the same question/story
In very severe dementia they are often
progressively impairs shopping and and social withdrawal.
bedfast. Many are virtually mute.
walking outside alone, meal preparation,
medications and begins to restrict light Clinical Frailty Scale ©2005–2020 Rockwood,
housework. Version 2.0 (EN). All rights reserved. For permission:
www.geriatricmedicineresearch.ca
Rockwood K et al. A global clinical measure of fitness
www.geriatricmedicineresearch.ca and frailty in elderly people. CMAJ 2005;173:489–495.

*Permission to reproduce the CFS was granted by the copyright holder.

Table 6.2: Cumulative Illness Score Rating-Geriatrics (CISR-G)

1 Cardiac (heart only)

2 Hypertension (rating is based on severity; affected systems are rated separately)
3 Vascular (blood, blood vessels and cells, marrow, spleen, lymphatics)
4 Respiratory (lungs, bronchi, trachea below the larynx)
5 ENT (eye, ear, nose, throat, larynx)
6 Upper GI (oesophagus, stomach, duodenum. Biliar and pancreatic trees; do not include diabetes)
7 Lower GI (intestines, hernias)
8 Hepatic (liver only)
9 Renal (kidneys only)
10 Other GU (ureters, bladder, urethra, prostate, genitals)
11 Musculo-Skeletal-Integumentary (muscles, bone, skin)
12 Neurological (brain, spinal cord, nerves; do not include dementia)
13 Endocrine-Metabolic (includes diabetes, diffuse infections, infections, toxicity)
14 Psychiatric/Behavioural (includes dementia, depression, anxiety, agitation, psychosis)
All body systems are scores on a 0 - 4 scale.
- 0: No problem affecting that system.
- 1: Current mild problem or past significant problem.
- 2: Moderate disability or morbidity and/or requires first line therapy.
- 3: Severe problem and/or constant and significant disability and/or hard to control chronic problems.
- 4: Extremely severe problem and/or immediate treatment required and/or organ failure and/or
severe functional impairment.
Total score 0-56

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6.1.5 Guidelines for evaluating health status and life expectancy

Recommendations Strength rating

Use individual life expectancy, health status, and co-morbidity in PCa management. Strong
Use the Geriatric-8, mini-COG and Clinical Frailty Scale tools for health status screening. Strong
Perform a full specialist geriatric evaluation in patients with a G8 score ≤ 14. Strong
Consider standard treatment in vulnerable patients with reversible impairments (after Weak
resolution of geriatric problems) similar to fit patients, if life expectancy is > 10 years.
Offer adapted treatment or watchful waiting to patients with irreversible impairment. Weak
Offer palliative symptom-directed therapy alone to frail patients. Strong

6.2 Treatment modalities

6.2.1 Expectant management strategies
Two different strategies of expectant management exist. For PCa in which curative therapy (using surgery or
radiation) is not possible or indicated and palliative hormonal therapy not yet indicated, may be followed until
local or metastatic symptomatic progression, to delay the side effects of androgen deprivation therapy (ADT).
This strategy is referred to as watchful waiting (WW).
In patients with low- to intermediate-risk PCa, curative therapy may be postponed, or avoided
altogether, using AS. As the prevalence of cancer cells in the prostate is so much higher than the risk of
dying from PCa, together with the increased rate of early detection of small tumours after the introduction
of PSA, there is a distinct risk of over-diagnosis and subsequent over-treatment of the disease (Chapter 3.1
Epidemiology) [9, 529, 530]. At the same time all available radical PCa treatment options may cause significant
side effects. The differences between WW and AS are presented in Table 6.2.1.

Table 6.2.1: Differences between active surveillance and watchful waiting [478]

Active surveillance Watchful waiting

Treatment intent Curative Palliative
Follow-up Pre-defined schedule Patient-specific
Assessment/markers* used DRE, PSA, re-biopsy, imaging (MRI) • None (wait for symptoms); or
• Annual/biannual PSA (consider
DRE if significant PSA-rise or
imaging if metastases suspected)
Life expectancy > 10 years < 10 years
Aim Minimise curative treatment-related Minimise palliative treatment-related
toxicity without compromising (ADT) toxicity without compromising
survival, as the PCa is so indolent survival, PCa is unlikely to affect
that it is unlikely to cause lifespan.
symptoms even with long life
expectancy
Eligible patients Low- and selected intermediate-risk Can apply to patients in all risk
patients groups
DRE = digital rectal examination; PSA = prostate-specific antigen; MRI = magnetic resonance imaging.
*Molecular markers and/or PSMA-PET/CT (-MRI) may be used.

Data from studies conducted on patients who did not undergo local treatment with up to 25 years of follow-up,
with endpoints of OS and CSS, are available. Several series have shown a consistent CSS rate of 82–87% at ten
years [531, 532], and 80–95% for T1/T2 and ISUP GG ≤ 2 PCa [533]. In three studies with data beyond 15 years,
the reported CSS rates were 80%, 79% and 58% [531, 532, 534]. Two studies reported 20-year CSS rates of 57%
and 32% [531, 534]. The observed heterogeneity in outcomes is due to different inclusion criteria, with some
older studies from the pre-PSA era showing worse outcomes [534]. In addition, many patients classified as ISUP
GG 1 would now be classified as ISUP GG 2–3 based on the 2005 Gleason classification, suggesting that the
above-mentioned results should be considered as minimal and current outcomes would be more favourable.
Patients with well-, moderately- and poorly-differentiated tumours had ten-year CSS rates of 91%, 90% and 74%,
respectively, correlating with data from a pooled analysis [533]. In screen-detected localised PCa there is also a

56 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

lead-time bias, resulting in a higher rate of early detected PCa, but also an even higher risk of detecting clinically
insignificant PCa that never would have caused any symptoms [530]. Cancer specific survival from untreated
screen-detected PCa in patients with ISUP grade groups 1–2 is therefore likely to be even more favourable than
for PCa detected of other reasons. Consequently, a high proportion of men with PSA-detected PCa are suitable
for conservative management.

The high CSS rate of localised PCa requires that a life expectancy of at least ten years should be considered
mandatory for any benefit from curative treatment. Co-morbidity is as important as age in predicting life
expectancy. Increasing co-morbidity greatly increases the risk of dying from non-PCa-related causes. In an
analysis of 19,639 patients aged > 65 years who were not given curative treatment, most men with a CCI score
≥ 2 had died from competing causes at ten years follow-up regardless of their age at time of diagnosis. Tumour
aggressiveness had little impact on OS suggesting that patients could have been spared biopsy and diagnosis
of cancer. Men with a CCI score ≤ 1 had a low risk of death at ten years, especially for well- or moderately
differentiated lesions [512]. Additionally, in the ProtecT trial (see section 6.2.1.2), prostate cancer-related death
was 3% at 15 years compared to death from any cause in 21.7% of patients, numbers that have been further
validated in two large population-based studies from Canada and Sweden [535-537].
When managed with non-curative intent, intermediate-risk PCa is associated with ten-year and
fifteen-year PCSM rates of 13.0% and 19.6%, respectively [538]. These estimates are based on systematic
biopsies and may be overestimated in the era of MRI-targeted biopsies.

The overall evidence indicates that for men with asymptomatic, clinically localised PCa, and with a life
expectancy of < 10 years based on co-morbidities and/or age, the oncological advantages of active treatment
are unlikely to be relevant to them. Consequently, WW should be adopted for such patients. Estimation of
competing benefits of active vs. conservative treatment and death from any cause at ten and fifteen years
can be estimated using the PREDICT Prostate tool (https://prostate.predict.nhs.uk/), which is endorsed by the
National Institute for Health and Care Excellence in the UK [539]. This highlights the importance of assessing
co-morbidity even before considering a biopsy, but also before advising a patient with a PCa diagnosis on the
optimal treatment for him.

6.2.1.1 Watchful Waiting

Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment
from the outset and in whom palliative therapy is not yet indicated. The aim of WW is to balance the potential
harms and benefits of early hormonal treatment, and patients are clinically ‘watched’ for the development of
local or systemic progression with (imminent) disease-related symptoms, at which stage they are then treated
palliatively according to their symptoms in order to maintain QoL. Traditionally WW has meant waiting for
symptoms of the tumour to develop and has, in some practices, not included regular follow-up in any active way.
However, today we have evidence that early hormonal treatment could prolong short term survival (within a few
years) for locally advanced disease, for patients with a PSA doubling time (PSA-DT) < 12 months, and for PSA-
values over 30-50 ng/mL [540, 541]. A more active follow-up of men on WW could therefore be beneficial for
the higher risk groups, so that a local or start of metastatic spread progression (often associated with a higher
ISUP GG) can be detected before they present with significant symptoms. Hormonal treatment could then be
considered before symptoms emerge. The WW strategy should therefore be individualised and planned together
with the patient. Biannual PSA, or annual after a period of stable disease, followed by DRE or bone scan if PSA
rises significantly, could then be of value.
In a Swedish registry study of men with non-metastatic PCa on WW, after five years 66.2% of patients
with low-risk and 36.1% with high-risk disease, and after ten years 25.5% and 10.4% were still alive and not
receiving ADT [542]. At ten years, 4.1% and 10.8% had transitioned to castration-resistant disease, respectively.
Importantly, 92.3% of low-risk and 84.1% of high-risk patients died due to other causes than PCa after ten years
[542].

Watchful waiting vs. radical prostatectomy

There are two RCTs and one Cochrane review comparing the outcomes of WW to radical prostatectomy (RP).
The SPCG-4 study was a RCT from the pre-PSA era, randomising patients to either WW or RP in 695 men (24%
with nonpalpable disease) [543]. The study found RP to provide superior CSS, OS and progression-free survival
(PFS) compared to WW at a median follow-up of 23.6 years (range 3 weeks–28 years). However, the benefit in
favour of RP over WW was only apparent after ten years.
The PIVOT trial, a RCT conducted in the early PSA era, made a similar comparison between RP vs.
WW in 731 men (50% with nonpalpable disease, 42% low-risk) but in contrast to the SPCG-4, it found little, to no,
benefit of RP (cumulative incidence of all-cause death, RP vs. observation: 68% vs. 73%; RR: 0.92, 95% CI: 0.84–
1.01) within a median follow-up period of 18.6 years (interquartile range, 16.6 to 20 years) [544]. Exploratory

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 57

subgroup analysis showed that the borderline benefit from RP was most marked for intermediate-risk disease
(RR: 0.84, 95% CI: 0.73–0.98) but there was no benefit in patients with low- or high-risk disease. Overall, no
adverse effects on health related QoL (HRQoL) and psychological well-being was apparent in the first five years
[545]. However, one of the criticisms of the PIVOT trial is the relatively high overall mortality rate in the WW
group compared with more contemporary series, suggesting a selection bias.
A Cochrane review performed a pooled analysis of RCTs comparing RP vs. WW [546]. Three studies
were included; the previously mentioned SPCG-4 [543] and PIVOT [544] and the Veteran’s Administration
Cooperative Urological Research Group (VACURG) study which was conducted in the pre-PSA era [547]. The
authors found that RP compared with WW reduced time to death by any cause (HR: 0.79, 95% CI: 0.70–0.90),
time to death by PCa (HR: 0.57, 95% CI: 0.44–0.73) and time to metastatic progression (HR: 0.56, 95% CI: 0.46–
0.70) at 29 years’ follow-up. However, RP was associated with higher rates of urinary incontinence (RR: 3.97,
95% CI: 2.34–6.74) and ED (RR: 2.67, 95% CI: 1.63–4.38).

6.2.1.2 Active surveillance

Active surveillance aims to delay or completely avoid unnecessary local curative treatment (surgery/radiation),
and consequently unnecessary side effects, in men with low-risk and selected intermediate-risk PCa, and a life
expectancy of ten years or more, who do not require immediate treatment. The strategy aims to achieve the
correct timing for curative treatment in those who show reclassification during follow-up [548]. Patients remain
under close surveillance through structured surveillance programmes with regular follow-up consisting of PSA
testing, clinical examination, repeat prostate biopsies, and an increasing role of imaging (usually MRI). Curative
treatment is prompted by pre-defined thresholds indicative of development to potentially significant disease,
which is still curable, while considering individual life expectancy.

No formal RCT is available comparing AS to curative treatment. Several cohorts have investigated AS in organ-
confined disease, the findings of which were summarised in a SR [549, 550]. Table 6.2.2 summarises the results
of selected AS cohorts. The long-term OS and CSS of patients on AS are very good. However, more than one-
third of patients are reclassified during follow-up, most of whom undergo curative treatment due to disease
upgrading, increase in disease extent, disease stage, progression, or patient preference. There is variation
and heterogeneity between studies regarding exact patient selection, eligibility criteria, and follow-up policies
(including frequency of clinical follow-up, use of PSA kinetics, PSA-density, frequency of standard repeat
prostate biopsies, frequency and type of imaging such as MRI, and type of biopsy strategy (systematic, MRI-
lesion targeted biopsies, combinations, or template biopsies), when active treatment should be instigated (i.e.,
reclassification criteria), and which outcome measures should be prioritised [548]. For specific guidelines on
inclusion criteria and follow-up strategies for AS, see section 6.2.1.2.1.

ProtecT study
ProtecT, randomised 1,643 patients into one of three arms: active treatment with either RP or EBRT or active
monitoring (AM) with outcomes reported at ten years and 15 years [535, 551]. ProtecT trial did not apply a
formal AS strategy. Active monitoring (AM), was a significantly less stringent surveillance strategy, using PSA
only, with relaxed criteria to define progression. No repeat biopsies were performed as in AS.
At enrolment sixty-six percent of the patients had low-risk disease, with 90% having a PSA
< 10 ng/mL, 77% ISUP GG 1 (20% ISUP GG 2–3), and 76% had T1c disease. The remaining patients had mainly
intermediate-risk disease (approximately 40%).
The key finding was that AM was as effective as active treatment at fifteen years (CSS = 96.9% in
the AM-group vs. 97.8% in the RP-group and 97.1% in the EBRT-group, p = 0.53), but an increased metastatic
progression risk (9.4% vs. 4.7% and 5.0% respectively), as well as clinical progression at fifteen years (25.9% for
AM vs. 10.7% for RP/RT). Death from any cause occurred in 21.7% of the cohort, with similar numbers across
treatment groups. Metastases, although rare, were more frequent than seen with comparable AS protocols
[549]. A comprehensive characterisation of the ProtecT study cohort was performed after ten years, stratifying
patients at baseline according to risk of progression using clinical stage, grade at diagnosis and PSA level [552].
Additionally, detailed clinico-pathological information on participants who received RP were analysed.
The fifteen-year paper reported updated contemporary risk-stratification according to D’Amico
(24.1% Intermediate risk, 9.6% high risk), CAPRA (26.4% Score 3-5, 2.5% Score 6-10) and Cambridge Prognostic
Group (20.5% Group 2, 8.8% Groups 3-5). Among patients who underwent RP, 50.5% were ISUP GG ≥2, while
28.5% had an increase in pathological stage and 32% had an increase in tumour grade. Additionally, 51% of
patients who developed metastases displayed ISUP GG 1 and 47.6% were low CAPRA risk. Over time, 61.1%
of patients in the AM group received radical treatment (from 54.8% at ten years). From the ten year report the
authors aimed to identify prognostic markers. The results showed that treatment received, age (65–69 vs.
50–64 years), PSA, ISUP GG at diagnosis, cT stage, risk group, number of PCa-involved biopsy cores, maximum
length of tumour (median 5.0 vs. 3.0 mm), aggregate length of tumour (median 8.0 vs. 4.0 mm), and presence

58 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

of perineural invasion were each associated with increased risk of disease progression (p < 0.001 for each).
However, these factors could not reliably predict progression in individuals. Notably, 53% (n = 105) of patients
who progressed had biopsy ISUP GG 1 disease, although, conversely, none of the participants who received
RP and subsequently progressed had pathological ISUP GG 1 tumours. This discrepancy in progression and
metastases rate between the AM arm of the ProtecT study and comparable AS protocols can, most likely, be
explained by differences in intensity of surveillance, inadequate sampling by PSA testing and 10-core TRUS-
guided biopsies.
Nevertheless, the ProtecT study has reinforced the role of deferred active treatment (i.e., either AS or
some form of initial AM) as a feasible alternative to active curative interventions in all patients with low-grade
and low-stage disease, as well as for many patients with favourable intermediate risk disease. Beyond fifteen
years, no RCT-data are available, as yet, although AS is likely to give more reassurance especially in younger
men, based on more accurate risk stratification at recruitment and more stringent criteria regarding follow-up,
imaging, repeat biopsy and reclassification. Individual life expectancy must continuously be evaluated before
considering any active treatment in low-risk patients and in those with up to ten to fifteen years’ individual life
expectancy [552].

6.2.1.2.1 Active surveillance - inclusion criteria

Active surveillance inclusion criteria aim to select cases in which delay caused by the initial expectant
management strategy does not lead to additional unfavourable outcomes.
Guidance regarding selection and follow-up criteria for AS is limited by the lack of data from
prospective RCTs. As a consequence, the international collaborative DETECTIVE study involving healthcare
practitioners and patients developed consensus statements for deferred treatment with curative intent for
localised PCa, covering all domains of AS [372], as well as a formal SR on the various AS protocols [553].
The most frequently applied criteria include: ISUP GG 1 (on systematic biopsy), clinical stage cT1c or cT2a,
PSA < 10 ng/mL and PSA-D < 0.15 ng/mL/cc [549, 554]. The latter threshold remains controversial [554, 555].
These criteria were supported by the DETECTIVE study consensus. There was no agreement on the maximum
number of systematic cores that can be involved with cancer or the maximum percentage core involvement (CI),
although there was recognition that extensive disease on MRI should exclude men from AS, even though there
is no firm definition on this, especially when targeted biopsies confirm ISUP GG 1 [372]. Magnetic resonance
imaging index lesions diameter may provide additional guidance, as thresholds of > 10mm and > 20mm have
been used to predict BCR after RP, but not yet used in AS criteria [556]. The Movember consensus group,
consisting of 27 healthcare professional and 12 lived experience participants from across the world, agreed that
ISUP GG and MRI were the most important criteria for determining eligibility to AS [557].
A SR and meta-analysis found three clinico-pathological variables which were significantly
associated with reclassification, high PSA-D, > 2 positive cores (on systematic biopsies), and African-American
descent [558]. A review on the risk of progression for African-American men on AS also indicated a potential
increased risk of progression, but the association was not strong enough to discourage African-American men
from undergoing AS, but thorough confirmatory testing is important [559].
In addition, a previous pathology consensus group suggested excluding men from AS when any of
the following features were present: cribriform histology, predominant ductal carcinoma (including pure IDC),
sarcomatoid carcinoma, small cell carcinoma, EPE or LVI in needle biopsy [560], or PNI [561].
In men eligible for AS based upon systematic biopsy findings alone who did not have a pre-biopsy
MRI, a re-biopsy within six to twelve months (usually referred to as ‘confirmatory biopsy’) is mandatory to
exclude sampling error.

6.2.1.2.2 Active surveillance – inclusion of intermediate risk disease

In the ProtecT trial, where 34% of the randomised patients had a D’Amico intermediate- or high-risk disease,
there was no statistically significant difference in CSS at 15 years [535].

The outcomes of AS in intermediate-risk PCa has also been analysed in three SRs and meta-analyses,
summarising available data on its oncological outcomes and comparing patients with intermediate-risk PCa to
patients with low-risk disease [562-564]. The definition of AS was not strictly defined in either of the reviews:
instead, the search strategies included ‘active surveillance’ as a search term, and no a priori study protocol was
available. The primary outcome was the proportion of patients who remained on AS, whilst secondary outcomes
included CSS, OS, and MFS in all three studies.

In the first review seventeen studies were included, incorporating 6,591 patients with intermediate risk
disease. Sixteen studies included patients with low- and intermediate-risk disease, hence enabling comparative
outcome assessment via pooled analysis. Only one study performed MRI at recruitment and during AS. There
was significant clinical heterogeneity in terms of inclusion criteria for intermediate-risk disease. The results

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 59

showed the proportion of patients who remained on AS was comparable between the low- and intermediate-
risk groups after ten- and fifteen-years’ follow-up (OR: 0.97; 95% CI: 0.83–1.14; and OR: 0.86; 95% CI: 0.65–1.13,
respectively). Cancer-specific survival was worse in the intermediate-risk group after ten years (OR: 0.47; 95% CI:
0.31–0.69) and fifteen years (OR: 0.34; 95% CI: 0.2–0.58), although it remains unclear whether this is due to less
favourable baseline characteristics or due to the delay caused by the initial period of AS. Overall survival was
not statistically significantly different at five years’ follow-up (OR: 0.84; 95% CI: 0.45–1.57) but was significantly
worse in the intermediate-risk group after ten years (OR: 0.43; 95% CI: 0.35–0.53). Metastases-free survival did
not significantly differ after five years (OR: 0.55; 95% CI: 0.2–1.53) but was worse in the intermediate-risk group
after ten years (OR: 0.46; 95% CI: 0.28–0.77) [564].

The second review, including 25 studies and a total of 29,673 low- or intermediate-risk patients, showed
similar results in terms of treatment-free survival at ten years (RR: 1.16, 95% CI: 0.99-1.36), risk of developing
metastases (RR: 5.79, 95% CI: 4.61-7.29), risk of dying from PCa (RR: 3.93, 95% CI: 2.93-5.27), and risk of dying
from any cause (RR: 1.44, 95% CI: 1.11-1.86) [562]. In a subgroup analysis of four studies comparing outcomes
of patients with intermediate- and low-risk PCa of ISUP GG ≤ 2 (n = 1,900) no statistically significant difference
could be found in terms of treatment free survival or risk of developing metastases (RR: 1.03, 95% CI: 0.62-1.71
and RR: 2.09, 95% CI: 0.75-5.82, respectively).

The third, most recent, review included 25 studies of which thirteen studies provided data on treatment free
survival, six on CSS and seven on OS. Treatment free survival was not statistically significantly different in the
intermediate risk group after five (RR: 0.92, 95% CI: 0.82-1.02), ten (RR: 0.83, 95% CI: 0.55-1.23) or fifteen years
(RR: 0.54, 95% CI: 0.21-1.39). Cancer-specific survival was significantly lower after 15 years (RR: 0.92, 95%
CI: 0.89-0.96) and OS was significantly lower after ten years (RR: 0.87, 95% CI: 0.82-0.93) in the intermediate
risk group. It should be noted that many of the studies included patients with ISUP GG 3 disease. When these
studies were excluded no difference in treatment free, cancer specific or OS could be observed [563].

The reviews indicate that AS in unselected intermediate-risk patients implies a higher risk of progression over
time. It remains unclear whether this difference only reflects the baseline difference in outcome, that can also
be seen when comparing immediate treatment of low- and intermediate-risk PCa, or if the delay in treatment
caused any worsening of the outcomes in the intermediate-risk group in any way. All three reviews conclude that
AS could be offered to patients with intermediate-risk disease, but they should be informed of a higher risk of
progression and the latter two reviews suggests limiting the inclusion of intermediate-risk patients to those with
low-volume ISUP GG 2 disease.
The safety of delayed definitive therapy in men with grade reclassification during AS was confirmed
in a study comparing 979 patients who underwent immediate RP after diagnosis of ISUP GG 2, 190 who
underwent RP within 12 months of upgrading to ISUP GG 2 on AS, and 90 men who underwent RP >12 months
after upgrading to ISUP GG 2. Significant predictors of recurrence in multivariable analysis included percentage
positive biopsy cores and PSA, but not timing of RP [565].

A Canadian consensus group proposes that low volume ISUP GG 2 (< 10% Gleason pattern 4 on systematic
biopsies) may also be considered for AS. These recommendations have been endorsed by the ASCO [245] and
the DETECTIVE study consensus [372] for those patients with a PSA < 10 ng/mL and low core positivity. The
DETECTIVE study concluded that men with favourable ISUP GG 2 PCa (PSA < 10 ng/mL, low PSA density, clinical
stage ≤ cT2a and a low number of positive systematic cores) should also be considered for deferred treatment
[372]. In this setting, re-biopsy within six to twelve months to exclude sampling error is even more relevant than
in low-risk disease [554, 566]. The DETECTIVE study-related qualitative SR aimed to determine appropriate
criteria for inclusion of intermediate-risk disease into AS protocols [553]. Out of 371 AS protocols included in
the review, more than 50% included patients with intermediate-risk disease on the basis of PSA up to 20 ng/
mL (25.3%), ISUP GG 2 or 3 (27.7%), clinical stage cT2b/c (41.6%) and/or direct use of D’Amico risk grouping of
intermediate risk or above (51.1%). The DETECTIVE study reached consensus that patients with ISUP GG 3, or
patients with intraductal or cribriform histology, should not be considered for AS. The presence of any grade 4
pattern is associated with a 3-fold increased risk of metastases compared to ISUP GG 1, while a PSA up to 20
ng/mL might be an acceptable threshold [566-568], especially in the context of low PSA-D.

The indicator of the tumour volume may be either the number of positive cores, and the length of cancer in each
core, based on systematic biopsies, or the volume of the dominant lesion seen on mpMRI [372]. If targeted
biopsies based upon mpMRI images are performed, the number of positive cores of the targeted biopsies are
not an indicator of the extent of disease or tumour volume when considering a patient for AS due to the altered
biopsy protocol.

60 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

MRI-targeted biopsies have been associated with up-grading of tumours but improved outcomes [103].

The large prospective PRIAS study on AS expanded inclusion criteria when MRI and targeted systematic
biopsies are used at inclusion (https://prias-project.org/modules/articles/article.php?id=1):
• cT ≤ 2
• ISUP: GG 1 or GG 2 without invasive cribriform growth and intraductal carcinoma
• PSA: ≤ 20 ng/mL
• PSA-density: < 0.25 ng/mL/cc
• Number of positive cores:
- For ISUP GG 1: No limit.
- F
 or ISUP GG 2 (without invasive cribriform growth and intraductal carcinoma): ≤ 50% systematic cores
(where multiple positive cores from the same lesion on MRI count for one positive core).

During follow-up, upgrading is the only criterium for discontinuation, defined as ISUP GG ≥ 3 or ISUP GG ≥ 2 with
cribriform growth or intraductal carcinoma, or ISUP GG ≥ 2 with > 50% positive cores.

A multi-disciplinary consensus conference on germline testing has suggested a genetic implementation

framework for the management of PCa [165]. Based on consensus, BRCA2-gene testing was recommended
for AS discussions and could be performed in men with family history of prostate, breast or ovarian cancers.
However, the nature of such discussions and how a positive result influences management were beyond the
scope of the project. Currently, BRCA2 mutation does not exclude a patient from AS if tumour factors are
otherwise favourable. Furthermore, if included in AS programmes, patients with a known BRCA2 mutation
should be cautiously monitored until such time that more robust data are available.

6.2.1.2.3 Tissue-based prognostic biomarker testing for selection for active surveillance
Biomarkers, including Oncotype Dx®, Prolaris®, Decipher®, PORTOS and ProMark® are promising; however,
further data and comparisons with other parameters (including MRI) will be needed before such markers can be
used in standard clinical practice [240].

6.2.1.2.4 Magnetic resonance imaging for selection for active surveillance

Two RCTs and a SR, showed that adding MRI-targeted biopsy to systematic sampling at confirmatory biopsy
increased the number of cancers labelled ISUP GG ≥ 2 and thus may aid patient selection for AS, although the
impact of MRI and targeted biopsies with corresponding stage shift on long-term oncological outcomes of AS
is lacking [126, 569-574]. Adding MRI-targeted biopsy to systematic sampling at confirmatory biopsy improved
upgrade detection by increments of 0-7.9 per 100 men depending on the series [569]. In a meta-analysis of 6
studies, the rate of upgrading to ISUP GG ≥ 2 cancer increased from 20% (95% CI: 16–25%) to 27% (95% CI:
22–34%) when MRI-targeted biopsy was added to systematic biopsy [574]. The Active Surveillance MRI Study
(ASIST) randomised men on AS scheduled for confirmatory biopsy to either 12-core systematic biopsy or to
MRI with targeted biopsy (when indicated), combined with systematic biopsy (up to 12 cores in total). After two
years of follow-up, use of MRI before confirmatory biopsy resulted in fewer failures of surveillance (19% vs. 35%,
p = 0.017) and in fewer patients progressing to ISUP GG ≥ 2 cancer (9.9% vs. 23%, p = 0.048) [572]. However,
systematic biopsy retains its additional value, which argues for a combined biopsy approach [569, 574]. The
DETECTIVE study agreed that men eligible for AS after combined systematic- and MRI-targeted biopsy do not
require a confirmatory biopsy, a recommendation further supported by the results of the MRIAS trial [372, 575].

If the PCa diagnosis is made on MRI-targeted biopsy alone in order to lower the risk of over detection of
insignificant (see section 5.4.1 and 5.4.2), and the number of positive systematic cores used as an indication
for tumour volume during AS is not available, MRI lesion diameter may be used as a surrogate, although specific
definitions have not yet been tested in an AS setting (e.g. for ISUP GG 2 tumours no PIRADS 5 or < 20 mm lesion
size) [556].

A few studies indicate that PSMA-PET-CT or PSMA-PET-MRI may have additional value to above mentioned
clinico-pathological variables for risk stratification before AS [127, 576]. However, so far, the studies are too
small, the follow-up too short, and association with long-term oncological outcomes is lacking, to draw any hard
conclusions and for this modality to be recommended outside clinical trials.

6.2.1.2.5 Active surveillance follow-up

Based on the DETECTIVE consensus study, the surveillance strategy should be based on serial DRE (at least
once yearly), PSA (at least once, every six months), and repeated biopsy (no consensus on frequency, but 1-4-7
years is an often-applied schedule).

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 A panel SR incorporating 263 surveillance protocols showed that 78.7% of protocols mandated per-
protocol repeat biopsies within the first two years and that 57.7% of the protocols performed repeat biopsy at
least every three years for ten years after the start of AS [553].
There was clear agreement in the DETECTIVE consensus meeting as well as in the Movember
consensus group that a PSA change alone, including PSA-doubling time (PSA-DT, < 3 years) should not change
management based on its weak link with grade progression [577, 578] but rather trigger further investigation
such as biopsy or repeat-MRI. It was also agreed that changes on repeat MRI during AS needed a repeat biopsy
before considering continuing to active treatment [372, 557].
The Movember consensus group made a number of recommendations that in some ways differ
from the DETECTIVE consensus study, e.g. routine DRE was not supported if MRI or other imaging was carried
out routinely during AS, if MRI combined with other parameters (PSA kinetics and density) are stable routine
biopsy may be omitted, and change in clinical parameters should prompt MRI with possible biopsy rather than
immediate biopsy [557].

6.2.1.2.6 Magnetic resonance imaging for follow-up during active surveillance

The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) criteria were
established to standardise the assessment of tumour progression on serial MRI [579]. PRECISE is a strong
predictor of histological upgrading [580, 581]. Two independent meta-analyses assessed the value of MRI
progression criteria for predicting histological progression (mostly defined as progression to ISUP GG ≥ 2). The
pooled histological progression rate was 27% in both reviews. If biopsies were triggered only by MRI progression
findings, approximately two thirds of the biopsies would be avoided, at the cost of missing 40% of men with
histological progression. In addition, at least half of biopsied men would have had negative findings for
histological progression and thus would have undergone unnecessary biopsies. If histological progression was
restricted to progression to ISUP GG > 3, approximately 30% of histological progression would be missed and
approximately 80% of the biopsies performed would be unnecessary. The use of the PRECISE criteria did not
seem to change these results [582, 583]. This supports maintaining protocol-mandated repeat biopsies during
the course of AS.

Another study analysed a prospectively-maintained AS cohort of 369 patients (272 with ISUP GG 1 cancer and
97 with ISUP GG 2 cancer) who had been selected for AS after combined systematic and MRI-targeted sampling
during confirmatory biopy [584]. At two years, systematic biopsy, MRI-targeted biopsy and combined biopsy
detected grade progression in 44 (15.9%), 73 (26.4%) and 90 patients (32.5%), respectively. This suggests that
both biopsy approaches retain added value, not only for confirmatory biopsy, but also during AS [584]. Systemtic
biopsy cores may thus be considered to be added to follow-up biopsy to rule out more widespread disease [208,
210, 314]. The disadvantage of overdiagnosis due to systematic cores is not present in the AS follow-up setting.
On the other hand, extra biopsy cores may cause discomfort and, as in the primary diagnostic setting, the risk of
leaving significant PCa undetected is small, and of limited relevance in a surveillance setting. As in the primary
setting, the strategy of targeted/perilesional cores is therefore also recommended during AS repeat biopsy.

6.2.1.2.7 Individualised repeat biopsy during active surveillance

The basis for AS protocols includes standard repeat biopsy. However, several factors have been found to
be associated with low re-classification rates and long PFS and can be used to individualise the need and
frequency of AS biopsy schedules: low PSA-D [575, 585-587], low PSA velocity (PSAV) [588, 589], negative
biopsy (i.e., no cancer at all) at confirmatory or repeat biopsy during AS [521], and negative baseline or repeat
MRI during AS [575, 585-587, 590-593]. Negative repeat biopsy during AS was associated with a 50% decrease
in the risk of future reclassification and upgrading [594]. In a single-centre AS cohort of 514 patients who
underwent at least three protocol-mandated biopsies after diagnosis (the confirmatory biopsy and at least
two additional surveillance biopsies), men with one negative biopsy (i.e., no cancer at all) at confirmatory or
second biopsy, or men with two consecutive negative biopsies had a lower likelihood of a positive third biopsy
and significantly better 10-year treatment free survival [595]. Patients with stable (PRECISE 3) on repeat MRI
during AS combined with a low PSA-D (<0.15) have a very low rate of progression and may be a group in whom
standard repeat biopsy may be omitted [596].

6.2.1.2.8 Active Surveillance - change in treatment

Men may remain on AS whilst they have a life expectancy of > 10 years and the disease remains insignificant.
A transition from AS to WW due to rising age or new comorbidity should be incorporated within conservative
management strategies for PCa and in discussion with patients [597].

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Histopathology criteria are the strongest reason to trigger a change in management, including. reclassification
to ISUP GG 3 or detection of cribriform or intraductal growth patterns, based on systematic biopsy. The exact
criteria in the targeted biopsy era remain debated. MRI-targeted biopsy induces a grade shift and ISUP GG
2–3 cancers detected by MRI-targeted biopsy have, on average, a better prognosis than those detected by
systematic sampling. Also, men upgraded during AS, have more favourable outcomes as men with the same
ISUP GG detected at first biopsy [598]. As an increasing number of men with favourable intermediate-risk
disease are managed with AS (see section 6.2.1.2), progression to ISUP GG 2 should not be used a hard
reason to stop AS, especially when found on targeted biopsy. In addition, as acknowledged in the DETECTIVE
consensus meeting, the number of positive cores is not an indicator of tumour volume anymore if targeted
biopsies are performed [372, 599]. Based on the findings of a SR incorporating 271 reclassification protocols,
patients with low-volume ISUP GG 2 disease at recruitment, and with increased systematic core positivity (> 3
cores involvement [> 50% per core]) on repeat systematic biopsies not using MRI, should be reclassified [553].
As for inclusion, MRI tumour volume may be used during follow-up as a surrogate for tumour volume estimation
based on systematic biopsies, though specific definitions are lacking. Furthermore, in a study from the MUSIC
registry over half of men with favourable intermediate-risk PCa on AS remained free of treatment five years after
diagnosis [600]. Their results are in concordance with the DETECTIVE and the Movember consensus statements
and indicate that most men on AS will not lose their window of cure and have similar short-term oncologic
outcomes as men undergoing up-front treatment and that AS is an oncologically safe option for appropriately
selected men with favourable intermediate-risk PCa.

6.2.1.2.9 Psychological factors during active surveillance

Anxiety about continued surveillance occurs in around 10% of patients on AS [601] and was recognised as a
valid reason for active treatment [369]. An alternative for patients suitable for continuing AS would be to offer
psychological support to reduce the level of anxiety, as also stated by the Movember consensus group [557].
A review on patient reported factor influencing the decision making, including thirteen qualitative papers and
426 men, identified several factors influencing the decision making when considering AS. Among the identified
factors were personal risk assessment, influence of family and friends, beliefs about treatment as well as doctor
and system factors, underscoring the importance of individualised, relevant, and clear information to support
decision making [602]. A population-based cohort study from Sweden on regional differences in AS uptake
and subsequent transition to radical treatment concluded that a regional tradition of a high uptake of AS was
associated with a lower probability of transition to radical treatment, but not with AS failure [603]. These studies
further emphasise the importance of thorough information and discussion with the patients on pros/cons of AS
versus active treatment already at the time of diagnosis for the patients to feel secure in their treatment choice
and to avoid over-treatment.

6.2.1.2.10 Interventions during active surveillance

A review on potential interventions during AS found that use of 5-ARIs was associated with improved
progression-free survival (PFS; hazard ratio: 0.59; 95% confidence interval 0.48-0.72), with limited increased
toxicity [604].
A phase II RCT randomised patients to AS plus enzalutamide or AS alone. This study indicated that
PSA progression could be delayed, and the odds of a negative biopsy increased during the median follow-up
time of 1.3 years, but patients had more side effects of the treatment without showing any long-term benefits of
the treatment [605].

Table 6.2.2 Active surveillance oncological outcomes in large cohorts with longer-term follow-up

Studies N Median FU (mo) 10-year OS (%) 10-year CSS (%)

Adamy, et al. 2011 [551] 533-1,000 48 90 99
Godtman, et al. 2013 [554] 439 72 81 99.5
Klotz, et al. 2015 [555] 993 77 85 98.1
Tosoian, et al. 2020 [557] 1,818 60 93 99.9
Carlsson, et al. 2020 [558] 2,664 52 94 100
Newcomb, et al. 2024 [606] 2,155 86 95 99.9
CSS = cancer-specific survival; FU = follow-up; mo = months; N = number of patients; OS = overall survival; RP =
radical prostatectomy.

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6.2.1.3 Summary of evidence and recommendations for active surveillance strategy

Summary of evidence LE
The AS strategy should be based on PSA (at least once every six months), serial DRE (at least once 3
yearly) and repeated biopsy. Serial DRE may be omitted if MRI is stable.
Magnetic resonance imaging detects more cancers labelled with higher ISUP GG and may be used
before starting AS (if not performed earlier), although impact on long-term oncological endpoints is
lacking.
Serial DRE may be omitted if MRI is stable.
A progression on MRI mandates a repeat biopsy, to confirm histological progression, before a change
in treatment strategy.
A stable MRI (PRECISE 1-3) does not make repeat biopsy superfluous, but in patients with low-risk
tumour and a stable low PSA-D < 0.15 may be excluded.
No modality has shown superiority over any other active management options or deferred active 2
treatment in terms of overall- and PCa-specific survival for clinically localised low/intermediate-risk
disease.

Recommendations Strength rating

Offer active surveillance (AS) as standard of care for low-risk disease. Strong
Exclude patients with cribriform or intraductal histology on biopsy from AS. Strong
Perform magnetic resonance imaging (MRI) before a confirmatory biopsy if no MRI has been Strong
performed before the initial biopsy.
Take targeted and perilesional biopsy cores (of any PI-RADS ≥ 3 lesion) if a confirmatory or Strong
repeat biopsy is performed.
Perform per-protocol confirmatory prostate biopsies if MRI is not available. Weak
Do not perform confirmatory biopsies if a patient has had upfront MRI and targeted biopsies. Weak
Base the strategy of AS on a strict follow-up protocol including PSA (at least once every six Strong
months), digital rectal examination (DRE) (at least once yearly), and repeated biopsy (every
2-3 years for 10 years).
Exclude patients with a low-risk PCa, a stable MRI (PRECISE 3) and a stable low PSA density Weak
(< 0.15) from repeat biopsy when MRI is repeated before repeat biopsy. In addition, serial
DRE may be omitted if MRI is stable.
Perform MRI and repeat biopsy if PSA is rising (PSA-doubling time < 3 years). Strong
Base change in treatment on biopsy progression, not on progression on MRI, PSA, and/or Weak
DRE.

6.2.2 Radical prostatectomy

6.2.2.1 Introduction
The goal of RP by any approach is the eradication of cancer while, whenever possible, preserving pelvic
organ function [607]. The procedure involves removing the entire prostate with its capsule intact and SVs,
followed by vesico-urethral anastomosis. Surgical approaches have expanded from perineal and retropubic
open approaches to laparoscopic and robotic-assisted techniques; anastomoses have evolved from Vest
approximation sutures to continuous suture watertight anastomoses under direct vision and mapping of the
anatomy of the dorsal venous complex (DVC) and cavernous nerves has led to excellent visualisation and
potential for preservation of erectile function [608]. The main results from multi-centre RCTs involving RP are
summarised in Table 6.2.3.

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Table 6.2.3: Oncological results of radical prostatectomy in organ-confined disease in RCTs

Study Acronym Population Treatment Median Risk category CSS (%)

period FU (mo)
Bill-Axelson, et al. 2018 SPCG-4 Pre-PSA era 1989-1999 283 Low risk & 80.4
[543] intermediate risk (at 23 yr.)
Wilt, et al. PIVOT Early years of 1994-2002 152 Low risk & 95.9
2017 [544] PSA testing intermediate risk 91.5
(at 19.5 yr.)
Hamdy, et al. ProtecT Screened 1999-2009 180 Mainly low- & 97
2023 [535] population intermediate risk (at 15 yr.)

CSS = cancer-specific survival; FU = follow-up; mo = months; PSA = prostate-specific antigen; yr. = year.

6.2.2.2 Pre-operative preparation

6.2.2.2.1 Pre-operative patient education
As before any surgery appropriate education and patient consent is mandatory prior to RP. Peri-operative
education has been shown to improve long-term patient satisfaction following RP [609]. Augmentation of
standard verbal and written educational materials such as use of interactive multimedia tools [610, 611] and
pre-operative patient-specific 3D printed prostate models has been shown to improve patient understanding and
satisfaction and should be considered to optimise patient-centred care [612].

Additional consideration should be given to patients who have undergone prior transurethral resection of
the prostate (TURP). According to SR and meta-analysis of non-randomised studies, prior TURP can prolong
operative and catheter time, have higher complications, require more bladder neck reconstruction and less nerve
sparing resulting in higher positive margin rate (RR 1.24, p = 0.03), higher incontinence (RR 1.24, p = 0.03) and
erectile function (RR 0.8, p < 0.001) at 12 months after RARP [613]. While patients with prior TURP are typically
older, which is also a predictor for these outcomes in RARP patients, prior TURP is worthy of consideration in
pre-operative counselling.

6.2.2.3 Surgical techniques

6.2.2.3.1 Prostatic anterior fat pad dissection and histologic analysis
Several multi-centre and large single-centre series have shown the presence of lymphoid tissue within the fat
pad anterior to the endopelvic fascia; the prostatic anterior fat pad (PAFP) [614-620]. This lymphoid tissue is
present in 5.5–10.6% of cases and contains metastatic PCa in up to 1.3% of intermediate- and high-risk patients.

When positive, the PAFP is often the only site of LN metastasis. The PAFP is therefore a rare but recognised
route of spread of disease. The PAFP is always removed at RP for exposure of the endopelvic fascia and should
be sent for histologic analysis as per all removed tissue.

6.2.2.3.2 Management of the dorsal venous complex

Since the description of the anatomical open RP by Walsh and Donker in the 1980s, various methods of
controlling bleeding from the DVC have been proposed to optimise visualisation [621].

In the open setting, blood loss and transfusion rates have been found to be significantly reduced when ligating
the DVC prior to transection [622]. However, concerns have been raised regarding the effect of prior DVC ligation
on apical margin positivity and continence recovery due to the proximity of the DVC to both the prostatic apex
and the urethral sphincter muscle fibres.

In the robotic-assisted laparoscopic technique, due to the increased pressure of pneumoperitoneum, whether
prior DVC ligation was used or not, blood loss was not found to be significantly different in one study [623].
In another study, mean blood loss was significantly less with prior DVC ligation (184 vs. 176 mL, p = 0.033),
however it is debatable whether this was clinically significant [624]. The positive apical margin rate was not
different, however, the latter study showed earlier return to full continence at five months post-operatively in the
no prior DVC ligation group (61% vs. 40%, p < 0.01). Ligation of the DVC can be performed with standard suture
or using a vascular stapler. One study found significantly reduced blood loss (494 mL vs. 288 mL) and improved
apical margin status (13% vs. 2%) when using the stapler [625].

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Given the relatively small differences in outcomes, the surgeon’s choice to ligate prior to transection or not,
or whether to use sutures or a stapler, will depend on their familiarity with the technique and the equipment
available.

6.2.2.3.3 Nerve-sparing surgery

During prostatectomy, preservation of the neurovascular bundles (NVB) with parasympathetic nerve branches of
the pelvic plexus can spare erectile function [626, 627].

Although age and pre-operative function may remain the most important predictors for post-operative erectile
function, NS has also been associated with improved continence outcomes and may therefore still be relevant
for men with poor erectile function [628, 629]. A large SR and meta-analysis reported that bilateral NS resulted
in improved urinary continence recovery (RR 1.08 at 12 months, p < 0.0001) across all time points with
heterogeneous pooled estimates [630]. The association with continence may be mainly due to the dissection
technique used during NS surgery, and not due to the preservation of the NVB themselves [628].

Extra-, inter-, and intra-fascial dissection planes can be planned, with those closer to the prostate and performed
bilaterally associated with superior (early) functional outcomes [631-634]. Furthermore, many different
techniques are propagated such as retrograde approach after anterior release (vs. antegrade), and athermal
and traction-free handling of bundles [635-637]. Nerve-sparing (NS) surgery may be performed using clips or low
bipolar energy without clear benefit favouring one technique over another regarding functional outcomes [638].

Patient selection for nerve sparing remains challenging for clinicians. A 2021 SR of nineteen studies analysing
the parameters used for selection of NS found that individual clinical and radiological factors were poor at
predicting EPE, and consequently, the appropriateness of NS. However, nomograms that incorporated mpMRI
performed better [639]. High-risk patients can be considered, as a large retrospective study prone to selection
bias for NS reported that NS did not affect BCR, risk of metastasis or of death regardless of stage or ISUP GG
[640].

A reasonable concern is the oncological compromise and positive surgical margin rate. A 2022 SR of 18
comparative studies (no RCTs) of NS vs. non-nerve-sparing RP showed a RR of side-specific positive margins
of 1.5, but none of them included patients with high-risk PCa [641]. There was no effect seen of NS on BCR.
However, follow-up was short, and studies were subject to selection bias with mainly low-risk patients. For those
patients with high-risk PCa, side-specific NS was avoided if disease was palpable or EPE was present on MRI.
Indeed, a 2019 SR showed that MRI affected the decision to perform NS or not in 35% of cases without any
negative impact on surgical margin rate [642].

In summary, the quality of data is not adequate to permit a strong recommendation in favour of NS or non-nerve-
sparing, but pre-operative risk factors for side-specific EPE such as PSA, PSA density, clinical stage, ISUP grade
group, and PIRADS score, EPE and capsule contact length on MRI, should be taken into account.

6.2.2.3.4 Removal of seminal vesicles

The more aggressive forms of PCa may spread directly into the SVs. For oncological clearance, the SVs have
traditionally been removed intact with the prostate specimen [643]. However, in some patients the tips of
the SVs can be challenging to dissect free. Furthermore, the cavernous nerves run past the SV tips such that
indiscriminate dissection of the SV tips could potentially lead to ED [644]. However, a RCT comparing nerve-
sparing RP with and without a SV-sparing approach found no difference in margin status, PSA recurrence,
continence or erectile function outcomes. Whilst complete SV removal should be the default, preservation of the
SV tips may be considered in cases of low risk of involvement.

6.2.2.3.5 Bladder neck management

Bladder neck mucosal eversion
Some surgeons perform mucosal eversion of the bladder neck as its own step in open RP with the aim of
securing a mucosa-to-mucosa vesico-urethral anastomosis and avoiding anastomotic stricture. Whilst bringing
bladder and urethral mucosa together by the everted bladder mucosa covering the bladder muscle layer, this
step may actually delay healing of the muscle layers. An alternative is to simply ensure bladder mucosa is
included in the full thickness anastomotic sutures. A non-randomised study of 211 patients with and without
bladder neck mucosal eversion showed no significant difference in anastomotic stricture rate [645]. The
strongest predictor of anastomotic stricture in RP is current cigarette smoking [646], but it is also 2.2 higher in
open RP than RARP [647].

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Bladder neck preservation
Whilst the majority of urinary continence is maintained by the external urethral sphincter at the membranous
urethra (see below), a minor component is contributed by the internal lissosphincter at the bladder neck [648].
Preservation of the bladder neck has therefore been proposed to improve continence recovery post-RP. A RCT
assessing continence recovery at twelve months and four years showed improved objective and subjective
urinary continence in both the short- and long term without any adverse effect on oncological outcome [649].
These findings were confirmed by a SR [650]. However, concern remains regarding margin status for cancers
located at the prostate base.
A SR addressing site-specific margin status found a mean base-specific positive margin rate of
4.9% with bladder neck preservation vs. only 1.9% without [648]. This study was inconclusive, but it would be
sensible to exercise caution when considering bladder neck preservation if significant cancer is known to be
at the prostate base. Bladder neck preservation should be performed routinely when the cancer is distant from
the base. However, bladder neck preservation cannot be performed in the presence of a large median lobe or a
previous transurethral resection of the prostate (TURP) [651].

6.2.2.3.6 Urethral length preservation

The membranous urethra sits immediately distal to the prostatic apex and is chiefly responsible, along with its
surrounding pelvic floor support structures, for urinary continence. It consists of the external rhabdosphincter
which surrounds an inner layer of smooth muscle. Using pre-operative MRI, the length of membranous urethra
has been shown to vary widely.

Systematic reviews and meta-analyses found that every extra millimetre of membranous urethral length
seen on MRI pre-operatively improves early return to continence post-RP [652-654]. A greater membranous
urethral length as measured on preoperative MRI was an independent prognostic factor for return to urinary
continence within one month after RP and remained prognostic at twelve months [654]. Therefore, it is likely
that preservation of as much urethral length as possible during RP will maximise the chance of early return to
continence. It may also be useful to measure urethral length pre-operatively on MRI to facilitate counselling of
patients on their relative likelihood of early post-operative continence [655].

6.2.2.3.7 Techniques of vesico-urethral anastomosis

Following prostate removal, the bladder neck is anastomosed to the membranous urethra. The objective is to
create a precisely aligned, watertight, tension-free, and stricture-free anastomosis that preserves the integrity
of the intrinsic sphincter mechanism. Several methods have been described, based on the direct or indirect
approach, the type of suture (i.e. barbed vs. non-barbed/monofilament), and variation in suturing technique
(e.g., continuous vs. interrupted, or single-needle vs. double-needle running suture). The direct vesico-urethral
anastomosis, which involves the construction of a primary end-to-end inter-mucosal anastomosis of the bladder
neck to the membranous urethra by using 6 interrupted sutures placed circumferentially, has become the
standard method of reconstruction for open RP [656].

The development of laparoscopic- and robotic-assisted techniques to perform RP have facilitated the
introduction of new suturing techniques for the anastomosis. A SR and meta-analysis compared unidirectional
barbed suture vs. conventional non-barbed suture for vesico-urethral anastomosis during robotic-assisted
radical prostatectomy (RARP) [657]. The review included three RCTs and found significantly reduced
anastomosis time, operative time and posterior reconstruction time in favour of the unidirectional barbed suture
technique, but there were no differences in post-operative leak rate, length of catheterisation and continence
rate. However, no definitive conclusions could be drawn due to the relatively low quality of the data. In regard
to suturing technique, a SR and meta-analysis compared continuous vs. interrupted suturing for vesico-
urethral anastomosis during RP [658]. The study included only one RCT with 60 patients [659]. Although the
review found slight advantages for continuous suturing over interrupted suturing in terms of catheterisation
time, anastomosis time and rate of extravasation, the overall quality of evidence was low and no clear
recommendations were possible. A RCT [660] compared the technique of suturing using a single absorbable
running suture vs. a double-needle single-knot running suture (i.e. Van Velthoven technique) in laparoscopic
RP [661]. The study found slightly reduced anastomosis time with the single running suture technique, but
anastomotic leak, stricture, and continence rates were similar.

Overall, although there are a variety of approaches, methods, and techniques for performing the vesico-urethral
anastomosis, no clear recommendations are possible due to the lack of high-certainty evidence. In practice, the
chosen method should be based on surgeon experience and individual preference [656-661].

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6.2.2.3.8 Urinary catheter
A urinary catheter is routinely placed during RP to enable bladder rest and drainage of urine while the
vesicourethral anastomosis heals. Compared to a traditional catheter duration of around 1 week, some centres
remove the transurethral catheter early (post-operative day 2–3), usually after thorough anastomosis with
posterior reconstruction or in patients selected peri-operatively on the basis of anastomosis quality [662-
665]. No higher complication rates were found. Although shorter catheterisation has been associated with
more favourable short-term functional outcomes, no differences in long-term function were found [666]. One
RCT has shown no difference in rate of UTI following indwelling catheter (IDC) removal whether prophylactic
ciprofloxacin was given prior to IDC removal or not, suggesting antibiotics should not be given at catheter
removal [667].
As an alternative to transurethral catheterisation, suprapubic catheter insertion during RP has been
suggested. Some reports suggest less bother regarding post-operative hygiene and pain [668-672], while others
did not find any differences [673, 674]. No impact on long-term functional outcomes were seen.

6.2.2.3.9 Cystography prior to catheter removal

Cystography may be used prior to catheter removal to check for a substantial anastomotic leak. If such a leak is
found, catheter removal may then be deferred to allow further healing and sealing of the anastomosis. However,
small comparative studies suggest that a cystogram to assess anastomotic leakage is not indicated as SOC
before catheter removal eight to ten days after surgery [675]. If a cystogram is used, men with LUTS, large
prostates, previous TURP or bladder neck reconstruction, may benefit as these factors have been associated
with leakage [676, 677]. Contrast-enhanced transrectal US is an alternative [678].

6.2.2.3.10 Use of a pelvic drain

A pelvic drain has traditionally been used in RP for potential drainage of urine leaking from the vesico-urethral
anastomosis, blood, or lymphatic fluid when a PLND has been performed. Two RCTs in the robotic-assisted
laparoscopic setting have been performed [679, 680]. Patients with urine leak at intra-operative anastomosis
watertight testing were excluded. Both trials showed non-inferiority in complication rates when no drain was
used. When the anastomosis is found to be watertight intra-operatively, it is reasonable to avoid inserting a pelvic
drain. There is no evidence to guide usage of a pelvic drain in PLND.

6.2.2.3.11 Considerations during minimally-invasive radical prostatectomy

Minimally-invasive radical prostatectomy, including LRP and RARP, is being used more commonly due to many
factors.

6.2.2.3.11.1 Pneumoperitoneum pressure

Reduced blood loss has been reported with minimally-invasive surgery [681], where use of pneumoperitoneum
is likely to be a significant contributing factor. Various pneumoperitoneum pressures are used, with higher
pressures associated with less bleeding and more surgical working space at the expense of increased
abdominal pressure and associated physiological changes. A randomised triple-blinded study comparing RARP
(with standard DVC ligation) low-pressure (7 mmHg) versus standard-pressure (12 mmHg) pneumoperitoneum
showed that in 98 patients, low pressure was associated with better post-operative quality of recovery and
improved pain (p = 0.001), physical comfort (p = 0.007) and emotional state (p = 0.006) on postoperative day
1 at the expense of statistically higher blood loss of questionable clinical relevance (mean 227 ml vs. 159.9ml;
p = 0.001) [682].

6.2.2.4 Acute and chronic complications of radical prostatectomy

Post-operative incontinence and ED are common problems following surgery for PCa. A key consideration
is whether these problems are reduced by using newer techniques such as RARP. Systematic reviews have
documented complication rates after RARP [681, 683-686], and can be compared with contemporaneous reports
after radical retropubic prostatectomy (RRP) [687]. A prospective controlled non-RCT of patients undergoing
RP in fourteen centres using RARP or RRP showed that twelve months after RARP, 21.3% of patients were
incontinent, as were 20.2% after RRP (adjusted OR: 1.08; 95% CI: 0.87–1.34) [688]. Erectile dysfunction was
observed in 70.4% after RARP and 74.7% after RRP. The adjusted OR was 0.81 (95% CI: 0.66–0.98) [688].
A SR and meta-analysis of unplanned hospital visits and re-admissions post-RP analysed 60 studies
with over 400,000 patients over a 20-year period up to 2020. It found an emergency room visit rate of 12% and a
hospital re-admission rate of 4% at 30 days post-operatively [689].
A RCT comparing RARP and RRP reported outcomes at twelve weeks in 326 patients and functional
outcomes at two years [690]. Urinary function scores did not differ significantly between RRP vs. RARP at
six and twelve weeks post-surgery (74–50 vs. 71–10, p = 0.09; 83–80 vs. 82–50, p = 0.48), with comparable
outcomes for sexual function scores (30–70 vs. 32–70, p = 0.45; 35–00 vs. 38–90, p = 0.18). In the RRP group

68 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

fourteen (9%) patients had post-operative complications vs. six (4%) in the RARP group. The intra- and peri-
operative complications of RRP and RARP are listed in Table 6.1.4. Table 6.1.5 lists the Clavien-Dindo definition
of surgical complications. The early use of phosphodiesterase-5 inhibitors (PDE5Is) in penile rehabilitation
remains controversial resulting in a lack of clear recommendations.
A subsequent meta-analysis of five RCTs (1,205 patients) that compared RARP with LRP showed
no difference in continence at twelve months (OR 1.95, 95% CI 0.67 – 5.62) or oncological outcomes (positive
margin rate, biochemical recurrence); however, RARP resulted in better 3- (OR 1.81) and 6-month (OR 1.88)
continence outcomes as well as erectile recovery in pre-operatively potent patients (OR 4.05, p = 0.003) [691].

Table 6.2.4: Intra-and peri-operative complications of retropubic RP, laparoscopic RP and RARP
(adapted from [681])

Predicted probability of event RARP (%) Laparoscopic RP (%) RRP (%)

Bladder neck contracture 1.0 2.1 4.9
Anastomotic leak 1.0 4.4 3.3
Infection 0.8 1.1 4.8
Organ injury 0.4 2.9 0.8
Ileus 1.1 2.4 0.3
Deep-vein thrombosis 0.6 0.2 1.4
Predicted rates of event RARP (%) Laparoscopic RP (%) RRP (%)
Clavien-Dindo I 2.1 4.1 4.2
Clavien-Dindo II 3.9 7.2 17.5
Clavien-Dindo IIIa 0.5 2.3 1.8
Clavien-Dindo IIIb 0.9 3.6 2.5
Clavien-Dindo IVa 0.6 0.8 2.1
Clavien-Dindo V < 0.1 0.2 0.2
RALP = robot-assisted laparoscopic prostatectomy; RP = radical prostatectomy; RRP = radical retropubic
prostatectomy.

Table 6.2.5: Clavien-Dindo grading of surgical complications [692]

Grade Definition
I Any deviation from the normal post-operative course not requiring surgical, endoscopic or
radiological intervention. This includes the need for certain drugs (e.g. antiemetics, antipyretics,
analgesics, diuretics and electrolytes), treatment with physiotherapy and wound infections that are
opened at the bedside
II Complications requiring drug treatments other than those allowed for Grade I complications; this
includes blood transfusion and total parenteral nutrition (TPN)
IIIa Complications requiring surgical, endoscopic or radiological intervention
- intervention not under general anaesthetic
IIIb Complications requiring surgical, endoscopic or radiological intervention
- intervention under general anaesthetic
IVa Life-threatening complications; this includes central nervous system (CNS) complications
(e.g. brain haemorrhage, ischaemic stroke, subarachnoid haemorrhage) which require intensive
care, but excludes transient ischaemic attacks (TIAs)
- single-organ dysfunction (including dialysis)
IVb Life-threatening complications; this includes CNS complications (e.g. brain haemorrhage,
ischaemic stroke, subarachnoid haemorrhage) which require intensive care, but excludes transient
ischaemic attacks (TIAs)
- multi-organ dysfunction
V Death of the patient

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6.2.2.4.1 Effect of anterior and posterior reconstruction on continence
Preservation of integrity of the external urethral sphincter is critical for continence post-RP. Less clear is the
effect of reconstruction of surrounding support structures to return to continence. Several small RCTs have
been conducted, however, pooling analyses is hampered by variation in the definitions of incontinence and
surgical approach, such as open vs. robotic and intra-peritoneal vs. extra-peritoneal. In addition, techniques used
to perform both anterior suspension or reconstruction and posterior reconstruction are varied. For example,
anterior suspension is performed either through periosteum of the pubis or the combination of ligated DVC
and puboprostatic ligaments (PPL). Posterior reconstruction from rhabdosphincter is described to either
Denonvilliers fascia posterior to bladder or to posterior bladder wall itself.
Two trials assessing posterior reconstruction in RARP found no significant improvement in return
to continence [693, 694]. A third trial using posterior bladder wall for reconstruction showed only an earlier
return to 1 pad per day (median 18 vs. 30 days, p = 0.024) [695]. When combining both anterior and posterior
reconstruction, where for anterior reconstruction the PPL were sutured to the anterior bladder neck, another RCT
found no improvement compared to a standard anastomosis with no reconstruction [696].

Four RCTs including anterior suspension have also shown conflicting results. Anterior suspension alone
through the pubic periosteum, in the setting of extra-peritoneal RARP, showed no advantage [697]. However,
when combined with posterior reconstruction in RRP, one RCT showed significant improvement in return to
continence at one month (7.1% vs. 26.5%, p = 0.047) and three months (15.4% vs. 45.2%, p = 0.016), but not
at six months (57.9% vs. 65.4%, p = 0.609) [698]. Another anterior plus posterior reconstruction RCT using the
Advanced Reconstruction of VesicoUrethral Support (ARVUS) technique and the strict definition of continence
of ‘no pads‘, showed statistically significant improvement in continence at 2 weeks (43.8% vs. 11.8%), 4 weeks
(62.5% vs. 14.7%), 8 weeks (68.8% vs. 20.6%), six months (75% vs. 44.1%) and twelve months (86.7% vs. 61.3%),
when compared to standard posterior Rocco reconstruction [699]. Anterior suspension alone through the DVC
and PPL combined without posterior construction in the setting of RARP has shown improvement in continence
at one month (20% vs. 53%, p = 0.029), three months (47% vs. 73%, p = 0.034) and six months (83% vs. 100%,
p = 0.02), but not at twelve months (97% vs. 100%, p = 0.313) [700]. Together, these results suggest a possible
earlier return to continence, but no long-term difference.

A novel method of urethral reconstruction with peritoneal support flaps was shown in a randomised trial
compared to standard RARP (n = 96) to improve urinary continence recovery (0-1 pad) at 1-month (73% vs.
49%, p = 0.017) and 3-months (93% vs 77%, p = 0.025); however, patient reported outcomes, complications and
oncological outcomes were similar [701].

As there is conflicting evidence on the effect of anterior and/or posterior reconstruction on return to continence
post-RP, no recommendations can be made. However, no studies showed an increase in adverse oncologic
outcome or complications with reconstruction.

6.2.2.4.2 Deep venous thrombosis prophylaxis

As with all pelvic cancer surgery lasting over one hour there is a measurable increased risk of deep vein
thrombosis and so consideration should be given to chemical thrombosis prophylaxis, commonly used for 3 to 4
weeks after surgery. This should be adapted based on national recommendations, when available.

6.2.3 Radiotherapy
Intensity-modulated RT (IMRT) or volumetric modulated arc therapy (VMAT) with image-guided RT (IGRT) is
currently widely recognised as the standard treatment approach for EBRT.

6.2.3.1 External beam radiation therapy

6.2.3.1.1 Technical aspects
Intensity-modulated RT and VMAT employ dynamic multi-leaf collimators, which automatically and continuously
adapt to the contours of the target volume seen by each beam. Viani et al., show significantly reduced acute and
late grade ≥ 2 genito-urinary (GU) and gastro-intestinal (GI) toxicity in favour of IMRT, while BCR-free rates did not
differ significantly when comparing IMRT with three-dimensional conformal RT (3D-CRT) in a RCT comprising
215 patients [702]. A meta-analysis by Yu et al., (23 studies, 9,556 patients) concluded that IMRT significantly
decreases the occurrence of grade 2–4 acute GI toxicity, late GI toxicity and late rectal bleeding, and achieves
better PSA relapse-free survival in comparison with 3D-CRT. Intensity-modulated EBRT and 3D-CRT show
comparable acute rectal toxicity, late GU toxicity and OS, while IMRT slightly increases the morbidity of acute GU
toxicity [703]. Thus, IMRT plus IGRT remain the SOC for the treatment of PCa.

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The advantage of VMAT over IMRT is shorter treatment times, generally two to three minutes in total. Both
techniques allow for a more complex distribution of the dose to be delivered and provide concave isodose
curves, which are particularly useful as a means of sparing the rectum. Radiotherapy treatment planning
for IMRT and VMAT differs from that used in conventional EBRT, requiring a computer system capable of
‘inverse planning’ and the appropriate physics expertise. Treatment plans must conform to pre-specified dose
constraints to critical organs at risk of normal tissue damage and a formal quality assurance process should be
routine.

With dose escalation using IMRT/VMAT, organ movement becomes a critical issue in terms of both tumour
control and treatment toxicity. Techniques will therefore combine IMRT/VMAT with some form of IGRT (usually
gold marker or cone-beam CT), in which organ movement can be visualised and corrected for in real time,
although the optimum means (number of applications per week) of achieving this is still unclear [704, 705].
Tomotherapy is another technique for the delivery of IMRT, using a linear accelerator mounted on a ring gantry
that rotates as the patient is delivered through the centre of the ring, analogous to spiral CT scanning.

The use of MR-guided adapted RT is still investigational [706]. Planning studies confirm that MR-based adaptive
RT significantly reduces doses to organs at risk (OAR) and this may translate into clinical benefit [707]. Although
the rates of acute GI- and GU toxicity appear low, mostly on the basis of patients treated with stereotactic
RT [708], follow-up is too short for definitive conclusions [706]. The daily fraction time of up to 45 minutes
[706, 708], the heavy MR-workflow and the limited field size (rendering most pelvic fields too large) make its
implementation not yet a routine [706]. A prospective single center RCT, the MIRAGE trial (CT-guided Stereotactic
Body Radiation Therapy and MRI-guided Stereotactic Body Radiation Therapy for Prostate Cancer) demonstrates
reduced acute GU and GI toxicity with MRI-guided SBRT and margin reduction from 4 mm to 2 mm [709]. The
impact on long term toxicity, biochemical control and cost effectiveness remains undefined.

6.2.3.1.2 Dose escalation

Local control is a critical issue for the outcome of RT of PCa. It has been shown that local failure due to
insufficient total dose is prognostic for death from PCa as a second wave of metastases is seen five to ten
years later on [710]. Several RCTs have shown that dose escalation (range 74–80 Gy) has a significant impact
on ten-year biochemical relapse as well as metastases and disease-specific mortality [711-718]. These trials
have generally included patients from several risk groups, and the use of neoadjuvant/adjuvant ADT has varied
(see Table 6.2.6). The best evidence of an OS benefit in patients with intermediate- or high-risk PCa, derives from
a non-randomised but well conducted propensity-matched retrospective analysis of the U.S. National Cancer
Database by Kalbasi et al., including a total of 42,481 patients [719]. If IMRT/VMAT and IGRT are used for dose
escalation, rates of severe late side effects (> grade 3) for the rectum are 2–4% and for the GU tract 2–6%
[713, 720].

The concept of a focal boost to the dominant intraprostatic lesion (DIL) visible on MRI rather than global
prostate dose escalation has been successfully validated in a RCT of 571 intermediate- and high-risk patients
[720]. Patients were randomised between 77 Gy in 35 fractions of 2.2 Gy and the same dose plus a focal boost
up to 18 Gy. Additional ADT was given to 65% of patients in both arms. However, the duration of the ADT was
not reported. With a median follow-up of 72 months there was a moderate improvement of biochemical PFS
(BPFS) (primary endpoint). In addition, focal boosting decreased local failure (HR: 0.33) and increased the rate
of regional + distant MFS (HR: 0.58) [721]. No significant difference for late GU- or GI toxicity grade ≥ 2 (23% and
12% vs. 28% and 13%) was documented. For grade ≥ 3 GU-toxicity these numbers were 3.5% and 5.6% (p > 0.05).
However, longer follow-up is needed to assess late GU-toxicity [721]. Of note, there was a clear decrease in
biochemical failure with increasing boost dose, individually given up to 18 Gy. Systematic review of MRI-defined
DIL focal boost studies using standard fractionation shows good tolerability and improved BPFS [722]. Its role
when using hypofractionation and ultra-hypofractionation is under investigation.

6.2.3.1.3 Hypofractionation
Fractionated RT utilises differences in the DNA repair capacity of normal and tumour tissue and slowly
proliferating cells are very sensitive to an increased dose per fraction [723]. A meta-analysis of 25 studies
including > 14,000 patients concluded that since PCa has a slow proliferation rate, hypofractionated RT could be
more effective than conventional fractions of 1.8–2 Gy [724]. Hypofractionation (HFX) has the added advantage
of being more convenient for the patient at lower cost.
Moderate HFX is defined as RT with 2.5–3.4 Gy/fx. Several studies report on moderate HFX applied
in various techniques also including ADT in part [725-732]. A Cochrane review on moderate HFX for clinically
localised PCa [733] included eleven studies (n = 8,278) with a median follow-up of 72 months showing little
or no difference in PCa-specific survival (HR: 1.00). Based on four studies (n = 3,848), moderate HFX to the

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 71

protstate alone probably makes little or no difference to late radiation GU toxicity (RR: 1.05) or GI toxicity (RR:
1.1). Toxicity outcomes in two RCTs recruiting high risk patients and adding elective pelvic nodal radiation
have reported. The PCS-5 multicentre RCT recruited high risk patients (25.9% T3-4) and an initial two-year
toxicity analysis demonstrated comparable G2+ GI toxicity across treatment arms with lower rates of late G2+
GU toxicity with HFX [734]. No differences were seen in survival outcomes at median follow-up of five years,
although as secondary endpoints extrapolation of survival results is limited by small sample size [735]. In
the single centre randomized pHART2-RCT an increase in five-year G3+ GI toxicity was noted when HFX was
combined with elective pelvic nodal RT [736]. In the post-operative setting, moderate HFX is non-inferior in terms
of two-year patient reported toxicity to conventional fractionation with similar rates of patient reported GI and
GU toxicity [737].

Ultra-HFX has been defined as RT with > 3.4 Gy per fraction [732]. It requires IGRT and (ideally) stereotactic body
RT (SBRT). Table 6.2.8 provides an overview of selected studies investigating its role in treating predominantly
intermediate risk localised disease. Short-term biochemical control (5-years) is comparable to conventional
fractionation. However, there are concerns about higher-grade GU toxicity and SBRT should be avoided in
patients with severe pre-existing LUTS and/or outflow obstruction with or without median lobe [738, 739]. In the
HYPO-RT-PC randomised trial by Widmark et al., (n = 1,200), no difference in failure-free survival was seen for
conventional or ultra-HFX but acute grade ≥ 2 GU toxicity was 23% vs. 28% (p = 0.057), favouring conventional
fractionation. There were no significant differences in long-term toxicity [738]. A SR by Jackson et al., included
38 studies with 6,116 patients who received RT with < 10 fractions and ≥ 5 Gy per fraction. Five and seven-year
biochemical recurrence-free survival (BRFS) rates were 95.3% and 93.7%, respectively, and estimated late grade
≥ 3 GU and GI toxicity rates were 2.0% and 1.1%, respectively [740]. The authors conclude that there is sufficient
evidence to support SBRT as a standard treatment option for localised PCa, even though the median follow-up
in this review was only 39 months and it included at least one trial (HYPO-RT-PC) which used 3D-CRT in 80% and
IMRT/VMAT in the remainder for ultra-HFX. In their review on SBRT, Cushman et al., evaluated fourteen trials,
including 2,038 patients and concluded that despite a lack of long-term follow-up and the heterogeneity of the
available evidence, prostate SBRT affords appropriate biochemical control with few high-grade toxicities [741].
In the Intensity-modulated fractionated RT vs. stereotactic body RT for PCa (PACE-B) trial, acute grade ≥ 2 GU
or GI toxicities did not differ significantly between conventional fractionation and ultra- HFX [742]. At two years,
treatment was well tolerated in both arms with no differences in RTOG ≥ Grade 2 GU or GI toxicities, but clinician
scoring of urinary toxicity using CTCAE and patient reported Expanded Prostate Cancer Index Composite (EPIC)-
26 urinary bother scores were both higher in the SBRT arm [743]. After 74 months median follow-up, 5-year
biochemical/clinical failure free-rates were 94.6% (95% CI 91.9%, 96.4%) in the control arm and 95.8% (95% CI
93.3%, 97.4%) in the SBRT arm confirming SBRT is non-inferior (HR 0.73 90% CI 0.48-1.12, p for non-inferiority
=0.004). The cumulative 5-year rate of late RTOG grade 2+ GI toxicity was similar in both arms (10%) but
higher rates of cumulative 5-year RTOG grade2+ GU toxicity occurred with SBRT, at 26.9% (95%CI 22.8,31.5%)
compared to the control arm at 18.3% (95%CI 14.8,22.5%). The GU toxicity is temporary with no statististical
difference in clinician reported toxicity between groups at 5 years and no clinically relevant difference in patient
reported outcomes in the five years of follow-up. Adopting planning dose constraints to the penile bulb might
minimise ED, especially in younger patients [744].

First results of a small (n = 30) randomised phase-II trial in intermediate-risk PCa of ‘ultra-high single dose RT’
(SDRT) with 24 Gy compared with an ultra HFX stereotactic body RT regime with 5x9 Gy, have been published
[745].

6.2.3.1.4 Neoadjuvant or adjuvant hormone therapy plus radiotherapy

The combination of RT with luteinising hormone releasing hormone (LHRH) ADT has superiority compared with
RT alone followed by deferred ADT on relapse, as shown by phase III RCTs [745-756] (Table 6.2.9). The main
message is that for intermediate-risk disease a short duration of four to six months is optimal while a longer
one, two to three years, is needed for high-risk patients. The largest RCT in intermediate risk disease comparing
dose escalated RT with or without six months of ADT failed to demonstrate an OS advantage with a median
follow-up time of 6.3 years. Six months of ADT use was associated with reduced PSA failure, fewer distant
metastases and improved prostate cancer specific mortality [756].

The question of the added value of EBRT combined with ADT has been clarified by three RCTs. All showed a
clear benefit of adding EBRT to long-term ADT (Table 6.2.10).

The combination of ADT with various forms of RT has been extensively studied, with extremely strong evidence
for the use of such combined modality therapy in several settings. The MARCAP (Individual Patient Data Meta-
Analysis of Randomised Trials in Cancer of the Prostate) consortium conducted a meta-analysis of trials using
individual patient data (IPD), and a primary endpoint of MFS, a validated surrogate for OS. Trials were eligible if

72 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

they studied the use or prolongation of ADT in patients receiving definitive RT, and included twelve trials with
10,853 patients. Median follow-up was over eleven years. The use of ADT was clearly associated with significant
improvements in BCR, metastatic recurrence, MFS, and OS. The benefits of ADT were independent of RT dose,
age, and risk groups comparing NCCN unfavourable intermediate-risk, high-risk and locally-advanced disease.
There were no demonstrable benefits from the extension of duration of neoadjuvant ADT [757].

A meta-analysis from two RCTs (RTOG 9413 and Ottawa 0101) has compared neoadjuvant/concomitant
vs. adjuvant ADT (without substratifying between favourable- and unfavourable intermediaterisk disease) in
conjunction with prostate RT and reported superior PFS with adjuvant ADT, but the data heterogeneity means
that this observation is hypothesis-generating only [758].

In addition, a Canadian two-arm dose-escalated (76 Gy) RCT compared neoadjuvant and concomitant with
adjuvant short-term ADT in 432 patients with intermediate-risk PCa. After ten years no significant difference in
OS or RT-related grade ≥ 3 GI or GU toxicity was seen [759]. Therefore, both regimen in combination with dose
escalation are reasonable standards.

6.2.3.2 Proton beam therapy

In theory, proton beams are an attractive alternative to photon-beam RT for PCa, as they deposit almost all
their radiation dose at the end of the particle’s path in tissue (the Bragg peak), in contrast to photons which
deposit radiation along their path. There is also a very sharp fall-off for proton beams beyond their deposition
depth, meaning that critical normal tissues beyond this depth could be effectively spared. In contrast, photon
beams continue to deposit energy until they leave the body, including an exit dose. The PARTIQoL Phase III
RCT compared proton beam therapy (PBT) with IMRT in 450 participants with localised prostate cancer. With
a median follow-up of 60.3 months, no difference in any QoL domain or PFS was found [760]. Proton beam
therapy has no advantages over less resource intensive IMRT/VMAT; however, the publication of the full study is
awaited to confirm the results.

Table 6.2.6: Randomised trials of dose escalation in localised PCa

Trial n PCa condition Radiotherapy Follow-up Outcome Results

Dose (median)
MD Anderson 301 T1-T3, N0, M0, 70 vs.78 Gy 15 yr. DM, DSM, All patients:
study 2011 PSA ≤ 10 ng/mL FFF 18.9% FFF at 70 Gy;
[718] PSA 10-20 ng/mL 12% FFF at 78 Gy;
PSA > 20 ng/mL (p = 0.042)
3.4% DM at 70 Gy;
1.1% DM at 78 Gy;
(p = 0.018)
6.2% DSM at 70 Gy;
3.2% DSM at 78 Gy;
(p = 0.043)
No difference in OS
(p > 0.05)
PROG 393 T1b-T2b, PSA ≤ 70.2 vs.79.2 Gy 8.9 yr. 10-yr. ASTRO All patients:
95-09 15 ng/mL including proton BCF 32% BF at 70.2 Gy;
2010 [712] 75% low-risk pts. boost 19.8 vs. 17% BF at 79.2 Gy;
Low-risk: T1-2a, 28.8 Gy (p < 0.0001)
PSA < 10 mg/mL, Low-risk patients:
GS ≤ 6. 28% BF at 70.2 Gy;
Interm-risk: PSA 7% BF at 79.2 Gy;
10-15 ng/mL or (p < 0.0001)
GS 7 or T2b.
High-risk: GS
8-10.
MRC RT01 843 T1b-T3a, N0, M0 64 vs. 74 Gy 10 yr. BFS, OS 43% BFS at 64 Gy;
2014 [717] PSA < 50 ng/mL 55% BFS at 74 Gy;
neoadjuvant ADT (p = 0.0003)
71% OS both groups
(p = 0.96)

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 73

Dutch RCT 664 T1b-T4 143 68 vs. 78 Gy 110 mo. Freedom 43% FFF at 68 Gy; 49%
2014 [716] pts. with (neo) biochemical FFF at 78 Gy;
adjuvant ADT (Phoenix) (p = 0.045)
and/or
clinical
failure at 10
yr.
GETUG 06 306 T1b-T3a, N0, M0 70 vs. 80 Gy 61 mo. BCF (ASTRO) 39% BF at 70 Gy;
2011 [715] PSA < 50 ng/mL 28% BF at 80 Gy
RTOG 0126 1,532 T1b-T2b 70.2 vs. 79.2 Gy 100 mo. OS, DM, BCF 75% OS at 70.2 Gy;
2018 [711] ISUP GG 1 + PSA (ASTRO) 76% OS at 79.2 Gy
10-20 ng/mL or 6% DM at 70.2 Gy;
ISUP GG 2/3 + 4% DM at 79.2 Gy;
PSA < 15 ng/mL (p = 0.05)
47% BCF at 70.2 Gy;
31% BCF at 79.2 Gy;
(p < 0.001; Phoenix,
p < 0.001)
FLAME Trial 571 EAU risk 77 Gy (35 Fx. 72 mo. BFS (5 yr.) BFS: 92% at 77 Gy +
[720, 721] classification: 2.2 Gy) vs. 77 DSM (5 yr.) boost; 85% at 77 Gy;
Intermediate risk Gy 35 Fx.) + (p < 0.001, HR: 0.45)
(15%) focal boost (up DSM: p= 0.49
High risk (84%) to 18 Gy) Focal boost in favour
ADT (65% both of: Local control
arms - duration (HR: 0.33); Distant
unknown) MFS (HR: 0.58)
ADT = androgen-deprivation therapy; BF = biochemical failure; BFS = biochemical progression-free survival; DM =
distant metastases; DSM = 50disease specific mortality; FFF = freedom from biochemical or clinical failure; Fx =
fractions; GS = Gleason score; ISUP = International Society of Urological Pathology; MFS = metastasis-free survival;
mo. = months; n = number of patients; OS = overall survival; PSA = prostate-specific antigen; yr. = year.

Table 6.2.7: Major phase III randomised trials of moderate hypofractionation for primary treatment

Study/ n Risk, ISUP ADT RT Regimen BED, Gy Follow-up Outcome

Author GG, or NCCN (median)
Lee, et al. 550 low risk None 70 Gy/28 fx 80 150 mo. 12 yr. DFS 56.1%
2024 [761] 542 73.8 Gy/41 fx 69.6 (95% CI, 51.5
to 60.5) control
arm and 61.8%
(95% CI, 57.2 to
66.0) for HFX.
HR 0.85 (95% CI,
0.71 to 1.03)
Dearnaley, 1,077/19 fx 15% low 3-6 mo. 57 Gy/19 fx 73.3 62 mo. 5 yr. BCDF
et al. CHHiP 1,074/20 fx 73% before 60 Gy/20 fx 77.1 85.9% (19 fx)
2016 [728] 1,065/37 fx intermediate and 74 Gy/37 fx 74 90.6% (20 fx)
12% high during 88.3% (37 fx)
EBRT
De Vries, et 403 30% ISUP None 64.6 Gy/19 fx 90.4 89 mo. 8-yr. OS 80.8%
al. 2020 392 GG 1 78 Gy/39 fx 78 vs. 77.6%
45% ISUP GG (p = 0.17)
2-3, 8 yr. TF 24.4% vs.
25% ISUP GG 26.3%
4-5

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Catton, et al. 608 Intermediate None 60 Gy/20 fx 77.1 72 mo. 5 yr. BCDF both
2017 [730] risk arms 85%
53% T1c HR: 0.96 (n.s)
46% T2a-c
598 9% ISUP 77.1 78 Gy/39 78
GG 1 fx
63% ISUP
GG 2
28% ISUP
GG 3
Glicksman 186 All high risk 22 mo. 68Gy to 82 67 mo. No difference
et al. 2024 N0M0 median prostate (SIB) in acute toxicity
PHART-2 T1-2 82.8% + 48Gy to and PROs
[736] T3-4 12.2% pelvis in 25 fx Higher 5-yr
cumulative G3+
78Gy to 78 GI in HFX 13.5%
prostate + (95% CI, 7.1%-
46Gy to pelvis 21.9%) vs 2.4%
in 39 fx (95% CI, 0.5%-
7.6%) (P = .01)
Niazi, et al. 329 All high risk 28 mo. 68Gy to 82 24 mo. Similar 2yr
2023 N0M0 - 3 mo. prostate (SIB) G2+ GI toxicity
PCS-5 [734] T1-2 73.8% before + 45Gy to (8-10%)
T3-4 25.9% during pelvis in 25 fx
and Reduced 2yr G2+
after 76Gy to 76 GU toxicity with
EBRT prostate + HFX
46Gy to pelvis (4.3% vs 15.9%;
in 38 fx p=0.035)
ADT = androgen deprivation therapy; BCDF = biochemical or clinical disease failure; BED = biologically equivalent
dose, calculated to be equivalent in 2 Gy fractions using an α/ß of 1.5 Gy; DFS = diseasefree survival; EBRT
= external beam radiotherapy; HFX = hypofractionation; FU = follow-up; fx = fractions; HR = hazard ratio;
ISUP = International Society of Urological Pathology; mo. = month; n = number of patients; NCCN = National
Comprehensive Cancer Network; n.s. = not significant; TF = treatment failure; yr. = year.

Table 6.2.8: Selected trials on ultra-hypofractionation for intact localised PCa

Study n med FU Risk-Group Regimen (TD/fx) Outcome

(mo)
Widmark et al. 1,200 60 89% intermediate 78 Gy / 39 fx, 8 wks FFS at 5 yrs
2019 HYPO-RT- 11% high 42.7 Gy / 7 fx, 2.5 wks 84% in both arms
PC [738] No SBRT
Brand et al. 2019 874 74 9.3% NCCN low 78 Gy / 39 fx, 7.5 wks or Biochemical/clinical
Tree et al. 2022 90.7% NCCN 62 Gy/ 20 fx 4wks FFS at 5 yrs 94.6%
Van As et al. intermediate 36.25 Gy / 5 fx, 1-2 wks (CRT) vs. 95.6% (SBRT)
2024 [743] ISUP GG 3 excluded SBRT Cumulative 5-yr G
PACE-B [742] 2+ GI toxicity similar
[739] (10%)
Cumulative 5-yr G2+
GU SBRT 26.9% (95%CI
22.8,31.5%)
CRT 18.3% (95%CI
14.8,22.5%).
FFS = failure-free survival; FU = follow-up; fx = number fractions; mo. = months; n = number of patients; TD = total
dose; SBRT = stereotactic body radiotherapy; CRT = control arm RT; wk. = weeks; yr. = years; ns=not significant.

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 75

Table 6.2.9: Selected studies of use and duration of ADT in combination with RT for PCa

Study TNM stage n Trial ADT RT Effect on OS

RTOG 85-31 T3 or N1 M0 977 EBRT ± ADT Orchiectomy or 65–70 Gy Significant benefit for
2005 [747] LHRH agonist combined treatment
15% RP (p = 0.002) seems to
be mostly caused by
patients with ISUP grade
group 2-5
RTOG 94-13 T1c–4 N0–1 1,292 ADT timing 2 mo. Whole No significant difference
2007 [751] M0 comparison neoadjuvant pelvic RT vs. between neoadjuvant
plus prostate plus concomitant vs.
concomitant vs. only; 70.2 Gy adjuvant androgen
4 mo. Adjuvant suppression therapy
suppression groups (interaction
suspected)
RTOG 86-10 T2–4 N0–1 456 EBRT ± ADT Goserelin plus 65–70 Gy RT No significant difference
2008 [748] flutamide at 10 yr.
2 mo. before,
plus
Concomitant
therapy
D’Amico AV, T2 N0 M0 206 EBRT ± ADT LHRH agonist 70 Gy Significant benefit that
et al. 2008 (localised plus flutamide 3D-CRT may pertain only to
[749] unfavourable for 6 mo. men with no or minimal
risk) co-morbidity (HR: 0.55,
95% CI: 0.34-0.90, p =
0.01)
RTOG 92-02 T2c–4 N0–1 1,554 Short vs. LHRH agonist 65–70 Gy p = 0.73, p = 0.36 overall;
2008 [752] M0 prolonged given for 2 yr. significant benefit (p =
ADT as adjuvant 0.044) (p = 0.0061) in
after 4 mo. as subset with ISUP grade
neoadjuvant group 4-5
EORTC T1c-2ab N1 970 Short vs. LHRH agonist 70 Gy Better result with 3 yr.
22961 2009 M0, T2c-4 prolonged for 6 mo. vs. 3D-CRT treatment than with 6 mo.
[753] N0-1 M0 ADT 3 yr. (3.8% improvement in
survival at 5 yr.)
EORTC T1-2 poorly 415 EBRT ± ADT LHRH agonist 70 Gy RT Significant benefit at
22863 2010 differentiated for 3 yr. 10 yr. for combined
[746] and M0, or (adjuvant) treatment (HR: 0.60,
T3-4 N0-1 M0 95% CI: 0.45-0.80, p =
0.0004).
TROG 96-01 T2b–4 N0 M0 802 Neoadjuvant Goserelin plus 66 Gy No significant difference
2011 [750] ADT flutamide 3D-CRT in OS reported; benefit in
Duration 3 or 6 mo. PCa-specific survival (HR:
before, plus 0.56, 95% CI: 0.32-0.98, p
concomitant = 0.04) (10 yr.: HR: 0.84,
suppression 0.65-1.08, p = 0.18)
RTOG 99-10 intermediate 1,579 Short vs. LHRH + 70.2 Gy 67 vs. 68%, p = 0.62,
2015 [754] risk 94% prolonged bicalutamide 2D/3D confirms 8 + 8 wk. LHRH
T1-T2; 6% T3-4 ADT 6 mo. 4 as a standard
mo.prior to RT
PCSIII 2020 Intermediate 600 76 Gy alone LHRH + 70 vs. 76 Gy Significantly improved
[755] risk vs. 76 Gy + bicalutamide biochemical failure-free
ADT vs. 70 6 mo. and PCa-specific survival
Gy + ADT 4 mo. prior to for ADT arms, with no
RT difference in OS.

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RTOG 0815 Intermediate 1,492 Dose LHRH agonist/ 79.2Gy (89%) No difference in OS.
2023 [756] risk escalated RT antagonist + 45Gy + BT Significantly improved
± ADT bicalutamide boost biochemical failure-free,
or flutamide 6 (11%) metastatic-free survival
mo. 2 mo. prior and PCa-specific survival
to RT for ADT arm.
ADT = androgen deprivation therapy; CI = confidence interval; EBRT = external beam radiotherapy in standard
fractionation; HR = hazard ratio; ISUP = International Society of Urological Patholohy; LHRH = luteinising hormone-
releasing hormone; mo. = months; n = number of patients; OS = overall survival; RP = radical prostatectomy; RT =
radiotherapy; BT = brachytherapy; wk = week; yr. = year; 3D-CRT = three-dimensional conformal radiotherapy.

Table 6.2.10: Selected studies of ADT in combination with, or without, RT for PCa

Study TNM stage n Trial design ADT RT Effect on OS

SPCG-7/ T1b-2 WHO 875 ADT ± EBRT LHRH agonist 70 Gy 34% (95% CI: 29-39%) vs.
SFUO-3 2016 Grade 1-3, T3 for 3 mo. Plus 3D-CRT 17% (95% CI: 13-22% CSM
[763] N0 M0 continuous vs. no RT at 12 (15) yr. favouring
flutamide combined treatment (p <
0.0001 for 15-yr. results)
NCIC CTG PR.3/MRC
PRO7/NCIC T3-4 (88%), PSA 1,205 ADT ± EBRT Continuous 65–70 Gy 10-yr. OS = 49% vs. 55%
2015 [764] > 20 ng/mL LHRH agonist 3D-CRT favouring combined
(64%), ISUP GG vs. no RT treatment HR: 0.7, p <
4-5 (36%) N0 M0 0.001)
Sargos, et al., T3-4 N0 M0 273 ADT ± EBRT LHRH agonist 70 Gy Significant reduction of
2020 [765] for 3 yr. 3D-CRT clinical progression; 5-yr. OS
vs. no RT 71.4% vs. 71.5%
ADT = androgen-deprivation therapy; CSM = cancer-specific mortality; EBRT = external beam radiotherapy; HR =
hazard ratio; LHRH = luteinising hormone-releasing hormone; mo. = months; n = number of patients; OS = overall
survival; PSA = prostate-specific antigen; RT = radiotherapy; 3D-CRT = three-dimensional conformal radiotherapy;
yr = years.

6.2.3.3 Spacer during external beam radiation therapy

Biodegradable spacer insertion involves using a liquid gel or balloon to increase the distance between the
prostate and rectum and consequently reduce the amount of radiation reaching the rectum. Various materials
have been used with most evidence available for CE-marked hydrogel spacers [766]. A meta-analysis including
one RCT and six cohort studies using the hydrogel spacer demonstrated a 5–8% reduction in the rectal volume
receiving high-dose radiation, although heterogeneity between studies is found [767]. In the final analysis of
the RCT with a median follow-up of 37 months and with approximately two-thirds of patients evaluable, those
treated with spacer in situ had no deterioration from baseline bowel function whilst those treated without
spacer had a lower mean bowel summary score of 5.8 points which met the threshold for a minimally important
difference of 4–6 points [768].
This meta-analysis highlights inconsistent reporting of procedural complications. In addition, with
more widespread clinical use safety reports describe uncommon, but severe and life changing, complications
including prostatic abscess, fistulae and sepsis [769]. Implantation is associated with a learning curve and
should only be undertaken by teams with experience of TRUS and transperineal procedures with robust audit
reporting in place [769]. Its role in the context of moderate or extreme HFX is as yet unclear.

6.2.3.4 Brachytherapy
6.2.3.4.1 Low-dose rate brachytherapy
Low-dose rate (LDR) BT uses radioactive seeds permanently implanted into the prostate. Low-dose rate
monotherapy [770] can be offered to patients with NCCN favourable intermediate-risk and good urinary function
defined as an International Prostatic Symptom Score (IPSS) < 12 and maximum flow rate > 15 mL/min on
urinary flow tests [771]. The RTOG phase III RCT compared LDR BT +/- EBRT in participants with Gleason grade 6
and PSA < 20 or Gleason grade 7 and PSA < 10 and found that the addition of EBRT resulted in increased toxicity
but no improvement in freedom from progression [772].

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Patients having had a previous TURP can undergo BT without an increase in risk of urinary toxicity with due
attention to dose distribution. A minimal channel TURP is recommended, leaving at least 1 cm rim of prostate
tissue around the post-TURP urethral defect at the postero-lateral sides of the prostate and there should be at
least a three-month interval between TURP and BT to allow for adequate healing [773-776].

The only available RCT comparing RP and LDR BT as monotherapy was closed due to poor accrual [777].
Outcome data are available from a number of large population cohorts with mature follow-up [778-782]. A
significant correlation has been shown between the implanted dose and biochemical control [783]. A D90 (dose
covering 90% of the prostate volume) of > 140 Gy leads to a significantly higher biochemical control rate (PSA <
1.0 ng/mL) after four years (92 vs. 68%). There is no OS benefit in adding neoadjuvant or adjuvant ADT to LDR
monotherapy [784].

Low-dose rate BT can be combined with EBRT in NCCN unfavourable intermediate-risk PCa and high-risk
patients. External beam RT (total dose of 78 Gy) has been compared with EBRT (total dose 46 Gy) followed
by LDR BT boost (prescribed dose 115 Gy) in intermediate-risk and high-risk patients in the ASCENDE-RT
randomised trial with twelve months of ADT in both arms [785, 786]. The LDR boost resulted in 5-, 7-year and
10-year PSA PFS increase (89%, 86% and 85% respectively, compared to 84%, 75%, 70%) but with no impact
on distant metastasis or OS. This improvement in biochemical control was achieved at a cost of increased
late grade 3+ GU toxicity (18% compared to 8%) and two treatment related deaths [786, 787]. Urinary toxicity
was mainly in the development of urethral strictures and incontinence and great care should be taken during
treatment planning.

6.2.3.4.2 High-dose rate brachytherapy

High-dose rate (HDR) BT uses a radioactive source temporarily introduced into the prostate to deliver radiation.
The technical differences are outlined in Table 6.2.11. The use of the GEC (Groupe Europeen de Curietherapie)/
ESTRO Guidelines is strongly recommended [788]. High-dose rate BT can be delivered in single or multiple
fractions and is often combined with EBRT of at least 45 Gy, conventionally fractionated [789]. A retrospective
analysis on 1641 intermediate and high-risk patients demonstrated a better distant-metastasis free survival
when a HDR BT boost was added to 50 – 54 Gy EBRT. The difference mounted to 12% at ten years [790]. A SR
of non-RCTs and data from population studies suggest outcomes with EBRT plus HDR BT are superior to EBRT
alone [791, 792].

A single-centre RCT of EBRT (55 Gy in 20 fractions) vs. EBRT (35.75 Gy in 13 fractions), followed by HDR BT
(17 Gy in two fractions over 24 hours) has been reported [793]. In 218 patients with T1–3 N0M0 PCa the
combination of EBRT and HDR BT showed a significant improvement in the biochemical disease-free rate (p =
0.04) at five and ten years (75% and 46% compared to 61% and 39%). However, an unexpectedly high rate of
early recurrences was observed in the EBRT arm alone, even after two years, possibly due to a dose lower than
the current standard used [793].

Supporting, but not definitive, evidence of the benefit of HDR boost is available from the TROG 03.04 RADAR
trial. This multi-centre study had upfront radiation dose escalation (non-randomised) with dosing options of 66,
70, or 74 Gy EBRT, or 46 Gy EBRT plus HDR BT boost and randomised men with locally-advanced PCa to 6 or
18 months ADT. After a minimum follow-up of ten years HDR boost significantly reduced distant progression,
the study primary endpoint (HR: 0.68, 95% CI: 0.57–0.80; p < 0.0001), when compared to EBRT alone and,
independent of duration of ADT, HDR boost was associated with increased IPSS of 3 points at eighteen months
post-treatment resolving by three years but decreased rectal symptoms when compared to EBRT [794]. Although
radiation dose escalation using BT boost provides much higher biological doses, the TROG 03.04 RADAR RCT
and SRs show ADT use independently predicts better outcomes regardless of radiation dose intensification
[784, 794, 795]. Omitting ADT may result in inferior OS and based on current evidence ADT use and duration
should be in line with that used when delivering EBRT alone.

Fractionated HDR BT as monotherapy can be offered to patients with intermediate-risk PCa, who should be
informed that results are only available from limited series in very experienced centres. Five-year PSA control
rates of 93.5% for intermediate-risk PCa are reported, with late grade 3+ GU toxicity rates < 5% and no, or very
minimal, grade 3+ GI toxicity rates [796]. Single fraction HDR monotherapy should not be used as it has inferior
biochemical control rates compared to fractionated HDR monotherapy [797].

78 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Table 6.2.11: Difference between LDR and HDR brachytherapy

Differences in prostate brachytherapy techniques

Low dose rate (LDR) • Permanent seeds implanted
• Uses Iodine-125 (I-125) (most common)
• Palladium-103 (103Pd-) or Cesium-131 isotopes
• Radiation dose delivered over weeks and months
• Acute side effects resolve over months
• Radiation protection issues for patient and carers
High dose rate (HDR) • Temporary implantation
• Iridium-192 (IR-192) isotope introduced through implanted needles or
catheters
• Radiation dose delivered in minutes
• Acute side effects resolve over weeks
• No radiation protection issues for patient or carers

6.2.3.5 Acute side effects of external beam radiotherapy and brachytherapy

Gastro-intestinal and urinary side effects are common during and after EBRT. In the EORTC 22991 trial,
approximately 50% of patients reported acute GU toxicity of grade 1, 20% of grade 2, and 2% grade 3. In the
same trial, approximately 30% of patients reported acute grade 1 GI toxicity, 10% grade 2, and less than 1%
grade 3. Common toxicities included dysuria, urinary frequency, urinary retention, haematuria, diarrhoea, rectal
bleeding and proctitis [798]. In addition, general side effects such as fatigue are common. It should be noted
that the incidence of acute side effects is greater than that of late effects, implying that most acute effects
resolve.
In a RCT comparing patient reported QoL after LDR or HDR boost combined with external beam
radiotherapy to the pelvis, more intense and prolonged acute urinary side-effects are noted with LDR boost [799].
In a RCT of conventional dose EBRT vs. EBRT and LDR BT the incidence of acute proctitis was reduced in the BT
arm, but other acute toxicities were equivalent [785]. In a pooled analysis of 864 patients treated using extreme
HFX and stereotactic RT, declines in urinary and bowel domains were noted at three months which returned to
baseline, or better, by six months [800].

6.2.4 Investigational therapies

6.2.4.1 Background
Besides RP, EBRT and BT, other modalities have emerged as potential therapeutic options in patients with
clinically localised PCa [801-803]. These new modalities have been developed as minimally invasive procedures
with the aim of providing equivalent oncological safety, reduced toxicity, and improved functional outcomes. In
this section, both whole gland- and focal treatment [804, 805] will be considered, looking particularly at high-
intensity focused US (HIFU), cryotherapeutic ablation of the prostate (cryotherapy) and focal photodynamic
therapy (PDT), as sufficient data are available to form the basis of some initial judgements. Other options such
as radiofrequency ablation (RFA) and electroporation, among others, are considered to be in the early phases of
evaluation [804].

High-intensity focused US consists of focused US waves emitted from a transducer that cause tissue damage
by mechanical and thermal effects as well as by cavitation [806]. The goal of HIFU is to heat malignant tissue
above 65°C, so that it is destroyed by coagulative necrosis. High-intensity focused US is performed under
general or spinal anaesthesia, with the patient lying in the lateral or supine position. Since the ultrasound energy
is most often delivered from the rectal cavity, HIFU faces challenges in delivering energy to the anterior part in
large prostates.

Cryotherapy uses freezing techniques to induce cell death by dehydration resulting in protein denaturation, direct
rupture of cellular membranes by ice crystals and vascular stasis and microthrombi, resulting in stagnation of
the microcirculation with consecutive ischaemic apoptosis [801-803]. Freezing of the prostate is ensured by
the placement of 17-gauge cryo-needles under TRUS guidance, placement of thermosensors at the level of the
external sphincter and rectal wall, and insertion of a urethral warmer. Two freeze-thaw cycles are used under
TRUS guidance resulting in a temperature of -40°C in the mid-gland and at the neurovascular bundle. Currently,
third and fourth generation cryotherapy devices are mainly used.

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6.2.4.2 Whole-gland therapies
Whole gland treatments using cryosurgery and HIFU were investigated as a replacement for surgery or
radiotherapy, with limited success. The main adverse effects of whole-gland cryosurgery are ED (18%), urinary
incontinence (2–20%), urethral sloughing (0–38%), rectal pain and bleeding (3%) and recto-urethral fistula
formation (0–6%) [807]. There is a lack of prospective comparative data regarding oncological outcomes of
whole-gland cryosurgery as a curative treatment option for men with localised PCa, with most studies being
non-comparative single-arm case series with short follow-up [807].

High-intensity focused US has previously been widely used for whole-gland therapy with the following adverse
effects: acute urinary retention (10%), ED (23%), urethral stricture (8%), rectal pain or bleeding (11%), recto-
urethral fistula (0–5%) and urinary incontinence (10%) [807]. Combining the whole-gland HIFU treatment with
TURP reduces the rate of urethral strictures, maintains the level of incontinence, but increases the rate of ED
[808].

Overall, the lack of any long-term prospective comparative studies, and data to suggest poor long-term
oncological outcomes for men with high-risk localised disease [809] prevents whole-gland HIFU from being
considered as a reasonable alternative to the established curative treatment options [807]. In addition, the
expected improvements in functional outcome failed to materialise with 12% of patient developing incontinence
and 61% developing ED [810].

6.2.4.3 Focal therapy

During the past two decades, there has been a trend towards earlier diagnosis of PCa as a result of greater
public and professional awareness leading to the adoption of both formal and informal screening strategies.
The effect of this has been that men are identified at an earlier stage with smaller tumours, with a greater
propensity for unifocal disease [811-813]. There is also greater awareness of the risks of the consequences
of treatment leading to attempts to ablate only a region of the prostate containing the tumour thereby limiting
toxicity by sparing the neurovascular bundles, sphincter, and urethra [814-816]. The question remains which if
any of these small unifocal tumours need treatment.

A SR included data from 5,827 patients across 72 studies and covered different energy sources including HIFU,
cryotherapy, Photodynamic Therapy (PDT), laser interstitial thermotherapy, focal BT, irreversible electroporation
(IRE) and radiofrequency ablation (RFA) [817]. The review favours HIFU and PDT for their higher quality data,
over 95% of pad-free incontinence and 85–90% of patients without clinically significant cancer in short-term
analysis. This has to be critically analysed, because 45% of all patients with a focal approach included in this
SR had an ISUP Grade GG 1 cancer. The overall quality of the evidence was low, due to the majority of studies
being single-centre, non-comparative and retrospective in design, heterogeneity of definitions and approaches,
follow-up strategies, outcomes, and duration of follow-up. Although the review finds high quality evidence that
focal therapy has favourable functional outcomes and minimises AEs, definitive evidence of oncological benefit
remains unavailable.
A more stringent SR including only prospective studies and per protocol post-treatment biopsies
found that after 1 year 8.8% of patients had an infield failure with ≥ ISUP GG 2 cancers and 13.0% had ≥ ISUP GG
2 cancers anywhere in the prostate [818]. This work did not include any definition of clinical relevant cancer and
included 35% of patients with ISUP GG 1 at initial diagnosis. Focal ablation showed only 9% reduction in sexual
function scores, compared to 43% for whole gland ablation, at one year.

At this time, the largest analysis on oncologic outcomes following focal HIFU includes 1,379 men with a median
follow-up of 32 months (65% of patients were D’Amico intermediate risk and 28% high risk) [819]. In this study,
one repeated focal HIFU session was allowed and performed in 18% of all patients. Parametric MRI was
performed if consecutive PSA rises were identified and biopsies were offered if the mpMRI was suspicious.
Eighty percent of patients had at least one follow-up mpMRI and 44% had a follow-up biopsy. The primary
outcome was failure-free survival (FFS) which was defined as evidence of cancer requiring whole-gland salvage
treatment. At 7 years the FFS for intermediate- and high-risk cancers was 68% and 65%, respectively [819].

At present, there is no well-defined pathway for focal therapy or follow-up and the field is still developing.
The optimal energy source for tumours at different locations, the need for double treatments during initial
therapy, the use of MRI or PSA for follow-up are still a matter of research. The guideline panel acknowledges
the challenges for interventional RCTs [820-822]. The interim analysis and meeting reports demonstrate slow
recruitment, patients declining consent and rejecting their treatment allocation into the RP group (approx.
25%). In an attempt to overcome this propensity-matched analysis using prospective multi-centre databases
have been performed for comparison of focal therapy vs. radical therapy [823, 824]. Such analyses are always
susceptible to unmeasured selection biases in who was selected for each treatment.

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Oncological follow-up data up to eight years can be used to counsel patients in treatment decisions [823, 824].
Patients managed by focal therapy had a HIFU or cryotherapy, with one retreatment, if needed. Of these 17.1%
of patients in the focal arm received a retreatment. The primary outcome was FFS defined as “need for local
or systemic salvage treatment or metastasis”. Both groups included 246 patients with an average PSA of 7.9
ng/mL and 60% ISUP GG 2/3 cancers. The cancer core length was 5–6 mm with 45% having bilateral cancer.
The authors report similar cancer control 8 years after therapy, with FFS and BCR of 83% and 23.9% for focal
therapy vs. 79% and 24.8% for RP, respectively. Similar results were demonstrated in a cohort-based analysis
with a follow-up six years [824]. The use of different definitions for oncological failure in the two arms is another
limitation of these studies. While any recurrence after RP was seen as failure, a second HIFU was permitted
in the focal group. The current data from the HIFU Evaluation and Assessment of Treatment (HEAT) registry
indicates that a repeat-HIFU does not significantly decrease urinary or erectile function [825]. However, this
change of failure definition will have to be re-evaluated. It is important to note, that these results were achieved
in centres with a dedicated focal program where all patients had a mpMRI with targeted and systematic biopsies
or full template mapping biopsies. Therefore, it seems necessary to perform systematic biopsies in patients,
who are candidates for focal therapy.

The impact of salvage therapies after focal therapy was investigated in small series in specialized centres [826,
827]. If a salvage RP is necessary after focal therapy, the reported functional and oncological outcomes are
comparable to treatment-naive patients [828, 829]. In a recent SR including 482 patients from twelve studies, the
authors conclude that, when compared to primary surgery, the salvage radical prostatectomy after focal therapy
has a higher PSM rate of 27% and a slightly worse incontinence rate. Although the early complication rate was
also higher, most of them could be managed conservatively [830].

One comparative RCT was conducted in a very-low risk population, for which there is currently a strong
movement away from any form of active treatment. This study was comparing padeliporfin-based vascular
targeted PDT vs. AS and found at a median follow-up of 24 months that less patients progressed in the PDT
arm compared with the AS arm (adjusted HR: 0.34, 95% CI: 0.24–0.46), and needed less radical therapy (6%
vs. 29%, p < 0.0001). Updated results were published in 2018 showing that these benefits were maintained
after four years [831]. Nevertheless, limitations of the study include an unusually high observed rate of disease
progression in the AS arm (58% in two years) and more patients in the AS arm chose to undergo radical
therapy without a clinical indication which may have introduced confounding bias. Finally, the AS arm did not
undergo any confirmatory biopsy or any MRI scanning, which is not representative of contemporary practice. A
matched-pair analysis comparing focal cryotherapy to AS with 76% ISUP GG 1 cancers failed to demonstrate any
significant advantages for MFS and OS [832].

The available evidence indicates that focal therapy is associated with less AEs than whole gland or radical
treatments. Many of the patients included in these trials would currently be considered to have been over
treated. Robust prospective trials reporting standardised fifteen-year oncological outcomes [833] are needed in
patients with clinically significant cancers before unrestricted recommendations in support of focal therapy for
routine clinical practice can be made [804, 833, 834]. Currently, focal therapy using HIFU or cryotherapy should
be performed within the context of a prospective registry.

All other ablative modalities and treatment strategies should only be offered in well-designed prospective trial
setting. In order to allow quality analysis of the collected data, the prospective registry should adhere to the EMA
recommendations (Guideline on registry-based studies EMA/426390/2021), which emphasises the need for
clear follow-up timelines and timely recording, completeness of core data of consecutive patients enrolled, an
analysis plan in defined intervals and a data quality management.

6.3 Treatment by disease stages

6.3.1 Management of low-risk disease
6.3.1.1 Watchful waiting
For patients with a life expectancy of < 10 years (based on co-morbidities and age), where curative treatment
would not be an option in the case of progression after AS, WW is standard of care.

6.3.1.2 Active surveillance

Active surveillance should be considered standard of care for all patients with a life expectancy > 10 years
(based on co-morbidities and age) and where curative treatment would be considered in the case of disease
progression.

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6.3.1.2.1 Androgen deprivation monotherapy
The Early Prostate Cancer (EPC) Trial Programme found that in patients with localised disease, ADT
monotherapy did not improve PFS or OS in any of the subgroups, compared with placebo [835]. Instead, there
was a statistically insignificant numerical trend towards worse OS with ADT in the WW sub-group (HR: 1.16,
95% CI: 0.99–1.37; p = 0.07). Although the trial did not directly address men with low-risk disease, it offered
some evidence suggesting that otherwise asymptomatic men with localised disease should not receive ADT
monotherapy.

6.3.1.3 Other therapeutic options

Other treatments such as whole-gland therapy (e.g. RP or RT) or focal ablative therapy remain highly likely to be
overtreatment in the setting of low-risk disease and should not be used outside a trial setting.

6.3.1.4 Recommendations for the management of low-risk disease

Recommendations Strength rating

Manage patients with a life expectancy < 10 years by watchful waiting. Strong
Manage patients with a life expectancy > 10 years and low-risk disease by active Strong
surveillance.

6.3.2 Management of Intermediate-risk disease

6.3.2.1 Watchful waiting
For patients with a life expectancy of < 10 years (based on co-morbidities and age, where curative treatment is
not a direct option or would not be an option in the case of progression after AS, WW is standard of care.

6.3.2.2 Active Surveillance

Although men with less favourable disease characteristics have worse outcomes after any treatment, the
question is whether a delay in curative treatment due to initial AS, leads to additionally unfavourable outcomes.
Intuitively, the higher risk disease, the higher risk of adverse outcomes due to an initial delay. Inclusion is based
on favourable disease characteristics as discussed in section 6.2.1.2.2.

6.3.2.3 Radical prostatectomy

Patients with intermediate-risk PCa should be informed about the results of two RCTs (SPCG-4 and PIVOT)
comparing RRP vs. WW in localised PCa. In the SPCG-4 study, death from any cause (RR: 0.71, 95% CI: 0.53–
0.95), death from PCa (RR: 0.38, 95% CI: 0.23–0.62) and distant metastases (RR: 0.49, 95% CI: 0.32–0.74) were
significantly reduced in intermediate-risk PCa at 18 years. After 30 years follow-up overall (not risk-stratified), RP
reduced death from any cause (RR: 0.74, 95% CI: 0.64–0.87), death from PCa (RR: 0.52, 95% CI: 0.40–0.67) for a
mean of 2.2 life-years (95% CI: 1.4-2.9) gained. In the PIVOT trial, according to a pre-planned subgroup analysis
among men with intermediate-risk tumours, RP significantly reduced all-cause mortality (HR: 0.69, 95% CI:
0.49–0.98), but not death from PCa (0.50, 95% CI: 0.21–1.21) at ten years [836]. In the ProtecT trial, 24% of the
population were intermediate risk (at baseline) and no significant difference in prostate cancer deaths was seen
for RP versus active monitoring (with delayed active treatment, HR 0.68 (0.11–4.05). A meta-analysis based on
the findings of SPCG-4, PIVOT and ProtecT demonstrated a benefit from RP over observation with a significantly
decreased risk of death of 9% and of disease progression of 43% [837]. However, no stratification by disease
stages was performed. A large study found 2.9% of LN invasion in a contemporary cohort of 6,883 patients
undergoing RP and LND for intermediate risk PCa [838].

6.3.2.4 Radiation therapy

6.3.2.4.1 Recommended IMRT/VMAT
Ultra-hypofractionated IMRT/IGRT or SBRT, using either 36.25 Gy (40 Gy to prostate) in 5 fx or 42.7 Gy in 7 fx
can be offered to patients with NCCN favourable intermediate and good urinary function. Additional ADT is not
required in GG2 disease [739]. Patients undergoing conventional or moderate hypofractionation and suitable
for ADT can be treated with short-term ADT (four to six months) [839-841]. The RTOG 0815 RCT demonstrated
improved BFSR, metastasis free and prostate CSS with the addition of six months ADT to dose escalated
RT [756]. For adjuvant RT of the pelvic lymphatics (45-50 Gy) for NCCN unfavourable intermediate risk (cN0)
see section 6.2.3.2.1. For patients unsuitable (e.g., due to co-morbidities) or unwilling to accept ADT (e.g., to
preserve their sexual health) the recommended treatment is IMRT/VMAT (76–78 Gy or equivalent moderate
HFX) or a combination of IMRT/VMAT and BT as described below. A secondary analysis of the PCS III trial
has suggested that patients with NCCN favourable intermediate-risk disease (see Section 4.4) can safely omit
ADT if their RT dose is 76 Gy, but this is based on an unplanned subgroup analysis and only 138 patients had

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favourable intermediate-risk disease. An individual discussion between the physician and the patient of the
possible benefits and harms of omitting ADT in this group is essential [778].

6.3.2.4.2 Brachytherapy
Systematic review recommends LDR BT monotherapy can be offered to patients with NCCN favourable
intermediate-risk disease and good urinary function (see section 4.4) [842]. Fractionated HDR BT as
monotherapy can be offered to selected patients with intermediate-risk PCa although they should be informed
that results are only available from small series in very experienced centres. Five-year PSA control rates over
90% are reported, with late grade 3+ GU toxicity rates < 5% and no, or very minimal, grade 3+ GI toxicity rates
[796]. There are no direct data to inform on the use of ADT in this setting. Trimodality therapy with IMRT plus BT
boost and short-term ADT can be considered for NCCN unfavourable intermediate-risk PCa (see section 4.4) but
patients should be made aware that the potential improvements in biochemical control are accompanied with
an increased risk of long-term urinary problems [785, 787, 792].

6.3.2.5 Other therapeutic options

6.3.2.5.1 Focal therapy
A prospective study on focal therapy using HIFU in patients with localised intermediate-risk disease was
published but the data was derived from an uncontrolled single-arm case series [834]. There is a paucity of high-
certainty data for any form of focal ablative therapy in the setting of intermediate-risk disease. Consequently,
focal treatment cannot be considered as standard therapy for intermediate-risk patients and, if offered, it should
only be in the setting of clinical trials or prospective registries [804].

6.3.2.5.2 Androgen deprivation therapy monotherapy

Data regarding the use of ADT monotherapy for intermediate-risk disease have been inferred indirectly from
the EORTC 30891 trial, which was a RCT comparing deferred ADT vs. immediate ADT in 985 patients with T0–4
N0–2 M0 disease [843]. The trial showed a small, but statistically significant, difference in OS in favour of
immediate ADT monotherapy but there was no significant difference in CSS, predominantly because the risk of
cancer-specific mortality was low in patients with PSA < 8 ng/mL. Consequently, the use of ADT monotherapy
for this group of patients is not considered as standard, even if they are not eligible for radical treatment.

6.3.2.6 Recommendations for the management of intermediate-risk disease*

Recommendations Strength rating

Expectant management
Offer watchful waiting in asymptomatic patients with life expectancy < 10 years (based on Strong
comorbidities and age).
Offer active surveillance (AS) to selected patients with ISUP grade group 2 disease e.g., Weak
< 10% pattern 4, PSA < 10 ng/mL, ≤ cT2a, low disease extent on imaging and low extent
of tumour in biopsies (≤ 3 positive cores with Gleason score 3+4 and ≤ 50% cancer
involvement/core), or another single element of intermediate-risk disease with low disease
extent on imaging and low biopsy extent, accepting the potential increased risk of metastatic
progression.
Patients with ISUP grade group 3 disease should be excluded from AS protocols. Strong
Re-classify patients with low-volume ISUP grade group 2 disease included in AS protocols, if Weak
repeat non-MRI-based systematic biopsies performed during monitoring reveal > 3 positive
cores or maximum CI > 50%/core of ISUP grade group 2 disease.
Radical prostatectomy (RP)
Offer RP to patients with a life expectancy of > 10 years. Strong
Radical prostatectomy can be safely delayed for at least three months. Weak
Offer nerve-sparing surgery to patients with a low risk of extra-capsular disease on that side. Strong
Radiotherapeutic treatment
Offer low-dose rate (LDR) brachytherapy to patients with good urinary function and NCCN Strong
favourable intermediate-risk disease.
Offer intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) Strong
plus image-guided radiotherapy (IGRT), with a total dose of 76–78 Gy or moderate
hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with
short-term androgen deprivation therapy (ADT) (four to six months).

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Offer focal boosting to MRI-defined dominant intra-prostatic tumour when using Weak
conventionally fractionated IMRT/IGRT (1.8-2.0 Gy per fraction) ensuring that Organ at Risk
constraints are not exceeded
Offer ultra-hypofractionated IMRT/IGRT or SBRT, using either 36.25 Gy (40 Gy to prostate) in 5 Weak
fx or 42.7 Gy in 7 fx delivered alternate days.
Offer LDR brachytherapy boost combined with IMRT/VMAT plus IGRT to patients with good Weak
urinary function and NCCN unfavourable intermediate-risk disease, in combination with short-
term ADT (four to six months).
Offer high-dose rate (HDR) brachytherapy boost combined with IMRT/VMAT plus IGRT to Weak
patients with good urinary function and NCCN unfavourable intermediate-risk disease, in
combination with short-term ADT (four to six months).
Other therapeutic options
Only offer whole-gland ablative therapy (such as cryotherapy, high-intensity focused Strong
ultrasound, etc.) or focal ablative therapy within clinical trials or registries.
Do not offer ADT monotherapy to asymptomatic men not able to receive any local treatment. Weak
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.3.3 Management of high-risk localised disease

Patients with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic
progression and death from PCa. Nevertheless, not all high-risk PCa patients have a uniformly poor prognosis
after RP [844]. When managed with non-curative intent, high-risk PCa is associated with 10-year and 15-year
PCSM rates of 28.8 and 35.5%, respectively [845]. There is no consensus regarding the optimal treatment of
men with high-risk PCa.
Some evidence suggests that radical treatment for high-risk PCa can be delayed up to three months
after the diagnosis without any oncological consequences [846, 847]. Systematic reviews suggest that there is
a higher risk of biochemical recurrence and worse pathological outcomes when definitive treatment is given
beyond a 6 to 9 months delay. However, there is no conclusive data regarding stronger endpoints (CSS or OS).

6.3.3.1 Radical prostatectomy

Provided that the tumour is not fixed to the pelvic wall or there is no invasion of the urethral sphincter, RP is a
standard option in selected patients with a low tumour volume. Patients should be aware pre-operatively that
surgery may be part of multi-modal treatment, with adjuvant or SRT or ADT. Neoadjuvant therapy using ADT is
not indicated [848].

6.3.3.2 External beam radiation therapy

For high-risk localised PCa, a combined modality approach should be used consisting of IMRT/VMAT plus long-
term ADT. The duration of ADT has to take into account PS, co-morbidities and the number of poor prognostic
factors. It is important to recognise that in several studies EBRT plus short-term ADT did not improve OS in
high-risk localised PCa and long-term ADT (at least two to three years) is currently recommended for these
patients [748, 749, 757]. Moderate HFX is an option in high-risk patients with localised disease. The CHHiP study
included 12% high-risk patients (n = 386) but limited entry to those with a PSA < 30 ng/mL and a Roach formula
risk of SV involvement < 30% [728]. Patients were ineligible if they had both T3a tumours and ISUP grade group 4
or higher. The PCS-5 RCT used moderate HFX and elective nodal irradiation and efficiacy was equivalent in both
groups [734, 735].

6.3.3.2.1 Lymph node irradiation in cN0

There is no clear evidence for prophylactic irradiation of the pelvic LNs in intermediate- and high-risk disease.
The long-term results of the NRG/RTOG 9413-trial which randomised intermediate-risk and high-risk localised
PCa patients (1,322 cN0 patients were enrolled), showed that neoadjuvant HT plus whole pelvic RT improved
PFS only compared with neoadjuvant ADT plus prostate RT and whole pelvic RT plus adjuvant ADT [849].
However, at the increased risk of ≥ grade 3 GI-toxicity.
A well-conducted single-centre RCT randomised 224 patients comparing prostate-only RT (PORT)
vs. whole pelvic RT (WPRT) in localised high-risk- and locally-advanced tumours (cN0) with a risk of > 20% of
positive nodes (Roach formula). With a median follow-up of 68 months there was a significant improvement
of distant MFS (95.9% vs. 89.2%, HR: 0.35, p = 0.01) and DFS (89.5% vs.77.2%, p = 0.02). However, there was a
significant higher rate of late GU ≥ 2 effects (17.7% vs. 7.5%, p = 0.02), the trial was relatively small in size with
additional limitations and these findings are therefore insufficient to define a change in practice [850, 851]. The
benefits of pelvic nodal irradiation using IMRT/VMAT merit further investigation in large scale RCTs.

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6.3.3.2.2 Brachytherapy boost
In men with NCCN unfavourable intermediate- or high-risk PCa, BT boost with supplemental EBRT and HT may
be considered. See sections 6.2.3.4.1 and 6.2.3.4.2 for details on RCTs comparing EBRT alone and EBRT with
LDR or HDR boost, respectively.

6.3.3.3 Recommendations for the management of high-risk localised disease*

Recommendations Strength rating

Expectant management
Offer watchful waiting to asymptomatic patients with life expectancy < 10 years. Strong
Radical prostatectomy (RP)
Offer RP to selected patients as part of potential multi-modal therapy. Strong
Extended pelvic lymph node dissection (PLND)
In patients undergoing a lymph node dissection you should perform an extended PLND. Strong
Do not perform a frozen section of nodes during RP to decide whether to proceed with, or Strong
abandon, the procedure.
Radiotherapeutic treatment
Offer intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) Strong
plus image-guided radiotherapy (IGRT), with a total dose of 76–78 Gy or moderate
hypofractionation (60 Gy/20 fx in 4 weeks or 70 Gy/28 fx in 6 weeks), in combination with
long-term androgen deprivation therapy (ADT) (two to three years).
Offer focal boosting to MRI-defined dominant intra-prostatic tumour when using normo- Weak
fractionated IMRT/IGRT (1.8-2.0 Gy per fraction) ensuring that Organ at Risk constraints are
not exceeded.
Offer patients with good urinary function IMRT/VMAT plus IGRT with brachytherapy boost Weak
(either high-dose rate or low-dose rate), in combination with long-term ADT (two to three
years).
Therapeutic options outside surgery or radiotherapy
Do not offer either whole gland or focal therapy. Strong
Only offer ADT monotherapy to those patients unwilling or unable to receive any form of Strong
local treatment if they have a prostate-specific antigen (PSA)-doubling time < 12 months,
and either a PSA > 50 ng/mL or a poorly-differentiated tumour.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.3.4 Treatment of locally-advanced PCa

In the absence of high-level evidence, a SR could not define the most optimal treatment option [852].
Randomised controlled trials are only available for EBRT. A local treatment combined with a systemic treatment
provides the best outcome, provided the patient is fit enough to receive both. The initial results of the SCPG-15
trials suggested that randomisation between surgery and EBRT is feasible, but oncologic outcomes are awaited
[853].

6.3.4.1 Radical prostatectomy

Surgery for locally-advanced disease as part of a multi-modal therapy has been reported [845, 854, 855].
However, the comparative oncological effectiveness of RP as part of a multi-modal treatment strategy vs.
upfront EBRT with ADT for locally-advanced PCa remains unknown. A prospective phase III RCT (SPCG-15)
comparing RP (with or without adjuvant or salvage EBRT) against primary EBRT and ADT among patients with
locally-advanced (T3) disease is currently recruiting [856]. Data from retrospective case series demonstrated
over 60% CSS at 15 years and over 75% OS at ten years [828, 845, 854, 855, 857-859]. For cT3b–T4 disease, PCa
cohort studies showed 10-year CSS of over 87% and OS of 65% [829, 860]. The indication for RP in all previously
described stages assumes the absence of clinically detectable nodal involvement (cN0), based on conventional
imaging. In case of suspected positive LNs during RP (initially considered cN0) the procedure should not be
abandoned since RP may have a survival benefit in these patients. Intra-operative frozen section analysis is not
justified in this case [462].

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6.3.4.2 Treatment of cN1 M0 PCa
Lymph-node metastasized PCa is an entity where options for local therapy and systemic therapies overlap.
Approximately 5% to 10% of newly diagnosed PCa patients have synchronous suspected pelvic nodal
metastases on conventional imaging (CT/bone scan) without bone or visceral metastases (cN1 M0 stage).

6.3.4.2.1 Consideration of molecular imaging

Meta-analyses have shown that molecular imaging, such as PSMA-PET/CT, prior to primary treatment in
advanced PCa detected disease outside the prostate in 32% of cases despite prior negative conventional
imaging using bone scan and pelvic CT/MRI [453]. A RCT assessing PSMA-PET/CT as staging tool in high-risk
PCa confirmed these findings and showed a 32% increase in accuracy compared with conventional imaging for
the detection of pelvic nodal metastases [488]. Notably, more sensitive imaging also caused a stage shift with
more cases classified as N1 on “molecular imaging” (miN1), but with, on average, lower nodal disease burden
compared to cases classified as cN1.

The definition of miN1 is a subject of ongoing discussion given multiple guidelines exist as detection can be
influenced by size of the lymph nodes and PSMA expression [104, 861, 862]. For patients with high or equivocal
PSMA expression but normal size (< 10 mm), there is a lack of knowledge of the best treatment option and
prospective data are encouraged [863].

6.3.4.2.2 Local treatment of cN1 M0 PCa

The management of cN1M0 PCa is historically based on long-term ADT combined with a local treatment with
radiotherapy more commonly used than RP/pelvic nodal dissection. There is no randomised evidence available
and the potential benefit of adding local treatment to ADT has been assessed in a non-randomised post-hoc
analysis of STAMPEDE and retrospective studies summarised by Yaow et al. [864]. Pooled meta-analysis was
performed for local treatment versus no local treatment (four studies, n = 4,597, local treatment n = 2,646)
and showed improved estimated OS at all time points to ten years (OR: 1.49-1.81). The majority of patients
underwent RT as local therapy. Assessment of RT vs. no local therapy (four studies, n=3,768) showed similar
estimates for improvements in OS. Not included in this pooled analysis was STAMPEDE control arm data, that
showed improvements in failure-free survival (adjusted HR: 0.48, 95% CI: 0.29-0.79) without severe toxicity [865]
at median follow-up of seventeen months. Comparisons between local treatment modalities were limited by
inclusion of retrospective studies, which fail to describe clearly how cN1 was defined.

Local treatment of cN1M0 disease in the era of taxane chemotherapy and ARPIs is under studied. Extended
follow-up of STAMPEDE, reported as exploratory sub-analyses of patients who received docetaxel or control
according to receipt of RT after median follow-up of 81.2 months, maintained failure-free survival benefit
(HR: 0.68) in N+ patients but no prostate cancer specific survival (HR: 0.81) or OS (HR: 0.77) benefit was
demonstrated [866]. Greatest benefits from RT were seen in the control (without docetaxel) group, as no
significant benefits of RT receipt were seen in any category for the docetaxel group. Two RCTs from the
STAMPEDE platform protocol reported a pre-planned meta-analysis of men with de novo high-risk/locally-
advanced M0 disease, or relapse after primary curative therapy with high-risk features. Thirty-nine percent
of patients (n=774) were N1 on conventional imaging [867]. Radiotherapy in addition to long-term ADT was
administered in at least 71% of N1 patients. Data on survival according to whether RT was planned in N1
patients was not presented.

6.3.4.2.3 Systemic treatment of cN1 M0 PCa

The intensification of systemic treatment from initial ADT to other agents has been assessed within data from
the STAMPEDE multi-arm RCT with a pre-planned meta-analysis in M0 patients. In cN1 M0 patients (39% of the
cohort), improved metastasis free (HR: 0.49, 95% CI: 0.38-0.64) and overall (HR: 0.53, 95% CI: 0.39-0.70) survival
was observed with intensification (abiraterone and/or enzalutamide) above standard of care (ADT +/- prostate
radiotherapy in 85% of the whole cohort) in cN1M0 patients [867].

Considering intensification with docetaxel, exploratory sub-analyses of STAMPEDE non-metastatic (cN0/N1M0)

patients who received docetaxel or control showed failure-free survival benefit (HR: 0.70, 95% CI: 0.56-0.88) but
no metastatic progression-free (HR: 0.89) or OS (HR: 0.88) benefit [866]. Similar trends were observed in the
N0 and N+ sub-groups. Radiotherapy was delivered to 77% of the cohort (see section 6.3.4.2). The AFU-GETUG
12 trial compared the impact of docetaxel plus estramustine in addition to ADT and 29% of included high-risk
non-metastatic PCa patients had a nodal involvement (pN1) at randomisation [868]. Relapse-free survival rates
were higher for cN1 patients receiving docetaxel plus estramustine but did not achieve statistical significance
(HR: 0.66; 86 0.43–1.01). A meta-analysis of docetaxel trials in N0/N1-M0 patients concluded to an 8% four-year
failure-free survival advantage for docetaxel compared with ADT alone without OS benefit (HR: 0.87, 95% CI:
0.69-1.09) [869].

86 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Given the MFS and OS benefits observed in the overall population (see section 6.3.4.2), additional abiraterone
(for 2 years) above standard of care (combined ADT for 3 years with prostate +/- WPRT) should be a SOC in cN1
patients.

Table 6.3.1: Selected studies assessing local treatment in (any cT) cN1 M0 prostate cancer patients

Study n Design Study period/ Treatment Effect on survival

follow-up arms
ADT only
Bryant, et al. 648 Retrospective 2000-2015 ADT ± EBRT Significant benefit for
2018 [870] (National 61 mo. combined treatment only
Veterans if PSA levels less than the
Affairs) median (26 ng/mL)
All-cause mortality HR: 0.50
CSS, HR: 0.38
Sarkar, et al. 741 Retrospective 2000-2015 ADT ± local Significant benefit for RP
2019 [871] (National 51 mo. treatment All-cause mortality HR 0.36
Veterans (surgery or RT) CSS, HR: 0.32
Affairs)
No statistical difference for
RP vs. RT (p ≥ 0.1)
All-cause mortality HR: 047
CSS, HR: 0.88
Lin, et al. 2015 983 before Retrospective 2004-2006 ADT ± EBRT Significant benefit for
[872] propensity (NCDB) 48 mo. combined treatment 5-yr. OS:
score 73% vs. 52% HR: 0.5
matching
Tward, et al. 1,100 Retrospective 1988-2006 EBRT (n = 397) Significant benefit for EBRT
2013 [873] (SEER) 64 mo. vs. no EBRT 5-yr. CSS: 78% vs. 71% HR:
(n=703) 0.66
No 5-yr. OS: 68% vs. 56%, HR:
information on 0.70
ADT)
Rusthoven, et al. 796 Retrospective 1995-2005 EBRT vs. no Significant benefit for EBRT
2014 [874] (SEER) 61 mo. EBRT (no 10-yr. OS: 45% vs. 29% HR:
information on 0.58
ADT)
Seisen, et al. 1,987 Retrospective 2003-2011 ADT ± local Significant benefit for
2018 [875] (NCDB) 50 mo. treatment combined treatment
(surgery or RT) 5-yr. OS: 78.8% vs. 49.2% HR:
0.31
No difference between RP
and RT
Chierigo, et al. 4,685 Retrospective 2004–2016 RP or RT Propensity score matching
2022 [876] (SEER) (unknown ADT 5-yr OS: 84.6% (RP) vs. 75%
status) (RT), HR 0.62, p < 0.001
5-yr CSS: 90.7% (RP) vs. 83%
(RT), HR 0.62, p < 0.001
5-yr other cause mortality,
6.1% RP vs. 8.0% RT, HR
0.71, p = 0.04
James, et al. 177 Unplanned 2005-2014 ADT ± EBRT Significant benefit for
2016 [865] subgroup (EBRT combined treatment
analysis RCT 17 mo. encouraged) 5-yr. OS: 93% vs. 71%
2-yr. FFS: 81% vs. 53% FFS,
HR: 0.48

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Elumalai, et al. 337 Retrospective 2022-2019 ADT +/- EBRT Significant benefit for
2023 [877] 4 centres UK combined treatment
5-yr.OS: 87% vs. 56% HR:
0.27
5-yr. BPFS: 74.1% vs. 34.2%
HR: 0.33
Other systemic therapies
James, et al. 258 (N1 Planned 2005-2018 Standard of 5-year estimated
2022 patients) subgroup 81.2 mo care (ADT Metastatic PFS (SOC +
[866] analysis RCT +/- EBRT) +/- docetaxel vs SOC, HR: 0.79)
docetaxel OS (RT 78% vs no RT 71%,
HR: 0.77)*
(EBRT planned CSS (RT 84% vs no RT 79%,
for 55% HR: 0.81)*
SOC, 40% of FFS (RT 51% vs no RT 36%,
docetaxel) HR: 0.68)*
*No stratification for
docetaxel use
Attard, et al. 774 (N1) Planned 2011-2016 Standard of MFS (SOC + Abiraterone with
2022 subgroup care (ADT or without enzalutamide vs
[867] analysis RCT 72 mo +/- EBRT) +/- SOC alone, HR: 0.49, 95% CI:
Abiraterone 0.38-0.64)
with or without
enzalutamide OS (SOC + Abiraterone with
(EBRT planned or without enzalutamide vs
for 71% of N1 SOC alone, HR: 0.53, 95% CI:
patients) 0.39-0.70)
ADT = androgen deprivation therapy; CSS = cancer-specific survival; EBRT = external beam radiotherapy; FFS =
failure-free survival; HR = hazard ratio; mo = months; n = number of patients; OS = overall survival; RP = radical
prostatectomy; RT = radiotherapy; yr = year.

6.3.4.3 Options other than surgery or radiotherapy for primary treatment

6.3.4.3.1 Investigational therapies
Currently cryotherapy, HIFU or focal therapies have no place in the management of locally-advanced PCa.

6.3.4.3.2 Androgen deprivation therapy monotherapy

The deferred use of ADT as single treatment modality has been answered by the EORTC 30891 trial [843].
Nine hundred and eighty-five patients with T0–4 N0–2 M0 PCa received ADT alone, either immediately or after
symptomatic progression or occurrence of serious complications. After a median follow-up of 12.8 years,
the OS favoured immediate treatment (HR: 1.21, 95% CI: 1.05–1.39). Surprisingly, no different disease-free or
symptom-free survival was observed, raising the question of survival benefit. In locally-advanced T3–T4 M0
HSPC unsuitable for surgery or RT, immediate ADT may only benefit patients with a PSA > 50 ng/mL and a PSA-
DT < twelve months or those that are symptomatic [843, 878]. The median time to start deferred treatment was
seven years. In the deferred treatment arm 25.6% of patients died without needing treatment.

6.3.4.4 Recommendation for management of locally-advanced disease*

Recommendations Strength rating

Radical prostatectomy (RP)
Offer RP to patients with cN0 disease as part of multi-modal therapy. Weak
Extended pelvic lymph node dissection (PLND)
In patients undergoing a lymph node dissection you should perform an extended PLND. Strong
Radiotherapeutic treatments
Offer patients with cN0 disease intensity-modulated radiation therapy (IMRT)/volumetric Strong
modulated arc therapy (VMAT) plus image-guide radiation therapy in combination with long-
term androgen deprivation therapy (ADT).

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Offer patients with cN0 disease and good urinary function, IMRT/VMAT plus IGRT with Weak
brachytherapy boost (either high-dose or low-dose rate), in combination with long-term ADT.
Offer long-term ADT for at least two years. Strong
Offer IMRT/VMAT plus IGRT to the prostate in combination with long-term ADT and two Strong
years of abiraterone to cN0M0 patients with ≥ two high-risk factors (cT3-4, Gleason ≥ 8 or
PSA ≥ 40 ng/mL).
Offer IMRT/VMAT plus IGRT to the prostate plus pelvis in combination with long-term ADT Strong
and two years of abiraterone to cN1M0 patients.
Other therapeutic options
Do not offer whole gland treatment or focal treatment. Strong
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.3.5 Adjuvant treatment after radical prostatectomy

6.3.5.1 Introduction
Adjuvant treatment is by definition additional to the primary or initial therapy with the aim of decreasing the
risk of relapse, despite the apparent full control following surgery. A post-operative detectable PSA is an
indication of persistent prostate cells (see section 6.3.6). All information listed below refers to patients with a
postoperative undetectable PSA.

6.3.5.2 Risk factors for relapse

Patients with ISUP grade group > 2 in combination with EPE (pT3a) and particularly those with SV invasion
(pT3b) and/or positive surgical margins are at high risk of progression, which can be as high as 50% after five
years [879]. Irrespective of the pT stage, the number of removed nodes [880-887], tumour volume within the LNs
and capsular perforation of the nodal metastases are predictors of early recurrence after RP for pN1 disease
[888]. A LN density (defined as ‘the percentage of positive LNs in relation to the total number of analysed/
removed LNs’) of over 20% was found to be associated with poor prognosis [889]. The number of involved
nodes seems to be a major factor for predicting relapse [882, 883, 890]; the threshold considered is less than 3
positive nodes from an ePLND [458, 882, 890]. However, prospective data are needed before defining a definitive
threshold value.

6.3.5.2.1 Biomarker-based risk stratification after radical prostatectomy

Biomarker-based risk stratification after radical prostatectomy
The Decipher® gene signature consists of a 22-gene panel representing multiple biological pathways and was
developed to predict systemic progression after definitive treatment. A meta-analysis of five studies analysed
the performance of the Decipher® Genomic Classifier (GC) test on men post-RP. The authors showed in
multivariable analysis that Decipher® GC remained a statistically significant predictor of metastasis (HR: 1.30,
95% CI: 1.14–1.47, p < 0.001) per 0.1 unit increase in score and concluded that it can independently improve
prognostication of patients post-RP within nearly all clinicopathologic, demographic, and treatment subgroups
[891]. A SR of the evidence for the Decipher® GC has confirmed the clinical utility of this test in post-RP decision-
making [892]. Further studies are needed to establish how to best incorporate Decipher® GC in clinical decision-
making.

6.3.5.3 Immediate (adjuvant) post-operative external irradiation after RP (cN0 or pN0)

Four prospective RCTs have assessed the role of immediate post-operative RT (adjuvant RT [ART]) (undetectable
PSA mostly defined as PSA < 0.1 ng/mL), demonstrating an advantage (endpoint, development of BCR) in
high-risk patients (e.g., pT2 with positive surgical margins and ISUP grade group 3–5 or pT3/4 with- or without
positive surgical margins and ISUP grade group 3–5) post-RP (Table 6.3.2). In the ARO 96-02 trial, 80% of
the pT3/R1/GS 8–10 patients randomised to observation developed BCR within ten years [893]. It must be
emphasised that PSA was undetectable at inclusion only in the ARO 96-02 trial which presents a major limitation
interpreting these findings as patients with a detectable PSA would now be considered for salvage therapy
rather than ART [893].

6.3.5.4 Comparison of adjuvant and salvage radiotherapy

Two retrospective matched studies (510 and 149 patients receiving ART) failed to show an advantage for MFS
[894, 895]. However, both studies were underpowered for high-risk patients (pT3b/R1/ISUP grade group 4–5
PCa). In contrast to these studies, a propensity score-matched retrospective analysis of two cohorts of 366
pT3 and/or R1 patients found that compared to SRT at a PSA between 0.1 and 0.5 ng/mL, ART given at an
undetectable PSA (< 0.1 ng/mL) improved all three endpoints; BCR, MFS, and OS [896].

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Both approaches (ART and early SRT) together with the efficacy of adjuvant ADT are compared in three
prospective RCTs: the Medical Research Council (MRC) Radiotherapy and Androgen Deprivation In Combination
After Local Surgery (RADICALS) trial [897], the Trans-Tasman Oncology Group (TROG) Radiotherapy Adjuvant
Versus Early Salvage (RAVES) trial [898], and the Groupe d’Etude des Tumeurs Uro- Genitales (GETUG-AFU 17)
trial [899]. In addition, a pre-planned meta-analysis of all three trials has been published (Table 6.3.3) [900].

Two trials closed early after randomising 333/470 patients (RAVES) and 424/718 (GETUG-AFU-17) patients.
RADICALS-RT included 1,396 patients, ninty-three percent (648/697) in the ART – Group. At the time of the
ten year analysis 39% (270/699) of the Savage-RT-Policy Group started SRT with a median pre-SRT PSA-level
of 0.2 ng/ml. With the option of subsequent inclusion in RADICALS-HT; 154/649 (24%) of patients starting in
the adjuvant RT group also received neoadjuvant or adjuvant HT; 90 patients for six months/45 for 2 years/19
patients outside RADICALS-HT. From the SRT group, 61/228 (27%) received neoadjuvant or adjuvant HT for six
months (n = 33) and two years (n = 13). Fifteen of these patients were treated outside the trial [897]. All men
in the GETUG-AFU-17 trial (n = 424) received six months of HT. All together, 684 out of 2,153 patients received
additional ADT for at least six months across both trials [900]. Radiotherapy to the pelvic lymphatics was
allowed in the GETUG-AFU and in the RADICALS-RT trials.

The primary endpoint for RAVES and GETUG-AFU 17 was biochemical PFS, and for RADICALS-RT MFS. So far
only RADICALS-RT have reported the ten year primary endpoint data [901]. With a median follow up of 7.8 years
the 10 year FFDM was 93% (ART) versus 90% (SRT)(HR 0.68, p=0.095) although based upon just 80 events
in 1,396 patients. BPFS and OS also showed no significant difference (Table 6.3.3). With a median follow-up
between 4.9 years and 6.25 years in the ARTISTIC-Metaanalysis there was no statistically significant difference
for biochemical PFS for both treatments in all three trials (see Table 6.2.3). Additionally, there was a significant
lower rate of grade ≥ 2 GU late side effects and grade 3–4 urethral strictures in favour of early SRT; which may
also be caused by the low number of patients with PSA-progression and subsequent need for early SRT at the
time of analysis (40% of patients) [900].It should be noted, the side-effect profile may have been impacted with a
larger proportion of ART patients receiving treatment with older 3D-treatment planning techniques as compared
to SRT patients (GETUG-AFU 17: ART, 69% 3D vs. 46% SRT) and patients treated more recently were more likely
to undergo IMRT techniques with a proven lower rate of late side effects [702]. However, on the basis of these
three trials patients with ‘low-risk factors’ of biochemical progression after RP should be closely followed up
with ultra-sensitive assays and SRT should be discussed if needed as soon as PSA starts to rise, which has to be
confirmed by a second PSA measurement.

The proportion of patients with adverse pathology at RP (ISUP GG 4–5 and pT3 with or without positive
margins) in all three trials was low (between 10–20%) and therefore even the meta-analysis may be
underpowered to show an outcome in favour of SRT [900]. The subset analysis of this primary endpoint based
on the prerandomization strata (i.e. the high risk features Gleson 8-10 vs. < 7 and pT3b-4 vs. <=pT3a) is still
awaited to inform if these high risk groups benefit from ART compared with SRT. However, a retrospective multi-
centre study comparing ART and SRT in 26,118 patients of whom 2,424 had high-risk features (pN1 or ISUP
GG 4–5 and pT3/4-tumours) after RP [902] does support ART. With a median follow-up of 8.2 years and after
excluding men with persistent PSA after RP, ART when compared with early SRT showed a significantly lower
acute mortality risk (p = 0.02, HR: 0.33). Therefore, ART remains a recommended treatment option in highly
selected patients with adverse pathology (‘high-risk patients’) i.e. ISUP grade group 4–5 and pT3 with or without
positive margins [903, 904].

In conclusion, the vast majority of patients with an undetectable PSA (<0.1 ng/ml) after RP do not need ART.
However, in patients with high risk factors (pT3/4 and ISUP 4-5) ART to the prostatic bed should be given as
they were underrepresented in RADICALS and in the metaanalysis too [897-900] on the one hand and the proven
effect in RCT‘s on the other hand [893, 905, 906].

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Table 6.3.2: Overview of all four randomised trials for adjuvant surgical bed radiation therapy after RP*
(without ADT)

Study n Inclusion Randomisation Definition of Median Biochemical Overall

criteria BCR PSA (ng/ FU (mo) Progression- survival
mL) free survival
SWOG 8794 431 pT3 cN0 ± 60-64 Gy vs. > 0.4 152 10 yr.: 53% vs. 10 yr.: 74%
2009 [905] involved SM observation 30% vs. 66%
(p < 0.05) Median
time:
15.2 vs.
13.3 yr.,
p = 0.023
EORTC 1,005 pT3 ± 60 Gy vs. > 0.2 127 10 yr.: 60.6% 81% vs.
22911 2012 involved SM observation vs. 41% 77% n.s.
[906] pN0 pT2 (p < 0.001)
involved SM
pN0
ARO 96-02 388 pT3 (± 60 Gy vs. > 0.05 + 112 10 yr.: 56% vs. 10 yr.: 82%
2014 [893] involved observation confirmation 35% vs. 86%
SM) pN0 (p = 0.0001) n.s.
PSA post-RP
undetectable
FinnProstate 250 pT2,R1/ 66.6 Gy vs. > 0.4 (in 2 112 vs. 10 yr.: 82% vs. 10 yr.: 92%
Group 2019 pT3a observation successive 103 61% vs. 87%
[907] (+ SRT) measure- (patients p < 0.001 n.s.
ments) alive)
*See Section 6.3.5.1 for delayed (salvage) post-radical prostatectomy external irradiation.
BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; n.s. = not significant;
OS = overall survival; PSA = prostate-specific antigen; RP = radical prostatectomy; SM = surgical margin;
SRT = salvage radiotherapy.

Table 6.3.3: Overview of all three randomised trials and one meta-analysis for patients treated with adjuvant
vs. early salvage RT after RP

Study n Inclusion Randomisation Definition of Median BPFS OS Side effects

criteria BCR PSA FU (yr) or
(ng/mL) MFS
RAVES 333 pT3a/pT3b 64 Gy ART PSA: > 0.4 post 6.1 5 yr.: n.r. LT grade ≥
TROG 08.03/ target any T - SM+ < 0.1 ng/mL vs. RT 86% vs. GU: 70% vs.
ANZUP was PSA post-RP: 64 Gy early SRT 87% 54%
2020 [898] 470 < 0.1 ng/mL at PSA (p > 0.05) (p = 0.002)
early > 0.2 ng/mL
closed med. pre-SRT: n.r.
RADICALS-RT 1,396 pT3a/ 52.5 Gy (20 Fx) > 0.4 or 2 at 4.9 5 yr.: n.r. Self-reported
[897] pT3b/pT4 or 66 Gy (33 Fx) any time 85% vs. urinary
PSA ART 88% incontinence
> 10 ng/mL early SRT (p = 0.56) 1 yr: 4.8 vs.
pre-RP identical 4 (p = 0.023)
any T, SM+ at PSA > 0.1 urethral
Gleason med.pre-SRT: stricture
7-10 0.2 ng/mL grade 3/4
PSA post-RP: 2 yr:
< 0.2 ng/mL 6% vs. 4%
(p = 0.02)

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GETUG-AFU 424 pT3a/pT3b/ 66 Gy (ART) vs. > 0.4 6.25 5 yr: n.r. LT grade > 2
17 2020 [899] target pT4a and SM 66 Gy early SRT 92% vs. GU 27% vs.
was + PSA at PSA 0.1 90% 7%
718 post-RP: both groups: (p = 0.42) (p < 0.001)
early < 0.1 ng/mL 6 mo. LHRH-A ED: 28% vs.
closed med. pre-SRT 8%
0.24 (p < 0.001)
ARTISTIC 2,153 see above see above see above 4.5 5 yr.: n.r. n.r.
2020 [900] 89% vs.
88%
p = 0.7
ART = adjuvant radiotherapy; BCR = biochemical recurrence; BPFS = biochemical progression-free survival;
ED = erectile dysfunction; FU = follow-up; Fx = fraction; GU = genito-urinary; LHRH = luteinising hormonereleasing
hormone; LT = late toxicity; mo = months; med = median; MFS = metastasis-free survival; n.r. = not reported;
OS = overall survival; PSA = prostate-specific antigen; RP = radical prostatectomy; RT = radiotherapy;
SRT = salvage radiotherapy; + = positive; yr = year.

6.3.5.5 Adjuvant systemic therapy in N0 disease

The TAX3501 trial comparing the role of leuprolide (18 months) with and without docetaxel (6 cycles) ended
prematurely due to poor accrual. A phase III RCT comparing adjuvant docetaxel against surveillance after
RP for locally-advanced PCa showed that adjuvant docetaxel did not confer any oncological benefit [908].
Consequently, adjuvant chemotherapy after RP should only be considered in a clinical trial [909].

6.3.5.6 Adjuvant treatment in pN1 disease

6.3.5.6.1 Adjuvant androgen ablation alone
The combination of RP and early adjuvant HT in pN+ PCa has been shown to achieve a ten-year CSS rate of 80%
and has been shown to significantly improve CSS and OS in prospective RCTs [910, 911]. However, these trials
included mostly patients with high-volume nodal disease and multiple adverse tumour characteristics and these
findings may not apply to men with less extensive nodal metastases.

6.3.5.6.2 Adjuvant radiotherapy combined with ADT in pN1 disease

In a retrospective multi-centre cohort study, maximal local control with RT to the prostatic fossa appeared to
be beneficial in PCa patients with pN1 after RP, treated ‘adjuvantly‘ with continuous ADT (within six months
after surgery irrespective of PSA). The beneficial impact of adjuvant RT on survival in patients with pN1 PCa
was highly influenced by tumour characteristics. Men with low-volume nodal disease (< 3 LNs), ISUP grade
group 2–5 and pT3–4 or R1, as well as men with 3 to 4 positive nodes were more likely to benefit from RT
after surgery, while the other subgroups did not [912]. In contrast, a retrospective multi-centre study including
1,614 patients and a median follow-up of 7.02 years assessed ART + ADT. Adjuvant RT compared to SRT was
associated with a decreased all-cause mortality and this reduction increased with each additional positive
pelvic LN, from the first one on and the highest effect was for more than 3 positive nodes [913]. These data are
in agreement with a US National Cancer Database analysis based on 5,498 patients [914]. Another US National
Cancer Database study including 8,074 pN1 patients reports improved OS after ADT plus EBRT (including pelvic
LNs) vs. observation and vs. ADT alone in all men with single or multiple adverse pathological features. Men
without any adverse pathological features did not benefit from immediate adjuvant therapy [915].
In a SR of the literature, RT with or without ADT was associated with improved survival in men with
locally-advanced disease and a higher number of positive nodes [916]. Radiotherapy to the pelvic lymphatics
and the prostate fossa plus long-term ADT can be offered to patients with pN1 disease [912, 917]. However, the
optimal duration of ADT is still unkown.

6.3.5.6.3 Observation of pN1 patients after radical prostatectomy and extended lymph node dissection
Several retrospective studies and a SR addressed the management of patients with pN1 PCa at RP [890, 912,
916-918]. A subset of patients with limited nodal disease (1–2 positive LNs) showed favourable oncological
outcomes and did not require additional treatment.

An analysis of 209 pN1 patients with one or two positive LNs at RP showed that 37% remained metastasis-
free without need of salvage treatment at a median follow-up of 60.2 months [918]. Touijer et al., reported their
results of 369 pN1-positive patients (40 with and 329 without adjuvant treatment) and showed that higher
pathologic grade group and > 3 positive LNs were significantly associated with an increased risk of BCR on
multivariable analysis [890]. Biochemical-free survival rates in pN1 patients without adjuvant treatment ranged
from 43% at four years to 28% at ten years [916]. Reported CSS rates were 78% at five years and 72% at ten

92 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

years. The majority of these patients were managed with initial observation after surgery, had favourable
disease characteristics, and 63% had only one positive node [916]. Initial observation followed by early salvage
treatment at the time of recurrence may represent a safe option in selected patients with a low disease burden
[916].

6.3.5.7 Recommendations for adjuvant treatment for pN0 and pN1 disease after radical prostatectomy*

Recommendations Strength rating

Do not prescribe adjuvant androgen deprivation therapy (ADT) to pN0 patients. Strong
In pN0 patients with ISUP grade group 4–5 and pT3 ± positive margins, offer adjuvant Strong
intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) plus
image-guided radiation therapy (IGRT).
In pN1 patients, after an extended lymph node dissection, discuss three management Weak
options, based on nodal involvement characteristics:
1. Offer adjuvant ADT.
2. Offer adjuvant ADT with additional IMRT/VMAT plus IGRT.
3. Offer observation (expectant management) to a patient after ePLND and ≤ 2 nodes and
an undetectable PSA.
*All recommendations are based on conventional imaging with isotope bone scan and CT/MR abdomen/pelvis.

6.3.6 Persistent PSA after radical prostatectomy

Between five and 20% of men continue to have detectable or persistent PSA after RP (when defined in the
majority of studies as detectable post-RP PSA of ≥ 0.1 ng/mL within 4 to 8 weeks of surgery) [919, 920].
Improvements in the sensitivity of PSA assays now allow for the detection of PSA at much lower levels. It may
result from persistent local disease, pre-existing metastases or residual benign prostate tissue.

6.3.6.1 Natural history of persistently elevated PSA after RP

Two SRs addressing persistent PSA confirmed a strong correlation of PSA persistence with poor oncologic
outcomes [919, 920]. A meta-analysis of consecutive patient cohorts reported that persistent PSA was
more likely when risk factors, such as high D’Amico risk, Gleason score ≥ 8, pT stage ≥ 8 and presence of
extraprostatic extension, seminal vesicle invasion, lymph node involvement, positive margin, were present [921].
Salvage radiotherapy was also more likely to be given to patients with persistent PSA. Cribiform pattern or
intraductal carcinoma have also been associated with persistent PSA [922].
Considering oncological outcomes, patients with persistent PSA (≥ 0.1 ng/mL) had worse
biochemical recurrence-free (HR: 3.86, 95% CI: 2.4 – 6.22), metastasis-free (HR 3.6, 95% CI 2.94-4.42) and
prostate cancer-specific (HR: 3.54, 95% CI: 2.4-5.22) survival on meta-analysis of retrospective cohorts [921].
The largest study by Preisser et al. (n = 11,605) showed that persistent PSA is prognostic of an increased
risk of metastasis and death [923] [864]. At fifteen years after RP, MFS rates, OS and CSS rates were 53.0 vs.
93.2% (p < 0.001), 64.7 vs. 81.2% (p < 0.001) and 75.5 vs. 96.2% (p < 0.001) for persistent vs. undetectable
PSA, respectively. The median follow-up was 61.8 months for patients with undetectable PSA vs. 46.4 months
for patients with persistent PSA. In multivariable Cox regression models, persistent PSA represented an
independent predictor for metastasis (HR: 3.59, p < 0.001), death (HR: 1.86, p < 0.001) and cancer-specific death
(HR: 3.15, p < 0.001), similarly for pathologic stage pT3b and ISUP Grade Group 3-5.
However, not all patients with persistent PSA after RP experience disease recurrence. Xiang et
al., showed a 50% five-year BCR-free survival in men who had a persistent PSA level > 0.1 but ≤ 0.2 ng/mL at
six to eight weeks after RP [924]. Rogers et al., assessed the clinical outcome of 160 men with a persistently
detectable PSA level after RP [925]. No patient received adjuvant therapy before documented metastasis.
In their study, 38% of patients had no evidence of metastases for ≥ 7 years while 32% of the patients were
reported to develop metastases within three years. Most patients had Gleason score 7 (44%) or ≥ 8 (49%). In
multi-variable analysis, the PSA slope ≥ 0.05 after RP (as calculated using PSA levels three to twelve months
after surgery; HR: 2.7) and pathological ISUP GG (≥ 3 vs. ≤ 2; HR: 1.8) were significantly associated with the
development of distant metastases among patients with persistent PSA. Prostate-specific antigen slope is more
commonly reported as PSA doubling time (calculated by log [PSA slope]) [926].

6.3.6.2 Imaging in patients with persistently elevated PSA after RP

PSMA PET/CT is known to have superior detection efficiency, however dedicated studies for patients with
persistently elevated PSA after RP are limited compared to studies inclusive of patients with BCR with/without
persistent PSA.

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Considering the persistent PSA group, a multi-centre retrospective study included 191 patients with persistently
elevated PSA after RP and 68Ga-PSMA-PET/CT was positive in 68%, of which 35% had disease confined to the
pelvis (obturator, presacral/mesorectal most common) and 33% had distant metastases [927]. A subgroup
analysis of 33 patients with pre- and post-RP imaging showed PET-persistence in 45%, new lesions in 24%
and negative post-RP PET in 30%. Another retrospective study included 150 patients with persistent PSA after
RARP who were re-staged with both 68Ga-PSMA and 18F-DCFPyL PSMA. The authors found that in the presence
of persistent PSA the majority of patients already had involved pelvic LNs (33%) or distant metastases (26%)
which would support a role of PSMA PET/CT imaging in guiding (salvage) treatment strategies [928]. Schmidt-
Hegemann et al., studied 129 patients who had either persistent PSA (52%) or BCR (48%) after RP, showing that
men with a persistent PSA had significantly more pelvic nodal involvement on PSMA PET/CT than those with an
initially undetectable PSA [929].

Therefore, PSMA PET serves to identify sites of remnant disease in patients with persistent PSA after RP. At
present there is uncertainty regarding the best treatment if PSMA PET/CT shows metastatic disease outside the
pelvis.

6.3.6.3 Management options for patients with persistent PSA

6.3.6.3.1 Comparison with biochemical recurrence (BCR)
It is clear that persistent PSA after RP is a poor prognostic indicator, likely representative of low volume
synchronous metastatic disease rather than metachronous disease like in biochemical recurrence. A
retrospective analysis of the RTOG 9601 trial of SRT +/- ADT (bicalutamide) for biochemical failure after
RP considered patients with persistent PSA (n=90) or BCR (n=670) as the cause for biochemical failure
and, following statistical adjustment, showed higher 10-year metastatic progression rate (28.6% vs. 10.1%,
p < 0.0001), numerically higher 10-year overall mortality rate (24.9% vs. 11.9%, p = 0.03) and higher local
progression rate (3.2% vs. 1.4%, p = 0.0001) [930]. In the ARO 96-02, a prospective RCT, 74 patients with PSA
persistence (20%) received immediate SRT only (66 Gy per protocol [arm C]). The 10-year clinical relapse-free
survival was 63% and showed worse 10-year metastasis-free survival (67% vs 83%) and OS (68% vs 84%) than
BCR patients [931]. Therefore, it is likely that outcomes are worse than for men with persistent PSA than those
experiencing BCR [932]. Indeed, studies investigating PSA persistence were excluded from the EAU Guidelines
Biochemical Recurrence risk groups [933].

6.3.6.3.2 Post-operative RT
The benefit of post-operative RT (adjuvant or salvage) in patients with persistent PSA remains unclear due to a
lack of RCTs. Ploussard et al., reported following SR that SRT was associated with improved survival outcomes,
although the available evidence is of low quality [920].

Preisser et al., compared oncological outcomes of patients with persistent PSA who received SRT vs. those
who did not [923]. In the subgroup of patients with persistent PSA, after 1:1 propensity score matching
between patients with SRT vs. no RT, OS rates at ten years after RP were 86.6 vs. 72.6% in the entire cohort (p
< 0.01), 86.3 vs. 60.0% in patients with positive surgical margin (p = 0.02), 77.8 vs. 49.0% in pT3b disease (p <
0.001), 79.3 vs. 55.8% in ISUP grade group 3-5 disease (p < 0.01) and 87.4 vs. 50.5% in pN1 disease (p < 0.01),
respectively. Moreover, CSS rates for patients who underwent SRT vs. no RT at ten years after RP were 93.7 vs.
81.6% in the entire cohort (p < 0.01), 90.8 vs. 69.7% in patients with positive surgical margin (p = 0.04), 82.7 vs.
55.3% in pT3b disease (p < 0.01), 85.4 vs. 69.7% in ISUP grade group 3-5 disease (p < 0.01) and 96.2 vs. 55.8%
in pN1 disease (p < 0.01), respectively. In multi-variable models, after 1:1 propensity score matching, SRT was
associated with lower risk of death (HR: 0.42, p = 0.02) and lower cancer-specific death (HR: 0.29, p = 0.03).
SRT dose was 46Gy for the 54% of patients with available data, but SRT field and ADT use was unavailable. The
benefit of SRT in improving MFS (HR 0.39, p = 0.001), CSS (HR 0.34, p = 0.03) and OS (HR 0.24, p = 0.001) were
also observed in a retrospective analysis of 3,409 patients who underwent RP (9.2% persistent PSA, median
follow-up 4.5 years) by Özman et al. [934].

It is clear from a number of studies that poor outcomes are driven by the level of pre-RT PSA, the presence of
ISUP grade group ≥ 4 in the RP histology and pT3b disease [931, 935-939] [878-883]. Fossati et al., suggested
that only men with a persistent PSA after RP and ISUP grade group ≤ 3 benefit significantly [940], similarly
supported by Özman et al. where positive margins, higher T-stage, pN1 and lower ISUP Grade group were most
likely to benefit from SRT, although this was not supported by Preisser et al. [923, 934].

The current data do not allow clear treatment recommendations. However, these benefits in the SRT + ADT
group (compared to ADT alone) were associated with higher incidence of bowel symptoms (34 vs. 19%, p =
0.01) and bothersome incontinence if given within 6 months of surgery (p < 0.001) [934].

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6.3.6.3.3 Multimodal therapy (ADT with post-operative RT)
Addition of ADT may improve PFS [935]. Choo et al., prospectively studied the addition of two-year ADT to
immediate RT to the prostate bed in patients with pT3 and/or positive surgical margins after RP [935]. Twenty-
nine of the 78 included patients had persistently detectable post-operative PSA. The relapse-free rate was 85%
at five years and 68% at seven years, which was superior to the five-year progression-free estimates of 74% and
61% in the post-operative RT arms of the EORTC and the SWOG studies, respectively, which included patients
with undetectable PSA after RP [905, 906]. Patients with persistently detectable post-operative PSA comprised
approximately 50% and 12%, respectively, of the study cohorts in the EORTC and the SWOG studies.

A multi-centre, retrospective study from Japan considered 383 patients with pN1 and persistent PSA after RP
and reported that the addition of SRT (median 66Gy; prostate bed with pelvis 67%, prostate bed alone 24%) to
ADT showed better castration resistance-free (5-year p < 0.001, 10-year p = 0.02) and metastasis-free (5-year p <
0.001, 10-year p = 0.15) but not OS than ADT alone in patients with pre-treatment PSA ≥ 0.52 ug/L [941]. Similar
benefits have been reported for SRT with ADT compared to ADT alone in single centre retrospective studies
[942, 943].

The phase 2 GETUG-22 trial comparing RT (46Gy pelvis with 66Gy prostate bed boost) with RT plus short-term
ADT for post-RP PSA persistence (0.2–2.0 ng/mL) in 125 patients reported good tolerability of the combined
treatment. The oncological endpoints are yet to be published [944].

6.3.6.4 Conclusion
The available data suggest that patients with PSA persistence after RP have worse prostate-cancer outcomes
and serve to benefit most from early aggressive multimodality treatment, however, the lack of prospective RCTs
makes firm recommendations difficult.

6.3.6.5 Recommendations for the management of persistent PSA after radical prostatectomy

Recommendations Strength rating

Offer a prostate-specific membrane antigen (PSMA) positron emission tomography/ Weak
computed tomography (PET/CT) scan to men with a persistent prostate-specific antigen
(PSA) and rising if the results will influence subsequent treatment decisions.
Treat men with persistent PSA and no evidence of distant metastatic disease with salvage Weak
radiotherapy and additional hormonal therapy.

6.4 Management of PSA-only recurrence after treatment with curative intent

Follow-up will be addressed in Chapter 7 and is not discussed in this section.

6.4.1 Background
Between 27% and 53% of all patients undergoing RP or RT develop a rising PSA (PSA recurrence). Whilst
metastatic progression is universally preceded by rising PSA levels, physicians must inform the patient that the
natural history of PSA-only recurrence may be prolonged and that a measurable PSA may not necessarily lead
to clinically apparent metastatic disease. Physicians treating patients with PSA-only recurrence face a difficult
set of decisions in attempting to delay the onset of metastatic disease and death while avoiding overtreating
patients whose disease may never affect their OS or QoL. It should be emphasised that the treatment
recommendations for these patients should be given after discussion in a multidisciplinary team.

6.4.1.1 PSA velocity and doubling time

Various PSA kinetics definitions have been proposed with different methods of calculation (log transformed or
not) and eligible PSAs:
• PSA velocity (PSAV): absolute annual increase in serum PSA (ng/mL/year);
• PSA doubling time (PSA-DT): which measures the exponential increase in serum PSA over time.

Prostate-specific antigen velocity is more simple to calculate by subtracting the initial value from the final value,
dividing by time. However, by ignoring middle values, not all PSA values are accurately taken into account.

Prostate-specific antigen-DT is calculated assuming an exponential rise in serum PSA. The formula takes into
account the natural logarithm of 2 divided by the slope obtained from fitting a linear regression of the natural
log of PSA over time [945]. However, many different PSA-DT calculations have been assessed according
to the mathematical formula used and to the included PSA values (number, time period, intervals) [946].

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For example, the ‘MSKCC’ method calculates a regression slope integrating all PSA values. Other methods
transform PSA before calculating the slope and do not include all PSA values (different time frames and minimal
intervals) [947]. O’Brien and colleagues identified more than 20 different definitions of PSAV and PSA-DT and
demonstrated that obtained values could vary widely between definitions [947].

However, some rules can be considered for PSA-DT calculation [945]:

• At least three PSA measurements are required;
• A minimum time period between measurements (4 weeks) is preferable due to potential statistical ‘noise’
when PSA values are obtained too close together (this statement can be reconsidered in case of very
active disease);
• All included PSA values should be obtained within the past twelve months at most, to reflect the current
disease activity;
• PSA-DT is often mentioned in months, or in weeks in very active disease.

These measurements do not provide additional information compared with PSA alone [540, 947-949]. In
the post-local therapy relapse setting, PSA-DT has been correlated with distant progression and with poorer
outcomes after salvage treatments [950, 951]. Prostate-specific antigen-DT has been linked with metastasis-
free- and OS in non-metastatic CRPC (nmCRPC) and identifies patients with high-risk nmCRPC who benefit from
intensified therapy (PSA-DT threshold < ten months) [952].

6.4.2 Controversies in the definitions of clinically relevant PSA relapse

The PSA level that defines treatment failure depends on the primary treatment. Patients with rising PSA after RP
or primary RT have different risks of subsequent symptomatic metastatic disease based on various parameters,
including the PSA level. Therefore, physicians should carefully interpret BCR endpoints when comparing
treatments. Clinicians should interpret a PSA rise in light of the EAU BCR risk groups [933].

After RP, the threshold that best predicts further metastases is a PSA > 0.4 ng/mL and rising [953]. However,
with access to ultra-sensitive PSA testing, a rising PSA much below this level will be a cause for concern
for patients. After primary RT, with or without short-term hormonal manipulation, the RTOG-ASTRO Phoenix
Consensus Conference definition of PSA failure (with an accuracy of > 80% for clinical failure) is ‘any PSA
increase > 2 ng/mL higher than the PSA nadir value, regardless of the serum concentration of the nadir’ [954].
After HIFU or cryotherapy no endpoints have been validated against clinical progression or survival; therefore,
it is not possible to give a firm recommendation of an acceptable PSA threshold after these alternative local
treatments [933].

6.4.3 Natural history of biochemical recurrence

Once a PSA recurrence has been diagnosed, it is important to determine whether the recurrence has developed
at local or distant sites. A SR and meta-analysis investigated the impact of BCR on clinical endpoints and
concluded that patients experiencing BCR are at an increased risk of developing distant metastases, PCa-
specific and overall mortality [933]. However, the effect size of BCR as a risk factor for mortality is highly
variable. After primary RP its impact ranges from HR 1.03 (95% CI: 1.004–1.06) to HR 2.32 (95% CI: 1.45–3.71)
[955, 956]. After primary RT, OS rates are approximately 20% lower at eight to ten years follow-up even in men
with minimal co-morbidity [957, 958]. Still, the variability in reported effect sizes of BCR remains high and
suggests that only certain patient subgroups with BCR might be at an increased risk of mortality.
The risk of subsequent metastases, PCa-specific- and overall mortality may be predicted by the initial
clinical and pathologic factors (e.g., T-category, PSA, ISUP grade group) and PSA kinetics (PSA-DT and interval to
PSA failure), which was further investigated by the SR [933].

For patients with BCR after RP, the following outcomes were found to be associated with significant prognostic
factors:
• distant metastatic recurrence: positive surgical margins, high RP specimen pathological ISUP GG, high pT
category, short PSA-DT, high pre-SRT PSA;
• prostate-cancer-specific mortality: high RP specimen pathological ISUP grade group, short interval to
biochemical failure as defined by investigators, short PSA-DT;
• overall mortality: high RP specimen pathological ISUP grade group, short interval to biochemical failure,
high PSA-DT.

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For patients with BCR after RT, the corresponding outcomes are:
• distant metastatic recurrence: high biopsy ISUP grade group, high cT category, short interval to
biochemical failure;
• prostate-cancer-specific mortality: short interval to biochemical failure;
• overall mortality: high age, high biopsy ISUP grade group, short interval to biochemical failure, high initial
(pretreatment) PSA.

Based on this meta-analysis, proposal is to stratify patients into two risk categories since not all patients with
BCR will have similar outcomes (see Table 6.4.1). The stratification into ‘EAU Low-Risk’ or ‘EAU High-Risk’ BCR
after RP has been validated in a European cohort [959].

Table 6.4.1: EAU risk categories for patients developing biochemical recurrence

EAU Low Risk BCR EAU High Risk BCR

After RP PSA-DT > 1 yr PSA-DT ≤ 1 yr
AND OR
pathological ISUP grade group < 4 pathological ISUP grade group 4–5
After RT interval to biochemical failure > 18 mo interval to biochemical failure ≤ 18 mo
AND OR
biopsy ISUP grade group < 4 biopsy ISUP grade group 4–5

6.4.4 The role of imaging in PSA-only recurrence

Imaging is only of value if it leads to a treatment change which results in an improved outcome. In practice,
however, there are very limited data available regarding the outcome’s consequent on imaging at recurrence.

6.4.4.1 Assessment of metastases (including nodal)

6.4.4.1.1 Bone scan and abdominopelvic CT
Because BCR after RP or RT precedes clinical metastases by seven to eight years on average [884, 960], the
diagnostic yield of conventional imaging techniques (bone scan and abdominopelvic CT) is low in asymptomatic
patients [961]. In men with PSA-only recurrence after RP the probability of a positive bone scan is < 5%, when
the PSA level is < 7 ng/mL [962, 963]. Only 11–14% of patients with BCR after RP have a positive CT [962]. In a
series of 132 men with BCR after RP the mean PSA level and PSA velocity associated with a positive CT were
27.4 ng/mL and 1.8 ng/mL/month, respectively [964].

6.4.4.1.2 Choline PET/CT

In two different meta-analyses the combined sensitivities and specificities of choline PET/CT for all sites of
recurrence in patients with BCR were 86–89% and 89–93%, respectively [965, 966]. Choline PET/CT may detect
multiple bone metastases in patients showing a single metastasis on bone scan [967] and may be positive
for bone metastases in up to 15% of patients with BCR after RP and negative bone scan [968]. The specificity
of choline PET/CT is also higher than bone scan, with fewer false positive and indeterminate findings [473].
Detection of LN metastases using choline PET/CT remains limited by the relatively poor sensitivity of the
technique. Choline PET/CT sensitivity is strongly dependent on the PSA level and kinetics [483, 969, 970]. In
patients with BCR after RP, PET/CT detection rates are only 5–24% when the PSA level is < 1 ng/mL but rise
to 67–100% when the PSA level is > 5 ng/mL. Despite its limitations, choline PET/CT may change medical
management in 18–48% of patients with BCR after primary treatment [971-973].
Choline PET/CT should only be recommended in patients fit enough for curative loco-regional
salvage treatment.

6.4.4.1.3 Fluoride PET/CT

18F-NaF PET/CT has a higher sensitivity than bone scan in detecting bone metastases [974]. However, 18F -NaF
PET/CT is limited by a relative lack of specificity and by the fact that it does not assess soft-tissue metastases
[975].

6.4.4.1.4 Fluciclovine PET/CT

18F-Fluciclovine PET/CT has been approved in the U.S. and Europe and it is therefore one of the PCa-specific
radiotracers widely commercially available [975-978].
18F-Fluciclovine PET/CT has a slightly higher sensitivity than choline PET/CT in detecting the site of relapse in

BCR [979]. In a multi-centre trial evaluating 596 patients with BCR in a mixed population, fluciclovine PET/CT
showed an overall detection rate of 67.7%; lesions could be visualised either at local level (38.7%) or in pelvic

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LNs (32.6%) [980]. As for choline PET/CT, fluciclovine PET/CT sensitivity is dependent on the PSA level, with a
sensitivity likely inferior to 50% at PSA level < 1 ng/mL.
In a prospective RCT evaluating the impact of 18F-fluciclovine PET/CT on SRT management
decisions in patients with recurrence post-prostatectomy, in 28 of 79 (35.4%) patients overall radiotherapeutic
management changed following 18F-fluciclovine PET/CT [981]. 18F-Fluciclovine PET/CT had a significantly higher
positivity rate than conventional imaging (abdominopelvic CT or MRI plus bone scan) for whole body (79.7% vs.
13.9%, p < 0.001), prostate bed (69.6% vs. 5.1%, p < 0.001), and pelvic LNs (38.0% vs. 10.1%, p < 0.001) [981].
However, as yet, no data demonstrating that these changes translate into a survival benefit are available.

6.4.4.1.5 Prostate-specific membrane antigen based PET/CT

PSMA PET/CT has shown good potential in patients with BCR. The diagnostic performance of 18F-PSMA PET/
CT in patients with BCR has been recently investigated by means of a systematic review and meta-analysis. The
pooled sensitivity, specificity, and AUC values for 18F-PSMA PET/CT in the diagnosis of prostate recurrence and/
or metastasis were 0.93 (0.89–0.95), 0.94 (0.85–0.98), and 0.96 (0,94–0.98), respectively the per-patient pooled
sensitivity and specificity values were 0.92 (0.86–0.96) and 0.83 (0.41–0.97), respectively. The per-lesion pooled
sensitivity and specificity values were identical, 0.91 (0.86–0.94) [982].
Reported predictors of 68Ga-PSMA PET in the recurrence setting were updated based on a high-
volume series (Table 6.4.2) [867]. High sensitivity (75%) and specificity (99%) were observed on per-lesion
analysis.

PSMA PET/CT seems substantially more sensitive than choline PET/CT, especially for PSA levels < 1 ng/
mL [983, 984]. In a study of 314 patients with BCR after treatment and a median PSA level of 0.83 ng/mL,
68Ga-PSMA PET/CT was positive in 197 patients (67%) [985]. In a phase III, prospective, multicentre, randomised

study, comparing 18F-PSMA-1007 and 18FCholine PET/CT in PCa patients with biochemical recurrence, the
overall correct detection rate (DR) was 84% (95% CI: 0.7967–0.8830) for PSMA and 69% (95% CI: 0.6191–
0.7489) for choline. This yielded a significant proportion difference of 16% (P < 0.0001). Also, the DR for cutoff
point PSA ≤ 1ng/ml was higher for PSMA compared to Choline (61.8% vs. 39.5%) [986].

A prospective multi-centre, multi-reader, open-label, phase II/III trial (OSPREY) evaluated the diagnostic
performance of 18F-DCFPyL in patients with presumptive radiologic evidence of recurrent or metastatic PCa on
conventional imaging [907]. Median sensitivity and median PPV were 95.8% (95% CI: 87.8%–99.0%) and 81.9%
(95% CI: 73.7%–90.2%), respectively.
Another prospective study evaluated the diagnostic performance of 18F-DCFPyL in 208 men with BCR
after RP or RT. The primary endpoint, the correct localisation rate was achieved, demonstrating positive findings
on 18F-DCFPyL PET/CT in the setting of negative standard conventional imaging [987]. At present there are no
conclusive data about comparison of such tracers [988].
A prospective, open label, cross-over study, the PYTHON trial, has compared the per-patient
detection rates (DR) of 18F-DCFPyL versus 18F-fluoromethylcholine PET/CT, in biochemical recurrence
(BCR) setting. A total of 201 high-risk PCa patients with first BCR after radical prostatectomy or radiation
therapy have completed the study. The per-patient DR was significantly higher for 18F-DCFPyL compared to
18F-fluoromethylcholine PET/CT (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased

with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/
ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%)
vs. 39/57 (68%) for 18FDCFPyL- and 18F-fluoromethylcholine -PET/CT, respectively) [989]. Comparable results
were found in a phase III trial of 18F-PSMA-1007 versus 18F-Fluorocholine PET/CT for the localisation of prostate
cancer biochemical recurrence. In this prospective, randomised, crossover multi-centre study, the overall correct
detection rates were significantly higher for 18F-PSMA-1007 than for 18F-fluorocholine when undetermined
findings were considered positive for malignancy (0.82 vs. 0.65; p < 0.0001) [990].

Table 6.4.2: PSMA-positivity separated by PSA level category [991]

PSA (ng/mL) 68Ga-PMSA PET positivity

< 0.2 33% (CI: 16–51)
0.2–0.49 45% (CI: 39–52)
0.5–0.99 59% (CI: 50–68)
1.0–1.99 75% (CI: 66–84)
2.0+ 95% (CI: 92–97)
PSA = prostate-specific antigen; 68Ga-PSMA PET = Gallium-68 prostate-specific membrane antigen positron
emission tomography.

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6.4.4.1.6 Whole-body and axial MRI
Whole body MRI has not been widely evaluated in BCR because of its limited value in the detection of early
metastatic involvement in normal-sized LNs [455, 486, 992]. In a prospective series of 68 patients with BCR, the
diagnostic performance of DW-MRI was significantly lower than that of 68Ga-PSMA PET/CT and 18NaF PET/CT
for diagnosing bone metastases [993].

6.4.4.2 Assessment of local recurrences

6.4.4.2.1 Local recurrence after radical prostatectomy
Because the sensitivity of anastomotic biopsies is low, especially for PSA levels < 1 ng/mL [961], SRT is usually
decided on the basis of BCR without histological proof of local recurrence.

Magnetic resonance imaging can detect local recurrences in the prostatic bed. The PSA threshold for MRI
positivity seems between 0.3 and 0.5 ng/mL; PSA kinetics also influence the MRI positivity, even at low PSA
values [994]. Two single-centre studies found that a negative MRI was an independent predictor of failure of
SRT [995, 996]. Conversely, a small (≤0.4 cc) relapse located at the vesico-urethral anastomosis is associated
with excellent prognosis at salvage RT [997]. The Prostate Imaging for Recurrence Reporting (PI-RR) system
has been recently launched to standardise MRI interpretation in the context of BCR after RP or RT [998]. Initial
assessment suggests good reproducibility of the score [999].
Choline PET/CT is less sensitive for local relapse than MRI but detects more regional and distant
metastases [1000].
The detection rates of 68Ga-PSMA PET/CT in patients with BCR after RP increase with the PSA level
[1001]. PSMA PET/CT studies showed that a substantial part of recurrences after RP were located outside the
prostatic fossa, even at low PSA levels [1002, 1003]. Combining 68Ga-PSMA PET and MRI may improve the
detection of local recurrences, as compared to 68Ga-PSMA PET/CT alone [1004-1006].

The EMPIRE-1, a single-centre, open-label, phase II/III RCT included 365 patients with detectable PSA after RP,
but negative results on conventional imaging. They were randomised to RT directed by conventional imaging
alone or to conventional imaging plus 18F-fluciclovine-PET/CT; patients with M1 disease in the PET/CT group (n
= 4) were excluded Patients with cN1 were irradiated to the pelvic nodes, but without a boost to the metastases.
After a median follow-up of 3.5 years, the PET/CT group was significantly associated with longer event-free
survival (HR: 2.04, 95% CI: 1.06–3.93, p = 0.0327) [1007].

6.4.4.2.2 Local recurrence after radiation therapy

In patients with BCR after RT, biopsy status is a major predictor of outcome, provided the biopsies are obtained
18–24 months after initial treatment. Given the morbidity of local salvage options it is necessary to obtain
histological proof of the local recurrence before treating the patient [961].
MRI has yielded excellent results in identifying local recurrence and can be used for biopsy targeting and guiding
local salvage treatment [961, 1008, 1009], even if it slightly underestimates the volume of the local recurrence
[1010]. Prostate-specific membrane antigen PET/CT can also detect local recurrences after RT [991] and
concordance between PSMA PET/CT and MRI is highly suggestive of cancer recurrence [1011].

6.4.4.3 Summary of evidence of imaging in case of biochemical recurrence

In patients with BCR imaging can detect both local recurrences and distant metastases, however, the sensitivity
of detection depends on the PSA level. After RP, PSMA PET/CT is the imaging modality with the highest
sensitivity at low PSA levels (< 0.5 ng/mL) and may help distinguishing patients with recurrences confined to
the prostatic fossa from those with distant metastases which may impact the design and use of post-RP SRT.
After RT, MRI has shown excellent results at detecting local recurrences and guiding prostate biopsy. Given the
substantial morbidity of post-RT local salvage treatments, distant metastases must be ruled out in patients
with local recurrences and who are fit for these salvage therapies. Choline-, fluciclovine- or PSMA-PET/CT can
be used to detect metastases in these patients but for this indication PSMA PET/CT seems the most sensitive
technique.

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6.4.4.4 Recommendations for imaging in patients with biochemical recurrence

Recommendations Strength rating

Prostate-specific antigen (PSA) recurrence after radical prostatectomy
Perform prostate-specific membrane antigen (PSMA) positron emission tomography/ Weak
computed tomography (PET/CT) if the PSA level is > 0.2 ng/mL and if the results will
influence subsequent treatment decisions (EAU BCR risk groups).
In PSMA PET/CT is not available, and the PSA level is ≥ 1 ng/mL, perform fluciclovine PET/ Weak
CT or choline PET/CT imaging if the results will influence subsequent treatment decisions.
PSA recurrence after radiotherapy
Perform prostate magnetic resonance imaging to localise abnormal areas and guide Weak
biopsies in patients fit for local salvage therapy.
Perform PSMA PET/CT (if available) or fluciclovine PET/CT or choline PET/CT in patients fit Strong
for curative salvage treatment.

6.4.5 Treatment of PSA-only recurrences

The timing and treatment modality for PSA-only recurrences after RP or RT remain a matter of controversy
based on the limited evidence.

6.4.5.1 Treatment of PSA-only recurrences after radical prostatectomy

6.4.5.1.1 Salvage radiotherapy for PSA-only recurrence after radical prostatectomy (cTxcN0M0, without PET/
CT)
Early SRT provides the possibility of cure for patients with an increasing PSA after RP. Boorjian et al., reported
a 75% reduced risk of systemic progression with SRT when comparing 856 SRT patients with 1,801 non-SRT
patients [1012]. The RAVES and RADICAL trials assessing SRT in post-RP patients with PSA levels exceeding
0.1–0.2 ng/mL showed 5-year freedom from BCR and BCR-free survival rates of 88% [999, 1013]. Tilki et al.
demonstrated the results of a matched pair analysis of 1832 patients with BCR, 32.9% (n = 603) received SRT
without ADT, 1229 (67,1%) had a observational strategy. The median follow-up was 95.9 months. Median total
SRT dose was 70.2 Gy. After 1:1 propensity score matching, at fiveteen years after RP, MFS and OS rates were
84.3 versus 76.9% (p < 0.001) and 85.3 versus 74.4% (p = 0.04) for SRT and noRT, respectively [1014].
The PSA level at BCR was shown to be prognostic [1012]. More than 60% of patients who are treated
before the PSA level rises to > 0.5 ng/mL will achieve an undetectable PSA level [1015-1017], corresponding to
a ~80% chance of being progression-free five years later [1018]. A retrospective analysis of 635 patients who
were followed after RP and experienced BCR and/or local recurrence and either received no salvage treatment
(n = 397) or SRT alone (n = 160) within two years of BCR showed that SRT was associated with a 3-fold increase
in PCa-specific survival relative to those who received no salvage treatment (p < 0.001). Salvage RT has been
shown to be effective mainly in patients with a short PSA-DT [1019].

In a retrospective multi-centre study including 25,551 patients with at most one high-risk factor after RP (ISUP
grade group 4-5 or pT3/4), initiating sRT above a PSA level of 0.25 ng/mL was associated with increased
ACM-risk. After a median follow-up of six years, patients who received sRT at a PSA level >0.25 ng/mL had a
significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P =.008) compared with men who received sRT
when the PSA was ≤0.25 mg/mL [1020]. For an overview of SRT see Table 6.4.3.

Although biochemical progression is now widely accepted as a surrogate marker of PCa recurrence; metastatic
disease, disease-specific and OS are more meaningful endpoints to support clinical decision-making. A SR and
meta-analysis on the impact of BCR after RP reports SRT to be favourable for OS and PCSM. In particular SRT
should be initiated in patients with rapid PSA kinetics after RP and with a PSA cut-off of 0.4 ng/mL [933]. An
international multi-institutional analysis of pooled data from RCTs has suggested that MFS is the most valid
surrogate endpoint with respect to impact on OS [1021, 1022]. Table 6.4.4 summarises results of recent studies
on clinical endpoints after SRT.

The EAU BCR definitions have been externally validated and may be helpful for individualised treatment
decisions [933, 959]. Despite the indication for salvage RT, a ‘wait and see‘ strategy remains an option for the
EAU BCR ‘Low-Risk’ group [933, 959].

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6.4.5.1.2 Salvage radiotherapy combined with androgen deprivation therapy (cTxcN0, without PET/CT)
Data from RTOG 9601 suggest both CSS and OS benefit when adding two years of bicalutamide (150 mg o.d.)
to SRT [1023]. According to GETUG-AFU 16 also 6-months treatment with a LHRH-analogue can significantly
improve 10-year BCR, biochemical PFS and, modestly, MFS. However, SRT combined with either goserelin or
placebo showed similar DSS and OS rates [1024].

In addition, Pollack et al., reported on the results of a randomised 3-arm phase III trial (NRG Oncology/RTOG
0534 SPPORT) adding six months treatment with a LHRH-analogue to SRT of the prostate bed (PBRT) (group
2) compared with PBRT alone (group 1) or the former combination with PBRT-RT and pelvic LN RT (PLNRT)
(group 3) [1025]. The primary endpoint was freedom from progression (FFP) after five years. However, using
the phoenix-definition of biochemical progression (nadir + 2 ng/mL used for definitive RT), and not the criterion
of nadir + 0.2, as is used commonly (but without clear evidence) will have resulted in a later diagnosis of
progression in the SPPORT trial.

With a median follow-up of 8.2 years of the surviving patients FFP increased significantly for group 3 (87.4%)
compared with group 2 (81.3%) (p = 0.0027) and group 1 (70.9%) (p < 0.0001) [1025]. The difference between
group 2 and group 1 was also significant (p < 0.0001). Distant metastasis incidence rates (secondary endpoint)
were lowest in group 3 (including RT of the pelvic lymphatics) and were significantly lower only compared with
group 1 (PBRT only, HR: 0.52) similar to the rate of PCa deaths (HR: 0.51). No significant difference was seen
for OS. There was a significantly higher risk of both acute- and late side effects in group 3. Therefore, the role of
additional PLNRT remains unclear and should be further proven in RCTs including PSMA PET-CT [1026].

RADICALS HD investigated the role of RT without ADT (n = 737) versus RT plus 6 months ADT (n = 747) and
RT plus 6 months ADT (n = 761) versus RT plus 24 months long term ADT (n = 762) in both the salvage and
adjuvant settings [1027-1029]. The design of RADICALS HD was complex and included components of the
RADICALS RT trial together with the RADICALS HD component. RADICALS RT was a phase III comparison of ART
versus observation and early SRT and has been published previously [901] (see table 6.3.5.2).

RADICALS HD included men after prostatectomy (indications for ART or early SRT), median pre SRT-PSA was
0.2 ng/ml with conventional staging imaging (M0) without PET-CT. Due to the complex design some patients
were enrolled in a three-way randomisation (including patients from RADICALS RT, n = 492) and in a two-way
randomisation (SRT + 6 months- or 24 months ADT, n = 1,197). The randomisation was influenced by physician
preference. For this reason, more patients had high risk factors in the short term ADT- versus long term ADT-
study (ISUP >3: 29% versus 11% and for > pT3B-tumours: 31% vs. 17%) compared with the no ADT- and the short
term ADT-study [1030].

With a median FU of nine years the ten-year MFS (primary endpoint, inclusion of deaths from PCa only) for
no ADT vs. short term ADT showed no significant difference for both arms (88.1% vs. 89.9%, p>0.05) but for
“Clinical progression free survival” (68.3% versus 79.4%, p<0.0001 with some evidence of non proportional
hazards) and “10-year freedom from non protocol ADT” (73.3% vs. 82.3%, p<0.0001 but with clear evidence of
non-proportional hazards). Max. GU-Tox grade 3 was 16% (no ADT) versus 13% (short term ADT) (p>0.05). With
a median FU of 8.9 years the 10-year MFS (primary endpoint) in the second radomisation showed a moderate
significant difference (78.1% vs. 71.9%) in favour of the long term ADT arm compared with the short term ADT
arm (p=0.029, HR 0.773). Comparable significant differences were seen for “Clinical progression free survival”
and for “10-year freedom from non-protocol ADT”. Max. GU-Tox grade 3 was 14% (short term ADT) vs. 20% (long
term ADT).

The authors concluded, that the findings for short term ADT versus no ADT do not support the use of ADT in this
patient population. For the comparison of long term ADT versus short term ADT the conclusion was that “individuals
who can accept the additional duration of adverse effects, long-course ADT should be offered” with SRT.

Table 6.4.5 provides an overview of these five RCTs. One of these RCTs reports improved OS (RTOG 96-01),
another (GETUG-AFU 16) improved moderately MFS (7%) at 10 years. The SPPORT trial improved FFP for all
three arms and the distant metastasis rate only in the comparison of PBRT+ RT of the pelvic lymphatics + 6
month ADT what makes the interpretation difficult. The two arm comparision (SRT versus SRT + 6 months
ADT) of RADICALS HD did not improve MFS after 10 years, this is in contrast to the results of the GETUG-AFU
16 trial. Only the comparison of SRT + 6 months ADT versus SRT+ 24 months ADT of RADICALS HD improved
moderately 10 year MFS (6.2%). This improvement came on the cost of increased side effects of the additional
18 months ADT including a double rate of patients with testosteron-supression after 10 years compared with 6
months of ADT [1031].

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Due to methodological discrepancies and also related to follow-up and risk, it is, as yet, not evident which
patients should receive ADT, which type of ADT, and for how long. Men at high risk of further progression (e.g.,
with a PSA ≥ 0.7 ng/mL and GS ≥ 8) may benefit from SRT combined with two years of ADT; for those at lower
risk (e.g., PSA < 0.7 ng/mL and GS = 8) SRT combined with six months of ADT may be sufficient [1023]. Men
with a low-risk profile (PSA < 0.5 ng/mL and GS < 8) and a PSA level <0.5 ng/ml may receive SRT alone. In a
unplanned subgroup-analysis [1032] (RTOG 96-01) of men with a PSA of 0.61 to 1.5 (n = 253) there was an OS
benefit associated with antiandrogen assignment (HR: 0.61, 95% CI: 0.39–0.94) [1032]. In those receiving early
SRT (PSA <0.6 ng/mL, n = 389), there was no improvement in OS (HR: 1.16, 95% CI: 0.79–1.70), with increased
other-cause mortality (sub-distribution HR: 1.94, 95% CI: 1.17–3.20, p = 0.01) and increased odds of late grades
3–5 cardiac and neurologic toxic side effects (OR: 3.57; 95% CI: 1.09–15.97, p = 0.05). These results suggest
that pre-SRT PSA level may be a prognostic biomarker for outcomes of anti-androgen treatment with SRT. A
SR addressing the benefit from combining HT with SRT suggested risk stratification of patients based on the
pre-SRT PSA (< 0.5, 0.6–1, > 1 ng/mL), margin status and ISUP grade as a framework to individualise treatment
[1033]. In addition, potential risk factors that should be considered are (short) PSA-doubling time and pT3b-4-
tumours [1027, 1028, 1030].

In conclusion regarding the “weak” recommendation “offer hormonal therapy in addition to SRT to men with
BCR we have different results of three RCT’s for additional short term ADT (6 months) to SRT. One showed
an increase of MFS [1024], the second and third one did not [1025, 1028]. Of two RCT’s with long term ADT
in addition to SRT one RCT showed a significant better OS [1023], the second one did not [1028] but this
one showed a moderate increase in MFS with the cost of a higher rate of severe side effects. Additionally in
RADICALS HD no subgroup analysis of risk factors was performed. To establish more precise recommendations
10-year results of the other RCT’s and the meta-analysis have to be awaited.

6.4.5.1.2.1 Target volume, dose, toxicity

There have been various attempts to define common outlines for ‘clinical target volumes‘ for pN0 PCa [1034,
1035] and for organs at risk of normal tissue complications [1034]. However, given the variations of techniques
and dose-constraints, a satisfactory consensus has not yet been achieved. A benefit in biochemical PFS but
not MFS has been reported in patients receiving whole pelvis SRT (± ADT) but the advantages must be weighed
against possible side effects [1026]. This is supported by data from the SPPORTTrial (NRG Oncology/RTOG
0534 SPPORT) but it remains controversial [1025].

The optimal SRT dose has not been well defined. It should be at least 64 Gy to the prostatic fossa (± the base
of the SVs, depending on the pathological stage after RP) [904, 1036]. In a SR, the pre- SRT PSA level and SRT
dose both correlated with BCR, showing that relapse-free survival decreased by 2.4% per 0.1 ng/mL PSA and
improved by 2.6% per Gy, suggesting that the treatment dose above 70 Gy should be administered at the lowest
possible PSA level [1037]. The combination of pT stage, margin status and ISUP grade group and the PSA at SRT
seems to define the risk of biochemical progression, metastasis and overall mortality [894, 1038]. In a study on
894 node-negative PCa patients, doses ranging from 64 to > 74 Gy were assigned to twelve risk groups defined
by their pre-SRT PSA classes < 0.1, 0.1–0.2, 0.2–0.4, and > 0.4 ng/mL and ISUP grade group < 1 vs. 2/3 vs.
> 4 [1039]. The updated Stephenson nomograms incorporate the SRT and ADT doses as predictive factors for
biochemical failure and distant metastasis [1040].

Two RCT’s were published (Table 6.4.6). Intensity-modulated radiation therapy plus IGRT was used in 57% of
the patients in the SAKK-trial [1041] and in all patients of a Chinese trial [1042]. No patient had a PSMA PET/CT
before randomisation. The primary endpoint in both trials was ‘freedom from biochemical progression’, which
was not significantly improved with higher doses. However, in the Chinese trial a subgroup analysis showed a
significant improvement of this endpoint for patients with Gleason 8-10 tumours (66.5% vs. 30.2%, p = 0.012)
and for multiple positive surgical margins (82.5% vs. 57.5%, p=0.037) [1042]. In this trial, patients were treated
with ART or SRT and the number of patients was relatively small (n = 144). At this time it seems difficult to draw
final conclusions about the optimal total RT-dose and longer follow-up should be awaited but subgroups of high-
risk patients might profit from higher total doses.

Salvage RT is associated with toxicity. In one report on 464 SRT patients receiving median 66.6 (max. 72) Gy,
acute grade 2 toxicity was recorded in 4.7% for both the GI and GU tract. Two men had late grade 3 reactions
of the GI tract, but overall, severe GU tract toxicity was not observed. Late grade 2 complications occurred in
4.7% (GI tract) and 4.1% (GU tract), respectively, and 4.5% of the patients developed moderate urethral stricture
[1043].

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In a RCT on dose escalation for SRT (n = 350), acute grade 2 and 3 GU toxicity was observed in 13.0% and 0.6%,
respectively, with 64 Gy and in 16.6% and 1.7%, respectively, with 70 Gy. Gastro-intestinal tract grades 2 and 3
toxicity occurred in 16.0% and 0.6%, respectively, with 64 Gy, and in 15.4% and 2.3%, respectively, with 70 Gy
[1044, 1045]. Late grade 2 and 3 GI toxicity was significantly increased with higher doses but without significant
differences in QoL. In this study, however, the rectal wall dose constraints were rather permissive and in 44% of
the patients outdated 3-D-techniques were used [1041].

With dose escalation over 72 Gy and/or up to a median of 76 Gy, the rate of severe side effects, especially GU
symptoms, clearly increases, even with newer planning and treatment techniques [1046, 1047]. In particular,
when compared with 3D-CRT, IMRT was associated with a reduction in grade 2 GI toxicity from 10.2 to 1.9% (p =
0.02) but no effect on the relatively high level of GU toxicity was shown (5-year, 3D-CRT 15.8% vs. IMRT 16.8%)
[1046]. However, in a RCT comparing 66 Gy and 72 Gy with all patients having IMRT plus IGRT (n = 144), no
significant differences for GI and GU-toxicity was demonstrated [1048]. After a median salvage IMRT dose of
76 Gy however, the 5-year risk of grade 2–3 toxicity rose to 22% for GU and 8% for GI symptoms, respectively
[1047]. Doses of at least 64 Gy and up to 72 Gy in patients without PET/CT can be recommended [1043, 1044].

Table 6.4.3: Selected studies of post-prostatectomy salvage radiotherapy, stratified by pre-salvage

radiotherapy PSA level* (cTxcN0M0, without PET/CT)

Study n Median FU pre-SRT RT dose bNED/PFS 5-yr. results

(mo) PSA (ng/mL) ADT (year)
median
Bartkowiak, 464 71 0.31 66.6 Gy 54% (5.9) 73% vs. 56%; PSA
et al. 2018 < 0.2 vs. ≥ 0.2 ng/
[1043] mLp < 0.0001
Stish, et al. 1,106 107 0.6 68 Gy 50% (5) 44% vs. 58%; PSA
2016 [1015] 16% ADT 36% (10) < 0.5 vs. > 0.5 ng/mL
p < 0.001
Tendulkar, 2,460 60 0.5 66 Gy 56% (5) Pre-SRT PSA
et al. 2016 16% ADT 71% 0.01–0.2 ng/mL
[1040] 63% 0.21–0.5 ng/mL
54% 0.51–1.0 ng/mL
43% 1.01–2.0 ng/mL
37% > 2.0 ng/mL
p < 0.001
Tilki et al. 25,551 72 Not given Med. Not given ACM (six years): HR
2023 [1020] SRT at: 68.4 Gy 1.49 of higher risk
PSA < SRT+ADT:1489 when SRT at start was
0.25 ART:N= 673 > 0.25 (p=0.008)
n=1,556 ADT: 208
PSA >
0.25
n=1,677
No RT:
n=21,645
*Androgen deprivation therapy can influence the outcome ‘biochemically no evidence of disease (bNED)’ or
‘progression-free survival’. To facilitate comparisons, 5-year bNED/PFS read-outs from Kaplan-Meier plots are
included.
ADT = androgen deprivation therapy; bNED = biochemically no evidence of disease; FU = follow up; mo = months; n
= number of patients; PFS = progression-free survival; PSA = prostate-specific antigen; SRT = salvage radiotherapy;
yr = year.

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Table 6.4.4: Selected studies reporting clinical endpoints after SRT (cTxcN0M0, without PET/CT)
(the majority of included patients did not receive ADT)

Study n Median FU Regimen Outcome

(mo)
Bartkowiak, 464 71 66.6 (59.4-72) Gy no 5.9 yr. OS
et al. 2018 ADT post-SRT PSA < 0.1 ng/mL 98%
[1043] post-SRT PSA > 0.1 ng/mL 92%
p = 0.005
Jackson, 448 64 68.4 Gy no ADT 5 yr. DM
et al. 2014 post-SRT PSA < 0.1 ng/mL 5%
[1049] post-SRT PSA > 0.1 ng/mL 29%
p < 0.0001
5 yr. DSM
post-SRT PSA < 0.1 ng/mL 2%
post-SRT PSA > 0.1 ng/mL 7%
p < 0.0001
OS
post-SRT PSA < 0.1 ng/mL 97%
post-SRT PSA > 0.1 ng/mL 90%
p < 0.0001
Stish, et al. 1,106 107 68 (64.8-70.2) Gy 5 and 8.9 yr. DM
2016 [1015] 39% 2D treatment SRT: PSA < 0.5 ng/mL 7% and 12%
planning SRT: PSA > 0.5 ng/mL 14% and 23%
incl. 16% ADT p < 0.001
5 and 8.9 yr. DSM
SRT: PSA < 0.5 ng/mL < 1% and 6%
SRT: PSA > 0.5 ng/mL 5% and 10%
p = 0.02 5 and 8.9 yr. OS
SRT: PSA < 0.5 ng/mL 94% and 86%
SRT: PSA > 0.5 ng/mL 91% and 78%
p = 0.14
Tendulkar, 2,460 60 66 (64.8-68.4) Gy 10-yr. DM (19% all patients)
et al. 2016 incl. 16% ADT Pre-SRT PSA
[1040] 9% 0.01–0.2 ng/mL
15% 0.21–0.5 ng/mL
19% 0.51–1.0 ng/mL
20% 1.01–2.0 ng/mL
37% > 2.0 ng/mL
p < 0.001
ADT = androgen deprivation therapy; DM = distant metastasis; DSM = disease specific mortality;
FU = follow up; mo. = month; n = number of patients; OS = overall survival; PSA = prostate specific antigen;
SRT = salvage radiotherapy.

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Table 6.4.5: Randomised controlled trials comparing salvage radiotherapy combined with androgen deprivation
therapy vs. salvage radiotherapy alone

Study n Risk groups Median Regimen Outcome

FU (mo)
GETUG-AFU 16 369 SRT + ADT ISUP GG ≤ 2/3 112 66 Gy PBRT+ 6 mo. 10-yr.
2019 [1024] 374 RT 89% LHRH analogue 66 Gy PFS: RT + ADT, 64%
SUP GG ≥ 4 PBRT PFS: RT, 49%
11% cN0 p < 0.0001
MFS: RT + ADT, 75%
MFS: RT, 69%
p = 0.034
RTOG 9601 384 SRT + ADT pT2 R1, pT3 156 64.8 Gy PBRT + 12-yr.
2017 [1023] 376 SRT cN0 bicalutamide cumulative DM
24 mo. RT + ADT: 14%
64.8 Gy PBRT + RT + placebo: 23%
placebo p = 0.005
OS
RT + ADT: 76%
RT + placebo: 71%
p = 0.04
DSM
RT + ADT: 5.8%
RT + placebo: 13.4%
p < 0.001
NRG Oncology/ 564 SRT pT2 or pT3 survivors: 64.8–0.2 Gy PBRT 5-yr. FFP (primary
RTOG 0534 578 SRT + ADT ISUP GG <5 8.2 years 64.8–70.2 Gy PBRT endpoint)
SPPORT [1025] 574 SRT + Pre SRT PSA: 6 mo. LHRH analogue 70.9% Group 1
PBRT + ADT 0.1-2.0 64.8–70.2 Gy PBRT + 81.3% Group 2
45 Gy PLNRT 87.4% Group 3
6 mo. LHRH analogue Comparisons :
G 3 vs. G 1: p < 0.0001
G 2 vs. G 1: p < 0.0001
G 3 vs. G 2: p < 0.0027
RADICALS HD 737 SRT ISUP >7 (11%) 108 52.5 Gy, 20 Fx 10-yr. MFS:
0 vs. 6 mo. ADT 747 SRT+ADT ≥ pT3b (17%) PBRT (29%) SRT: 79.2%
[1027] R1 (62%) 66 Gy, 33 Fx SRT+ADT: 80.4%
PSA: < 0.3 PBRT (69%) p= 0.71; HR: 0.89
(61%) LHRH analogue (83%) CPFS:
≥ 0.5 (19%) SRT: 68.3%
R1 (62%) SRT+ADT: 79.4%
N1 (3%) p = 0.071, HR:0.54
Max.GU-Tox G 3:
SRT: 16%
SRT+ADT: 13%
p>0.05
RADICALS HD 761 6 mo. ADT ISUP > 7 (29%) 107 52.5 Gy 20 Fx 10 year. MFS:
6 versus 24 ≥ pT3b (31%) PBRT (19%) SRT+6 mo.: 71.9%
months ADT 762 24 mo. Med. Pre SRT 66 Gy, 33 Fx SRT+24 mo.: 78.1%
[1028] ADT PSA: PBRT (79%) p = 0.029, HR: 0.77
0.23 LHRH analogue (84%) Max.GU-Tox G3:
R1 (63%) SRT+6 mo.: 14%
N1 (8%) SRT+24 mo.:20%
p = 0.025
ADT = androgen deprivation therapy; CPFS= clinical progression free survival; DM = distant metastasis; DSM =
disease specific mortality; PFS = progression free survival; FFP = Freedom From Progression; FU = follow-up;
LHRH = luteinising hormone-releasing hormone; MFS = metastasis-free survival; OS = overall survival; PFS =
progression-free survival; mo = months; n = number of patients; RT = radiotherapy; yr = year, PBRT = prostate bed
radiotherapy; PLNRT = pelvic lymph node radiotherapy.

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Table 6.4.6: Randomised trials investigating dose escalation for SRT without ADT and without PET-CT

Trial n PCa condition Radiotherapy Follow-up Outcome Results

Dose (median)
SAKK 09/10 350 pT2a-3b 64 Gy vs.70 Gy 6.2 yr. Primary 6 yr. FFBP: 62% vs.
trial, 2021 R0 – R1 endpoint: 61%
[904] pN0 or cN0 No ADT allowed FFBP OS: no difference
PSA post op Late side effects:
undetectable VMAT+ IGRT: 57% GI grade 2: 7.3% vs.
(< 0.1 ng/mL) 3-D planning: 43% 20%
or persistent GI grade 3: 4.2% vs.
(> 0.1 ng/mL < 2.3%
0.4 ng/mL) p for ≥ grade 2/3:
0.009

Phase-III-Trial 144 pT2-4 66 Gy vs.72 Gy 89.5 mo. Primary 7 yr. FFBP: 70.3% vs.
Qi X, et al., ART: 33% R0-R1 All patients endpoint: 61.2% (p > 0.05)
2024 [1042] SRT: 67% pN0 or cN0 VMAT+ FFBP High risk (GS: 8–10):
Med. PSA pre- IGRT 66.5% vs. 30.2%
RT: 0.2 ng/mL No ADT allowed p < 0.012 HR: 0.73
High risk (pT3-4, Multiple SR+: 82.5%
GS: vs. 57.5% p=0.037 HR:
8-10, PSA >20 0.36
ng/mL): Late side effects: GI +
whole pelvis RT: GU grade 2 p > 0.05
126 No grade 3
(87.5%)
ADT = androgen deprivation therapy; ART = adjuvant radiotherapy; FFBP = freedom from biochemical failure; GI
= gastro-intestinal; GU = genito-urinary; Gy = Gray; IGRT = image guided radiotherapy; mo = month; n = number of
patients; PSA = prostate-specific antigen; RT = radiotherapy; SRT = y = year; vs. = versus; VMAT = volumetric arc
radiation therapy.

6.4.5.1.2.2 Salvage radiotherapy with or without ADT (cTx cN0/1) with PET/CT
In a prospective multi-centre study of 323 patients with BCR, PSMA PET/CT changed the management intent in
62% of patients as compared to conventional staging. This was due to a significant reduction in the number of
men in whom the site of disease recurrence was unknown (77% vs. 19%, p < 0.001) and a significant increase in
the number of men with metastatic disease (11% vs. 57%) [1050]. A prospective study in a subgroup of 119 BCR
patients with low PSA (< 0.5 ng/mL) reported a change in the intended treatment in 30.2% of patients [1003];
however, no data exist on the impact on final outcome.
Another prospective study in 272 patients with early biochemical recurrent PCa after RP showed that
68Ga-PSMA PET/CT may tailor further therapy decisions (e.g., local vs. systemic treatment) at low PSA values

(0.2–1 ng/mL) [1051].

A multi-centre retrospective study evaluated patients who underwent SRT for BCR after RP, without any signs of
distant metastatic disease on PET/CT. After case-control matching, two cohorts (n = 108 patients each), with
and without PSMA PET/CT prior to SRT were analysed. In the cohort without PSMA PET/CT, 23 patients (21%)
had BCR at one year after SRT vs. nine patients (8%) who underwent restaging with PSMA PET/C prior to SRT
(p = 0.007). PSMA-PET/CT was found to be associated with an improved oncological outcome in patients with
BCR after RP, receiving SRT to the prostatic fossa [1052]. It is worth mentioning that in this study the median
biologically effective radiation dose administered in the PSMA-cohort was significantly higher than in the
historical cohort (70 Gy vs. 66 Gy, respectively, p < 0.001).

A single-centre open-label, phase II/III RCT (EMPIRE-1) evaluated the role of 18F-fluciclovine-PET/CT compared
with conventional imaging for SRT. Three hundred and sixty five patients with detectable PSA after RP but
negative results on conventional imaging, were randomised to RT directed by conventional imaging alone or
to conventional imaging plus PET/CT; patients with M1 disease in the PET/CT group (n = 4) were excluded.
Patients with cN1 were irradiated to the pelvic lymphatics but without a boost to the metastasis. Median follow
103 up was 3.5 years. In adjusted analyses, the study group was significantly associated with an improvement
of the event-free survival (HR: 2.04, 95% CI: 1.06–3.93, p = 0.0327) [1007].

106 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

6.4.5.1.2.3 Nodal-directed therapy for rcN1 (with PET/CT)
Radiolabelled PSMA PET/CT is increasingly used as a diagnostic tool to assess metastatic disease burden in
patients with BCR following prior definitive therapy. A review including 30 studies and 4,476 patients showed
overall estimates of positivity in a restaging setting of 38% in pelvic LNs and 13% in extra-pelvic LN metastases
[991]. The percentage positivity of PSMA PET/CT was proven to increase with higher PSA values [991]. Results
of this review demonstrated a high sensitivity and specificity of 68Ga-PSMA in advanced PCa, with a per-lesion-
analysed sensitivity and specificity of 75% and 99%, respectively.

A large retrospective international study included patients with LN-recurrent PCa (cN1 and M1a) and PSA
progression following multi-modality treatment (surgery and post-operative RT) [1053]. The aim of the study
was to compare SOC with nodal metastasis-directed therapy (MDT). The nodal MDT-group showed significantly
better CSS than the SOC control group (5-year survival 98.6% vs. 95.7%, p < 0.01, respectively) [1053].
Another retrospective study compared stereotactic body radiation therapy (SABR) with elective
nodal irradiation (ENRT) in nodal oligo-recurrent PCa (n = 506 patients, 365 of which with N1 pelvic recurrence).
With a median follow-up of 36 months, ENRT (n = 197) was associated with a significant reduction of nodal
recurrences (p < 0.001), compared with SABR (n=309) of 2% vs. 18%, respectively. In a a multi-variable analysis,
patients with one LN at recurrence had longer adjusted MFS after ENRT (HR: 0.50, 95% CI: 0.30–0.85, p = 0.009).
The tendency to relapse was higher for pelvic- than extra-pelvic nodes (p < 0.001) [1054]. For patients presenting
with two or more (extra)pelvic LNs, adjusted MFS was not significantly different (HR: 0.92, 95% CI: 0.54– 1.59,
p = 0.8). In these situations, SABR should be used in highly selected patients in prospective cohorts or clinical
trials only, before any recommendations can be made.

Long term outcomes have been reported from a prospective single arm study with extended-nodal radiotherapy
(ENRT) and (11C)-choline PET-CT guided simultaneous integrated boost to positive lymph nodes in 60 patients
[1055] 34 (56.7%) had a pelvic recurrence only. Median PSA relapse was 2.3 ng/ml and med. number of
positive LN was 2. ADT was prescribed for 48/60 pts., median duration was 30.7 months, with 15/60 pts. had a
castration-resistent PCa at diagnosis metastasis. The distant metastasis free-survival at ten years of the entire
group was 45.2% [1055].

There is only one prospective Phase-II-trial (GETUG P07-OLIGOPELVIS) investigating the clinical outcome of
IMRT+ADT in 67 patients with oligorecurrent (<=5) pelvic node relapses in fluorocholine positron-emission
tomography CT-imaging [1056]. However, 61% of the patients had one positive node only. Median FU was
6.1 years. The 5-years PFS, bNED and ADT-free survival was 39%, 31% and 64% after elective RT of the pelvic
lymphatics and 6 months ADT (LHRH agonist and antagonist). G 2+ 5-years GI and GU tox were 4% and 4%. The
major site of relapse was para-aortic lymph nodes [1056].

In these situations, ENRT or SABR should be used in highly selected patients in prospective cohorts or clinical
trials only, before any recommendations can be made. The optimal duration of ADT is uncertain and durations >
6 months are likely to be more effective. For MDT in M1 patients see section 6.6.7.

6.4.5.1.3 Salvage lymph node dissection

The surgical management of recurrent nodal metastases in the pelvis has been the topic of several
retrospective analyses [1057-1059] and a SR [1060]. The reported 5-year BCR-free survival rates ranged from 6%
to 31%. Five-year OS was approximately 84% [1060]. Biochemical recurrence rates were found to be dependent
on PSA at salvage surgery and location and number of positive nodes [1061]. Addition of RT to the lymphatic
template after salvage LN dissection may improve the BCR rate [1062]. In a multi-centre retrospective study
long-term outcomes of 189 patients who underwent salvage LN dissection were reported to be worse than
previously described in studies with shorter follow-up [1063]. Biochemical recurrence (BCR)-free survival at ten
years was 11%. Patients with a PSA response after salvage LN dissection and patients receiving ADT within
six months from salvage LN dissection had a lower risk of death from PCa [1063]. The majority of the patients
(81%) had received a choline PET and median PSA at salvage LN dissection was 2.5 ng/mL. In a cohort study
including patients treated with salvage LN dissection via PSMA--radioguided surgery (PSMA-RGS), 2-year BCR-
free survival rate was 32% [1064]. In multi-variable analyses, higher pre-operative PSA, higher number of PSMA-
avid lesions, multiple (pelvic plus retroperitoneal), and retroperitoneal localisation of lesions at pre-operative
imaging were independent predictors of BCR after PSMA-RGS. High-level evidence for the oncological value of
salvage LN dissection (including adjuvant RT of the LNs) is still lacking [1060].

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6.4.5.2 Management of PSA failures after radiation therapy
Therapeutic options in these patients are ADT or salvage local procedures, as well as a ‘wait and see’ approach,
based on EAU BCR risk categories at relapse. A SR and meta-analysis included studies comparing the efficacy
and toxicity of salvage RP, salvage HIFU, salvage cryotherapy, SBRT, salvage LDR BT, and salvage HDR BT
in the management of locally recurrent PCa after primary radical EBRT [1065]. The outcomes were BCR-
free survival at two and five years. No significant differences with regards to recurrence-free survival (RFS)
between these modalities was found. Five-year RFS ranged from 50% after cryotherapy to 60% after HDR BT
and SBRT. The authors reported that severe GU toxicity exceeded 21% for whole-gland HIFU and RP, whereas
it ranged from 4.2% to 8.1% with re-irradiation. Differences in severe GI toxicity also appeared to favour
re-irradiation, particularly HDR BT [1065]. Due to the methodological limitations of this review (the majority
of the included studies were uncontrolled single-arm case series and there was considerable heterogeneity
in the definitions of core outcomes) the available evidence for these treatment options is of low quality and
strong recommendations regarding the choice of any of these techniques cannot be made. The following is an
overview of the most important findings for each of these techniques. Salvage cryo-therapy and focal HIFU are
discussed in section 6.4.5.2.2

6.4.5.2.1 Salvage radical prostatectomy

Salvage RP after RT is associated with a higher likelihood of AEs compared to primary surgery because of the
risk of fibrosis and poor wound healing due to radiation [1066].

6.4.5.2.1.1 Oncological outcomes

In a SR of the literature, Saouli et al., showed using data from 3836 patients in 55 studies across median follow-
up ranging 4.6 – 94 months that SRP provided five-year BCR occurrence 48-59%, cancer-specific survival 13.4-
98% and OS 62-100% [1067]. These figures are similar to those reported by Chade et al., in 2011, with 5-year and
10-year BCR-free survival estimates ranging from 47–82% and from 28–53%, respectively. The 10-year CSS and
OS rates ranged from 70–83% and from 54–89%, respectively. The pre-SRP PSA value and initial prostate biopsy
ISUP grade group were the strongest predictors of the presence of organ-confined disease, progression, and
CSS [1068]. In a multi-centre analysis including 414 patients, 5-year BCR-free survival, CSS and OS were 56.7%,
97.7% and 92.1%, respectively [1069]. Pathological T stage ≥ T3b (OR: 2.348) and GS (up to OR: 7.183 for GS >
8) were independent predictors for BCR. Appropriate risk-stratification according to EAU Guidelines Biochemical
Recurrence criteria may better select for SRP, with higher metastasis-free (90% vs 76%, p < 0.01) and OS
(89% vs 84%, p = 0.01) for low versus high EAU risk [1070, 1071].

Lymphadenectomy was performed in most cases (79%), with 20.5% of patients staged N+ at final pathology
[1067]. Detailed analysis of a multi-institutional series of 853 SRP patients reported that 87% underwent
lymphadenectomy, 21% were pN1 and these patients suffered worse overall and cancer-specific survival
[1072]. Like in primary surgery, patients with persistent PSA after SRP (42%) had worse BCR-free (6.6 vs
59%), metastasis-free (71 vs. 88%) and OS (77 vs. 94%) after median follow-up of 84 months according to a
retrospective, multi-institutional series of 580 patients [1073]. Persistent PSA after SRP was shown to be an
independent predictor for BCR and death.

6.4.5.2.1.2 Morbidity
Most reported cases have been open (60%) and robotic-assisted (38%) resulting in an overall complication
rate of 34%, with major (Clavien grade ≥ 3) complications occurring across a range 0 to 64% [1067]. Compared
to primary open RP, SRP is associated with a higher risk of later anastomotic stricture (47 vs. 5.8%), urinary
retention (25.3% vs. 3.5%), urinary fistula (4.1% vs. 0.06%), abscess (3.2% vs. 0.7%) and rectal injury (9.2 vs.
0.6%) [1074]. These complications appear to be less common with robotic compared to open surgery [1066,
1068, 1075].
Functional outcomes are also worse compared to primary surgery considering urinary incontinence
(47.9%, range 21% to 90%) and ED in nearly all patients [1067, 1068, 1075].
Complications may be lower and functional outcomes may be better with the robotic-assisted
approach but certainty of evidence is low [1071].

6.4.5.2.1.3 Summary of salvage radical prostatectomy

In general, SRP should be considered only in patients with low co-morbidity, a life expectancy of at least ten
years, a pre-SRP PSA < 10 ng/mL and initial biopsy ISUP grade group ≤ 2/3, localised disease (N0M0) according
to re-staging, and those whose initial clinical staging was T1 or T2 [1068].

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6.4.5.2.2 Salvage cryoablation of the prostate
6.4.5.2.2.1 Oncological outcomes
Salvage cryoablation of the prostate (SCAP) has been proposed as an alternative to salvage RP, as it has a
potentially lower risk of morbidity and equal efficacy.
In a SR a total of 32 studies assessed SCAP, recruiting a total of 5,513 patients. The overwhelming
majority of patients (93%) received whole-gland SCAP. The adjusted pooled analysis for 2-year BCR-free survival
for SCAP was 67.49% (95% CI: 61.68–72.81%), and for 5-year BCR-free survival was 50.25% (95% CI: 44.10–
56.40%). However, the certainty of the evidence was low. Table 6.4.7 summarises the results of a selection of
the largest series on SCAP to date in relation to oncological outcomes (BCR only) [1065].

Table 6.4.7: Oncological results of selected salvage cryoablation of the prostate case series, including at least
250 patients

Study n Median Time point BCR-free probability Definition of

FU (mo) of outcome failure
measurement (yr)
Ginsburg et al. 2017 [1076] 898 19.0 5 yr 71.3% Phoenix criteria
Spiess et al. 2010 [1077] 450 40.8 3.4 yr 39.6% PSA > 0.5 ng/mL
Li et al. 2015 [1078] 486 18.2 5 yr 63.8% Phoenix criteria
Kovac et al. 2016 [1079] 486 18.2 5 yr 75.5% Phoenix criteria
(nadir PSA < 0.4 ng/mL);
22.1%
(nadir PSA > 0.4 ng/mL)
Ahmad et al. 2013 [1080] 283 23.9 3 yr 67.0% Phoenix criteria
(nadir PSA < 1 ng/mL);
14.0%
(nadir PSA > 1 ng/mL)
Pisters et al. 2008 [1081] 279 21.6 5 yr 58.9% (ASTRO) ASTRO and
54.5% (Phoenix) Phoenix criteria
ASTRO = American Society for Therapeutic Radiology and Oncology; BCR = biochemical recurrence; FU = follow-up;
mo. = months; n = number of patients; PSA = prostate-specific antigen; yr. = year.

6.4.5.2.3 Salvage re-irradiation

6.4.5.2.3.1 Salvage brachytherapy for radiotherapy failure
Carefully selected patients with a good PS, primary localised PCa, good urinary function and histologically
proven local recurrence are candidates for salvage BT using either HDR or LDR.
In a SR a total of 16 studies (4 prospective) and 32 studies (2 prospective) assessed salvage HDR
and LDR BT, respectively, with the majority (> 85%) receiving whole-gland BT rather than focal treatment [1065].
The adjusted pooled analysis for 2-year BCR-free survival for HDR was 77% (95% CI: 70–83%) and for LDR was
81% (95% CI:74–86%). The 5-year BCR-free survival for HDR was 60% (95% CI: 52–67%) and for LDR was 56%
(95% CI: 48–63%). As noted above, BT techniques are associated with lower rates of severe GU toxicity when
compared to RP or HIFU, at 8% for HDR (95% CI: 5.1–11%) and 8.1% for LDR (95% CI: 4.3–13%). Rates of severe
GI toxicity are reported to be very low at 0% for HDR (95% CI: 0–0.2%) and 1.5% for LDR (95% CI: 0.2–3.4%).
High-dose-rate or LDR BT are effective treatment options with an acceptable toxicity profile. However, the
published series are small and likely under-report toxicity. Consequently, this treatment should be offered in
experienced centres ideally within randomised clinical trials or prospective registry studies (see Table 6.4.8).

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Table 6.4.8: Treatment-related toxicity and BCR-free probability in selected salvage brachytherapy studies
including at least 100 patients.

Study Study design n and BT type Median FU Treatment toxicity BCR-free probability
(mo)
Lopez et al. multi-centre 75 HDR 52 23.5% late G3+ GU 5 yr 71%
2019 [1082] retrospective 44 LDR (95% CI: 65.9-75.9%)
Crook et al. multi-centre 100 LDR 54 14% late G3 combined n.r.
2019 [1083] prospective GI/GU
Smith et al. single-centre 108 LDR 76 15.7%/2.8% late G3 5 yr. 63.1%
2020 [1084] retrospective GU/GI 10 yr. 52%
Lyczek et al. single-centre 115 HDR n.r. 12.2%/0.9% 60% at 40 mo.
2009 [1085] retrospective late G3+ GU/GI
BT = brachytherapy; CI = confidence interval; G = grade; GI = gastro-intestinal; GU = genito-urinary; HDR = high-
dose rate; LDR = low-dose rate; mo = months; n = number of patients; n.r. = not reported; yr = year.

6.4.5.2.3.2 Salvage stereotactic ablative body radiotherapy for radiotherapy failure

6.4.5.2.3.2.1 Oncological outcomes and morbidity
Stereotactic ablative body radiotherapy (CyberKnife® or linac-based treatment) is a potentially viable new option
to treat local recurrence after RT. Carefully selected patients with good IPSS-score, without obstruction, good PS
and histologically proven localised local recurrence are potential candidates for SABR. In a metaanalysis and SR
five mostly retrospective studies including 206 patients were treated with CyberKnife® or linac-based treatment
showing 2-year RFS estimates (61.6%, 95% CI: 52.6–69.9%) [1065]. In a retrospective multi-centre study (n =
100) the median pre-salvage PSA was 4.3 ng/mL with 34% of patients having received ADT for twelve months
(median). All recurrences were biopsy proven. Patients were treated with the CyberKnife® with a single dose of
6 Gy in six daily fractions (total dose 36 Gy). With a median followup of 30 months the estimated 3-year second
BCR-free survival was 55% [1086].
In a smaller retrospective series including 50 men with histologically proven local recurrence with
a median pre-salvage PSA of 3.9 ng/mL only 15% had received additional ADT. The estimated 5-year second
BCR-free survival was 60% (median follow-up of 44 months) which is an outcome comparable to series treating
patients with RP, HIFU or BT [1087]. Table 6.4.9 summarises the results of the two larger SABR series addressing
oncological outcomes and morbidity.

Table 6.4.9: Treatment-related toxicity and BCR-free survival in selected SABR studies

Study Study design n and Median Fractionation ADT Treatment BCR-free

RT-type FU (mo) (SD/TD) toxicity survival
Bergamin single-centre 25 25 SD 6-6.2 0/25 2 yr. late 2 yr. 80%
et al. 2020 prospective LINAC TD 36-38 Gy G1 GI 8%
[1088] based G2 GU 4%
Fuller et al. single-centre 50 44 SD 6.8 Gy 7/50 5 yr: 8% late 5 yr. 60%
2020 [1087] retrospective Cyber Knife TD 34 Gy G3+ GU
Pasquier multi-centre 100 30 SD 6 Gy 34/100 3 yr. grade 2+ 3 yr. 55%
et al. 2020 retrospective Cyber Knife TD 36 Gy median GU 20.8%
[1086] 12 mo. GI 1%
BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; RT-type = type of radio-
therapy; SD = single dose; TD = total dose; yr = year.

6.4.5.2.3.2.2 Morbidity
In a retrospective single-centre study with 50 consecutive patients chronic significant toxicity was only seen for
the GU domain with 5-year grade 2+ and grade 3+ GU rates of 17% and 8%, respectively. No GI toxicity > grade 1
was seen. Of note, of the fifteen patients who were sexually potent pre-salvage SBRT, twelve subsequently lost
potency [1087]. In a retrospective French (GETUG) multi-centre series (n = 100) the 3-year late grade 2+ GU and
GI toxicity was 20.8% (95% CI: 13–29%) and 1% (95% CI: 0.1–5.1%), respectively [1086]. A SR and meta-analysis
demonstrated salvage SABR resulted in comparable rates of G3+ GU toxicity when compared to salvage
cryotherapy and brachytherapy, but substantially lower rates than salvage HIFU [1089].

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6.4.5.2.3.2.3 Summary of salvage stereotactic ablative body radiotherapy
Despite the encouraging results so far the number of patients treated with SABR is relatively limited. In view of
the rates of higher grade 2+ GU side effects, SABR should only be offered to selected patients, in experienced
centres as part of a clinical trial or well-designed prospective study.

6.4.5.2.4 Salvage high-intensity focused ultrasound

6.4.5.2.4.1 Oncological outcomes
Salvage HIFU has emerged as an alternative thermal ablation option for radiation-recurrent PCa. Being relatively
newer than SCAP the data for salvage HIFU are even more limited. A SR and meta-analysis included 20 studies
(n = 1,783) assessing salvage HIFU [1065], which was also confirmed by another SR and meta-anaylsis
[1089]. The overwhelming majority of patients (86%) received whole-gland salvage HIFU. The adjusted pooled
analysis for 2-year BCR-free survival for salvage HIFU was 54.14% (95% CI: 47.77–60.38%) and for 5-year BCR-
free survival 52.72% (95% CI: 42.66– 62.56%). However, the certainty of the evidence was low. Table 6.4.10
summarises the results of a selection of the largest series on salvage HIFU to date in relation to oncological
outcomes (BCR only).

Table 6.4.10: Oncological results of selected salvage cryoablation of the prostate case series, including at
least 250 patients

Study n Median Time point BCR-free Definition of failure

FU (mo) of outcome probability
measurement
(yr)
Crouzet et al. 418 39.6 5 49.0% Phoenix criteria
2017 [1090]
Murat et al. 167 Mean 3 25.0% (high-risk) Phoenix criteria or positive
2009 [1091] 18.1 53.0% (low-risk)* biopsy or initiation of post-HIFU
salvage therapy
Kanthabalan et al. 150 35.0 3 48.0% Phoenix criteria
2017 [1092]
Jones et al. 100 12.0 1 50.0% Nadir PSA > 0.5 ng/mL or
2018 [1093] positive biopsy
*Results stratified by pre-EBRT D’Amico risk groups.
BCR = biochemical recurrence; FU = follow-up; mo = months; n = number of patients; yr = year.

6.4.5.2.4.2 Morbidity
The main adverse effects and complications relating to salvage HIFU include urinary incontinence, urinary
retention due to bladder outflow obstruction, rectourethral fistula and ED. The SR and meta-analysis showed an
adjusted pooled analysis for severe GU toxicity for salvage HIFU of 22.66% (95% CI: 16.98–28.85%) [1065]. The
certainty of the evidence was low. Table 6.4.11 summarises the results of a selection of the largest series on
salvage HIFU to date in relation to GU outcomes.

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Table 6.4.11: Peri-operative morbidity, erectile function and urinary incontinence in selected salvage HIFU
case series, including at least 100 patients

Study n Time point Incontinence* Obstruction/ Rectourethral ED (%)

of outcome (%) retention (%) fistula (%)
measurement
(yr)
Crouzet et al. 418 Median 39.6 42.3 18.0 2.3 n.r.
2017 [1090]
Murat et al. 167 Median 18.1 49.5 7.8 3.0 n.r.
2009 [1091]
Kanthabalan et al. 150 24 12.5 8.0 2.0 41.7
2017 [1092]
Jones et al. 100 12 42.0 49.0 5.0 74.0
2018 [1093]
*Incontinence was heterogeneously defined; figures represent at least 1 pad usage.
ED = erectile dysfunction; n.r. = not reported; n = number of patients.

6.4.5.2.4.3 Summary of salvage high-intensity focused ultrasound

There is a lack of high-certainty data which prohibits any recommendations regarding the indications for
salvage HIFU in routine clinical practice. There is also a risk of significant morbidity associated with its use in
the salvage setting. Consequently, salvage HIFU should only be performed in selected patients in experienced
centres as part of a clinical trial or well-designed prospective cohort study.

6.4.6 Hormonal therapy for relapsing patients

The objective of HT should be to improve OS, postpone distant metastases, and improve QoL. Biochemical
response alone to HT holds no clinical benefit for a patient. The Panel conducted a SR including studies
published from 2000 onwards [1094]. Conflicting results were found on the clinical effectiveness of HT after
previous curative therapy. Some studies reported a favourable effect of HT, including the only RCT addressing
the research question of this review (86% vs. 79% advantage in OS in the early HT group) [1095]. Other studies
did not find any differences between early vs. delayed, or no, HT. One study found an unfavourable effect of HT
[1096]. Variability appears to be driven by heterogeneous tumour biology with only a minority progressing to
metastases or PCa-related death. For older patients and those with comorbidities the side effects of HT may
even decrease life expectancy; in particular cardiovascular risk factors need to be considered [1097, 1098]. The
benefit of early HT seems most evident in high-risk patients, mainly defined by a high ISUP GG and a short PSA-
DT (most often less than six months) and a long-life expectancy [1099].

This is supported in a three-arm randomised phase III trial (EMBARK) which evaluated response in patients
with prostate cancer who had high-risk biochemical recurrence defined as a PSA-DT of ≤ 9 months and a PSA
level of ≥ 2 ng/mL above the nadir after radiation therapy or ≥ 1 ng/mL after radical prostatectomy with or
without postoperative radiation therapy [1100]. Patients were randomly assigned 1:1:1 to receive enzalutamide
daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or
enzalutamide monotherapy (monotherapy group). The primary end point was MFS, in the combination group as
compared with the leuprolide- alone group. The MFS in the monotherapy group as compared with the leuprolide-
alone group was a key secondary endpoint. A total of 1068 patients were randomised. After a median follow-
up of 60.7 months, the five year - MFS was 87.3% (95% CI, 83.0 - 90.6) in the combination group, 71.4% (95%
CI, 65.7 - 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 - 84.1) in the monotherapy group. The
combination of enzalutamide plus leuprolide was superior to leuprolide alone with regards to the MFS (HR 0.42;
95% CI, 0.30 - 0.61; P<0.001). Enzalutamide monotherapy also showed a superior MFS compared to leuprolide
alone (HR 0.63; 95% CI, 0.46 - 0.87; p = 0.005). These results led to the FDA approval for enzalutamide alone or
in combination with ADT for patients with high-risk biochemical recurrence in November 2023 [1101]. At the
time of the MFS analysis, OS data were immature with 12% deaths in the overall population.

Also, an intermittent treatment approach can be considered. Enzalutamide treatment can be suspended if PSA
is undetectable (< 0.2 ng/mL) after 36 weeks of therapy. Treatment may be reinitiated when PSA has increased
to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL for patients who had prior
primary radiation therapy. There were no new safety signals. Of note, at a median follow-up of five years, the
overall percentage of patients who had fractures was 14% [1102].

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Another three-arm-randomised phase-III trial (PRESTO) evaluated patients with biochemical recurrence defined
as a PSA-DT < 9 months with a median PSA of 1.8 ng/mL [1103]. Patients were randomly assigned 1:1:1 to
receive (52-week treatment) ADT-control, ADT + apalutamide, or ADT + apalutamide + Abiraterone acetate plus
prednisolone (AAP). A total of 503 patients were randomised. At the first interim analysis after a median follow
up of 21.5 months both experimental arms showed a moderate, significant prolonged PSA-PFS compared with
the control arm (24.9 months for ADT + apalutamide versus 20.3 months for ADT (HR 0.52, p = 0.00047 and 26
months for ADT + apalitamide + AAP versus 20.0 months for ADT (HR 0.48, p = 0.00008). The most common
grade > 3 AE was hypertension (7.5%, 7.4% and 18% in ADT, ADT + apalutamide and ADT + apalutamide + AAP).
These are results of the first planned interim analysis and longer follow up for definitive conclusions should be
awaited.

A Scandinavian Phase-III-trial (SPCG-14) [1104] evaluated the effect of docetaxel added to bicalutamide in
hormone-naïve non-metastatic PCa with a rising PSA after radical treatment (prostatectomy or radiotherapy,
n = 315) or not suitable for curative treatment (n = 3). Between 2009 and 2018 348 patients were randomized,
median follow up was 4.9 years. Adding docetaxel improved PFS (HR 0.68, p = 0.015) at the cost of 27% of one
event of neutropenic infection/fever. There were no data on metastasis-free-survival. It is therefore too early to
consider recommending at this time no recommendation for adding docetaxel in this setting of PSA-recurrence
only can be given.

6.4.7 Observation
In unselected relapsing patients the median actuarial time to the development of metastasis will be eight years
and the median time from metastasis to death will be a further five years [884]. For patients with EAU Low-Risk
BCR features, unfit patients with a life expectancy of less than ten years or patients unwilling to undergo salvage
treatment, active follow-up may represent a viable option.

6.4.8 Recommendations for second-line therapy after treatment with curative intent

Local salvage treatment Strength rating

Recommendations for biochemical recurrence (BCR) after radical prostatectomy
Offer early salvage intensity-modulated radiotherapy/volumetric arc radiation therapy plus Strong
image-guided radiotherapy to men with two consecutive prostate-specific antigen (PSA)
rises.
A negative positron emission tomography/computed tomography (PET/CT) scan should not Strong
delay salvage radiotherapy (SRT), if otherwise indicated.
Offer monitoring, including PSA, to EAU low-Risk BCR patients. Weak
Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has Strong
been made, SRT (at least 64 Gy) should be given as soon as possible.
Offer hormonal therapy in addition to SRT to men with BCR. Weak
Recommendations for BCR after radiotherapy
Offer monitoring, including PSA to EAU low-risk BCR patients. Weak
Only offer salvage radical prostatectomy (RP), brachytherapy, stereotactic body radiotherapy, Strong
high-intensity focused ultrasound, or cryosurgical ablation to highly selected patients with
biopsy-proven local recurrence within a clinical trial setting or well-designed prospective
cohort study undertaken in experienced centres.
Recommendations for systemic salvage treatment
Do not offer androgen deprivation therapy to M0 patients with a PSA-doubling time > 12 Strong
months.
Offer enzalutamide with or without ADT to M0 patients with a high-risk BCR , defined as a Strong
PSA doubling time of ≤ 9 months and a PSA level of ≥ 2ng/mL above nadir after radiation
therapy or ≥ 1 ng/m after radical prostatectomy with or without postoperative radiation
therapy.
Recommendations for follow-up after radical prostatectomy or radiotherapy
Routinely follow-up asymptomatic patients by obtaining at least a disease-specific history Strong
and serum PSA measurement.
At recurrence, only perform imaging if the result will affect treatment planning. Strong

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6.5 Systemic treatments for prostate cancer
6.5.1 Hormonal therapy
Androgen deprivation can be achieved by suppressing the secretion of testicular androgens in different ways.

6.5.1.1 Castration level

The castration level of testosterone is < 50 ng/dL (1.7 nmol/L), defined more than 40 years ago when
testosterone testing was less sensitive. Current methods have shown that the mean value after surgical
castration is 15 ng/dL [1035]. Therefore, a more appropriate level should be defined as < 20 ng/dL (< 0.7
nmol/L). This definition is important as better results are repeatedly observed in ADT monotherapy cohorts
with lower testosterone levels compared to 50 ng/dL [1036-1038]. However, the castrate level considered by
the regulatory authorities and in clinical trials addressing castration in PCa is still the historical < 50 ng/dL (1.7
nmol/L).

6.5.1.2 Bilateral orchiectomy

Bilateral orchiectomy or subcapsular pulpectomy is still considered the primary treatment modality for ADT. It
is a simple, cheap and low-complication procedure. It is easily performed under local anaesthesia, and it is the
quickest way to achieve a castration level which is usually reached within less than twelve hours. It is irreversible
and therefore does not allow for intermittent treatment [1039].

6.5.1.3 Luteinising-hormone-releasing hormone agonists

Long-acting LHRH agonists are currently the main forms of ADT. These synthetic analogues of LHRH are
delivered as depot injections on a 1-, 3-, 6-monthly, or yearly basis. The first injection induces a transient rise in
luteinising hormone (LH) and follicle-stimulating hormone (FSH) leading to the ‘testosterone surge’ or ‘flare-up’
phenomenon which starts two to three days after administration and lasts for about one week. This may lead
to detrimental clinical effects (the clinical flare) such as increased bone pain, acute bladder outlet obstruction,
obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status
[1105]. Patients at risk are usually those with high-volume symptomatic bony disease. Concomitant therapy
with an anti-androgen decreases the incidence of clinical flare but does not completely remove the risk. Anti-
androgen therapy is usually continued for 4 weeks but neither the timing nor the duration of anti-androgen
therapy are based on strong evidence. In addition, the long-term impact of preventing ‘flare up’ is unknown
[1106].
Chronic exposure to LHRH agonists results in the down-regulation of LHRH-receptors, suppressing
LH and FSH secretion and therefore testosterone production. A castration level is usually obtained within 2
to 4 weeks [1107]. Although there is no formal direct comparison between the various compounds, they are
considered to be equally effective [1108]. So far, no survival difference between LHRH agonists and orchiectomy
has been reported due to the lack of high-quality trials [1109]. The different products have practical differences
that need to be considered in everyday practice, including the storage temperature, whether a drug is ready
for immediate use or requires reconstitution, and whether a drug is given by subcutaneous or intramuscular
injection.

6.5.1.4 Luteinising-hormone-releasing hormone antagonists

Luteinising-hormone-releasing hormone antagonists immediately bind to LHRH receptors, leading to a rapid
decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds
is the lack of a long-acting depot formulation with, so far, only monthly formulations being available. Degarelix
is a LHRH antagonist. The standard dosage is 240 mg in the first month followed by monthly injections of 80
mg. Most patients achieve a castrate level at day three [1107]. A phase III RCT compared degarelix to monthly
leuprorelin following up patients for twelve months, suggesting a better PSA PFS for degarelix 240/80 mg
compared to monthly leuprorelin [1110]. A SR did not show a major difference between agonists and degarelix
and highlighted the paucity of on-treatment data beyond twelve months as well as the lack of survival data
[1111]. Its definitive superiority over the LHRH analogues remains to be proven. Short-term follow-up data from
a meta-analysis indicate that the use of LHRH antagonist is associated with significantly lower overall mortality
and cardiovascular events as compared with agonists. On the other hand, other adverse effects such as
decreased libido, hot flushes, ED, weight gain, and injection site reactions are seen less often with the agonists
[1112, 1113].

Relugolix is an oral LHRH antagonist. It was compared to the LHRH agonist leuprolide in a randomised phase
III trial [1114]. The primary endpoint was sustained testosterone suppression to castrate levels through 48
weeks. There was a significant difference of 7.9 percentage points (95% CI: 4.1–11.8) showing non-inferiority
and superiority of relugolix. The incidence of major adverse cardiovascular events was significantly lower with
relugolix (prespecified safety analysis). Relugolix has been approved by the FDA [1115] and EMA [1116] for
hormone sensitive PCa.

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6.5.1.5 Anti-androgens
These oral compounds are classified according to their chemical structure as:
• steroidal, e.g., cyproterone acetate (CPA), megestrol acetate and medroxyprogesterone acetate;
• non-steroidal or pure, e.g., nilutamide, flutamide and bicalutamide.

Both classes compete with androgens at the receptor level. This leads to an unchanged or slightly elevated
testosterone level. Conversely, steroidal anti-androgens have progestational properties leading to central
inhibition by crossing the blood-brain barrier.

6.5.1.5.1 Steroidal anti-androgens

These compounds are synthetic derivatives of hydroxyprogesterone. Their main pharmacological side effects
are secondary to castration (gynaecomastia is quite rare) whilst the non-pharmacological side effects are
cardiovascular toxicity (4–40% for CPA) and hepatotoxicity.

Cyproterone acetate was the first licensed anti-androgen but the least studied. Its most effective dose as
monotherapy is still unknown. It appears to be associated with a poorer OS when compared with LHRH
analogues and there is no benefit when compared with flutamide [1117, 1118].

6.5.1.5.2 Non-steroidal anti-androgens

Non-steroidal anti-androgen monotherapy with e.g. nilutamide, flutamide or bicalutamide does not suppress
testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density
(BMD) are frequently preserved [1119]. Non-androgen-related pharmacological side effects differ between
agents. Bicalutamide shows a more favourable safety and tolerability profile than flutamide and nilutamide
[1120]. The dosage licensed for use in combination with LHRH blockade is 50 mg/day, and 150 mg/day for
monotherapy. The androgen pharmacological side effects are mainly gynaecomastia (70%) and breast pain
(68%). However, non-steroidal anti-androgen monotherapy offers clear bone protection compared with LHRH
analogues and probably LHRH antagonists [1119, 1121]. All three agents share the potential for liver toxicity
(occasionally fatal), requiring regular monitoring of patients’ liver enzymes.

6.5.1.5.3 New androgen receptor pathway inhibitors (ARPIs)

Once on ADT the development of castration-resistance (CRPC) is only a matter of time. It is considered to be
mediated through two main overlapping mechanisms: androgen-receptor (AR)-independent and AR-dependent
mechanisms. In CRPC, the intracellular androgen level is increased compared to androgen sensitive cells and
an over-expression of the AR has been observed, suggesting an adaptive mechanism [1122]. This has led
to the development of several compounds targeting the androgen axis. The status of the different ARPIs is
summarised in table 6.5.1 [1123-1128]. For the updated approval status see EMA and FDA websites [1101,
1129-1132].

Table 6.5.1: Status of the different ARPIs

High-risk localised & High-risk BCR mHSPC nmCRPC nmCRPC

locally advanced**
Abiraterone X* X X
Enzalutamide X X X X
Apalutamide X X
Darolutamide X X
* Unlicenced indication
** STAMPEDE definition

6.5.1.5.3.1 Abiraterone acetate

Abiraterone acetate is a CYP17 inhibitor (a combination of 17α-hydrolase and 17,20-lyase inhibition). By
blocking CYP17, abiraterone acetate significantly decreases the intracellular testosterone level by suppressing
its synthesis at the adrenal level and inside the cancer cells (intracrine mechanism). This compound must be
used together with prednisone/prednisolone to prevent drug-induced hyperaldosteronism [1129, 1131].

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6.5.1.5.3.2 Apalutamide, darolutamide, enzalutamide and rezvilutamide (alphabetical order)
These agents are novel non-steroidal anti-androgens with a higher affinity for the AR receptor than traditional
non-steroidal anti-androgens. In addition, while previous non-steroidal anti-androgens still allow transfer of ARs
to the nucleus and would act as partial agonists, all four agents also block AR transfer and therefore suppress
any possible agonist-like activity [1123, 1124, 1132, 1133]. Darolutamide has structurally unique properties; in
particular, in preclinical studies, it was shown not to cross the blood-brain barrier [1134, 1135].

6.5.2 Cytotoxic drug treatment

6.5.2.1 Taxanes
Paclitaxel derivatives promote the assembly of microtubules and inhibit the subsequent depolymeization,
impairing the tubulin dynamics that foster the mitotic spindle assembly during interphase in mitosis [1136].
Docetaxel binds ß-tubulin dimers in a 1:1 stoichiometric ratio, exhibiting a stronger dynamic instability using its
inhibitory effect in tubulin depolymerization [1137]. It also activates NF-kB causing apoptosis via a mitochondria-
dependent pathway [1138]. Docetaxel shows significant activity against prostate tumours. Cabazitaxel also
works by binding to the microtubules. This prevents cellular mitosis and stabilises the tumour cells. As a result,
the cells do not divide. In addition, it inhibits androgen receptors by binding to the microtubules and microtubule-
associated motor protein dynein. As a consequence, androgen receptor nuclear translocation is prevented
[1136]. Common side-effects include peripheral neuropathy, myalgias, neutropenia and arthralgia.

6.5.3 Non-hormonal non-cytotoxic drug treatments

6.5.3.1 Poly (ADP-ribose) polymerase inhibitirs (PARPi)
Poly (ADP-ribose) polymerase inhibitors (PARPi) block the enzyme poly ADP-ribose polymerase (PARP) and
were developed aiming to selectively target cancer cells harbouring BRCA mutations and other mutations
inducing homologous recombination deficiency and high level of replication pressure with a sensitivity to PARPi
treatment. Due to the oncogenic loss of some DNA repair effectors and incomplete DNA repair repertoire, some
cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related
single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect
which means the simultaneously functional loss of two genes leads to cell death, while a defect in any single
gene only has a limited effect on cell viability [1139]. BRCA mutations both predispose patients to develop PCa
and develop in some tumours making some patients particularly responsive to these drugs.

6.5.3.2 Immune checkpoint inhibitors

Checkpoint inhibitors target the molecules CTLA4, programmed cell death protein 1 (PD-1), and programmed
death-ligand 1 (PD-L1). For advanced PCa patients that are microsatellite instability-high/deficient mismatch
repair (MSI-H/dMMR), the PD-1 inhibitor pembrolizumab has been approved by the FDA but not by the EMA. The
label is tumour agnostic [1140, 1141].

6.5.3.3 Radiopharmaceutical therapy

Radiopharmaceutical therapy (RPT) is based on the delivery of radioactive isotopes to tumour-associated
targets. The mechanism of action for RPT is radiation-induced killing of cells. Radionuclides with different
emission properties are used to deliver radiation. The most commonly used radionuclides are represented by
β-particles (e.g., 177Lu) or α-particles (e.g., 223Ra, 225Ac). 223Ra based on its biochemical similarity to Calcium,
is integrated in bones with increased osteoblastic activity, thus targeting skeletal PCa metastases. 177Lu is
increasingly used because of its optimal imaging range (100–200 keV), favourable half time (6.6 days) and
appropriate β-particle energy for therapy. The short path of the β-particles (0.05–0.08 mm) results in minimal
toxic effects in adjacent healthy tissue. These properties enable such radionuclides to be used as theranostics
(i.e., the same radionuclide may be used for both diagnostic and therapeutic purposes). However, an essential
requirement prior to any RPT is to assess the targeting of the agent, mainly using PET techniques which show
the tumour expression and the extent of cancer [1142]. 177Lu has been approved by the FDA for the treatment of
adult patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy
[1143, 1144].

6.6 Management of Metastatic prostate cancer

6.6.1 Introduction
Most prospective data available rely on the definition of M1 disease based on CT scan or MRI and bone
scintigraphy. The influence on treatment and outcome of newer, more accurate, imaging has not yet been
assessed in prospective randomised trials.

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6.6.2 Prognostic and predictive factors
Median survival of patients with newly diagnosed metastases (synchronous mHSPC) is approximately 50
months with ADT alone, however, it is highly variable since the M1 population is heterogeneous [1145]. Several
prognostic factors for survival have been suggested including the number and location of bone metastases,
presence of visceral metastases, ISUP GG, performance status and initial PSA and alkaline phosphatase level,
but only few have been validated [1146-1149].
‘Volume‘ of disease as a potential predictor was introduced by CHAARTED (Chemo-hormonal
Therapy versus Androgen Ablation Randomised Trial for Extensive Disease in Prostate Cancer) [1149-1151]
(Table 6.6.1) and subsequently, in STAMPEDE, was shown to be predictive in an adequately powered subgroup
analysis for benefit of addition of prostate RT to ADT in the subgroup of patients with low volume/burden
disease [1152] (Table 6.6.1).
‘Metachronous’ metastatic disease (after radical local treatment of the primary tumour) vs.
synchronous (or de novo) metastatic disease has also been shown to have generally a better prognosis [1153].
Based on a large SWOG 9346 cohort, the PSA level after seven months of ADT was used to create
three prognostic groups (Table 6.6.2) [1154]. A PSA ≤ 0.2 ng/mL at seven months has been confirmed as a
prognostic marker for men receiving ADT for metastatic disease in the CHAARTED study independent of the
addition of docetaxel [1155]. Similarly, reaching PSA levels of ≤ 0.1ng/ml after six months were shown to be
correlated with long-term outcomes in the LATITUDE study [1156]. Also for patients treated with ADT and
apalutamide a deep PSA decline defined by ≥ 90% from baseline or to PSA ≤ 0.2 ng/mL at a landmark of three
months was associated with longer OS [1157] for patients.

Table 6.6.1: Definition of high- and low-volume in CHAARTED [1149-1151] and high- and low-risk in LATITUDE
[1127]

High Low
CHAARTED > 4 Bone metastases including > 1 outside vertebral column or pelvis Not high
(volume) AND/OR
Visceral metastasis*
LATITUDE > 2 high-risk features of: Not high
(risk) • > 3 Bone metastasis
• Visceral metastasis
• > ISUP grade 4
*Lymph nodes are not considered as visceral metastases.

Table 6.6.2: Prognostic factors based on the SWOG 9346 study [1154]

PSA after 7 months after start of ADT Median survival on ADT monotherapy
< 0.2 ng/mL 75 months
0.2 < 4 ng/mL 44 months
> 4 ng/mL 13 months

6.6.3 First-line hormonal treatment

Primary ADT has been the SOC for over 50 years [1158]. There is no high-level evidence in favour of a specific
type of ADT for oncological outcomes, neither for orchiectomy nor for a LHRH agonist or antagonist. The level of
testosterone is reduced much faster with orchiectomy and LHRH antagonist, therefore patients with impending
spinal cord compression or other potential impending complications from the cancer should be treated with
either a bilateral orchidectomy or LHRH antagonists as the preferred options.
There is a suggestion in some studies and a SR and meta-analysis that cardiovascular side effects
are less frequent in patients treated with LHRH antagonists than patients treated with LHRH agonists [1114,
1159-1161]; therefore, patients with pre-existing cardiovascular disease or other cardio-vascular risk factors
might be considered to be treated with antagonists if a chemical castration is chosen.

6.6.3.1 Non-steroidal anti-androgen monotherapy

Based on a Cochrane review comparing older generation non-steroidal anti-androgen (NSAA) monotherapy to
ADT (either medical or surgical), NSAA was considered to be less effective in terms of OS, clinical progression,
treatment failure and treatment discontinuation due to AEs [1162] and is generally not recommended also
because ADT-based combination treatments have become SOC.

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6.6.3.2 Intermittent versus continuous androgen deprivation therapy
Three independent reviews [1163-1165] and two meta-analyses [1166, 1167] looked at the clinical efficacy of
intermittent androgen deprivation (IAD) therapy. All of these reviews included 8 RCTs of which only three were
conducted in patients with exclusively M1 disease.
So far, the SWOG 9346 is the largest trial addressing IAD in M1b patients [1168]. Of 3,040 screened
patients, only 1,535 patients met the inclusion criteria. This highlights that only about 50% of M1b patients
can be expected to be candidates for IAD, i.e. the best PSA responders. This was a non-inferiority trial leading
to inconclusive results: the actual upper limit was above the pre-specified 90% upper limit of 1.2 (HR: 1.1, CI:
0.99–1.23), the pre-specified non-inferiority limit was not achieved, and the results did not show a significant
inferiority for any treatment arm. However, based on this study inferior survival with IAD cannot be completely
ruled out even in this highly selected subgroup. The use of intermittent ADT has been superseded as continuous
ADT based combination therapy has become SOC.

6.6.3.3 Early versus deferred androgen deprivation therapy

Early treatment before the onset of symptoms is recommended in the majority of patients with metastatic
hormone-sensitive disease. A Cochrane analysis from 2019 about the topic concluded that early ADT probably
extends time to death of any cause and time to death from PCa [1169], but the analysis included only a very
limited number of metastatic patients. There is a lack of randomised phase III data in this specific setting and
specifically not with the combination therapies that are standard nowadays, however data is accumulating for
the use of long-term ADT earlier in the disease pathway.

The addition of RT/ SABR to ADT monotherapy or combination with ARPI as well as the use of SABR to delay
ADT is discussed in section 6.6.7.

6.6.4 Combination therapies

All of the following combination therapies have been studied with continuous ADT, not intermittent ADT.

6.6.4.1 ‘Combined’ androgen blockade with older generation NSAA (bicalutamide, flutamide, nilutamide)
Systematic reviews have shown that combined androgen blockade using a NSAA appears to provide a small
survival advantage (< 5%) vs. monotherapy (surgical castration or LHRH agonists) [1170, 1171]. This minimal
survival advantage must be balanced against the increased side effects especially as the newer combination
therapies are more effective as shown specifically for enzalutamide which was tested against NSAA in a
phase III trial [1172]. More recently another trial has demonstrated a significant OS benefit for the addition
of rezvilutamide vs. addition of bicalutamide to ADT in patients with high-volume mHSPC [1173]. Therefore,
combination with NSAAs should only be considered if other combination therapies are not available.

6.6.4.2 Androgen deprivation combined with other agents

6.6.4.2.1 Combination with an ARPI alone (abiraterone, apalutamide, enzalutamide, rezvilutamide,
darolutamide)
In two large RCTs (STAMPEDE, LATITUDE) the addition of abiraterone acetate (1000 mg daily) plus prednisone
(5 mg daily) to ADT in men with mHSPC was studied [1127, 1174, 1175] (Table 6.6.3). The primary objective of
both trials was an improvement in OS. Both trials showed a significant OS benefit. In LATITUDE with only de
novo high-risk metastatic patients included, the HR reached 0.62 (0.51–0.76) [1127]. The HR in STAMPEDE was
very similar with 0.63 (0.52–0.76) in the total patient population (metastatic and non-metastatic) and a HR of
0.61 in the subgroup of metastatic patients [1174]. While only high-risk patients were included in the LATITUDE
trial a post-hoc analysis from STAMPEDE showed the same benefit whatever the risk or the volume category
was [1176].

All secondary objectives such as PFS, time to radiographic progression, time to pain, or time to chemotherapy
were in favour of the combination. No difference in treatment-related deaths was observed with the combination
of ADT plus AAP compared to ADT monotherapy (HR: 1.37 [0.82–2.29]). However, twice as many patients
discontinued treatment due to toxicity in the combination arms in STAMPEDE (20%) compared to LATITUDE
(12%) [1175]. Based on these data upfront AAP combined with ADT should be considered as a standard in men
presenting with metastases at first presentation, provided they are fit enough to receive the drug.

In five large RCTs the addition of AR antagonists to ADT in men with mHSPC was tested [1125, 1126, 1172].
In ARCHES the primary endpoint was radiographic PFS (rPFS). In the primary analysis rPFS was significantly
improved for the combination of enzalutamide and ADT with a HR of 0.39 (0.3–0.5). Approximately 36% of the
patients had low-volume disease; around 25% had prior local therapy and 18% of the patients had received prior
docetaxel. In the final prespecified analysis the key secondary enpoint OS was significantly improved with a HR
of 0.66 (0.53-0.81) and a significant benefit for rPFS was maintained with a HR of 0.63 (0,52–0.76) [1177].

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 In ENZAMET the primary endpoint was OS. The addition of enzalutamide to ADT in the first analysis
improved OS with a HR of 0.67 (0.52–0.86) compared to ADT plus a non-steroidal antiandrogen. Approximately
half of the patients had concomitant docetaxel; about 40% had prior local therapy and about half of the patients
had low-volume disease [1126]. In a planned later analysis with a median follow-up of 68 months the OS benefit
of adding enzalutamide was maintained with a HR of 0.7 (0.58-0.84) (Table 6.6.4) [1178].
In the TITAN trial, ADT plus apalutamide was used and rPFS and OS were co-primary endpoints.
In the primary analysis rPFS was significantly improved by the addition of apalutamide with a HR of 0.48
(0.39–0.6); OS at 24 months was improved for the combination with a HR of 0.67 (0.51–0.89). In the final
analysis the HR for OS was 0.65 (0.53–0.79) without adjustment for cross-over. In this trial 16% of patients had
prior local therapy, 37% had low-volume disease and 11% received prior docetaxel [1125, 1179] (Table 6.6.4). A
secondary analysis of the Titan study found that nearly half of the patients developing subsequent radiographic
progression had no concomitant PSA progression, suggesting that heavy reliance on PSA monitoring may be
inadequate for assessing disease activity in this context [1180].
In the CHART trial, ADT plus rezvilutamide was tested vs. ADT plus bicalutamide in patients with
high-volume de novo metastatic disease. Ninety percent of the patients were recruited in China. Overall survival
and rPFS were co-primary endpoints. At the pre-planned interim analysis rezvilutamide significantly improved
rPFS compared with bicalutamide with a HR of 0.44 (0.33–0.58) and OS with a HR of 0.58 (0.44–0.77) (Table
6.6.5) [1173].
In ARANOTE, darolutamide plus ADT was randomised 2:1 vs. placebo plus ADT. It showed to
significantly improved rPFS which was the primary endpoint (HR 0.54 [95% CI, 0.41 to 0.71]; p < 0.0001), with
consistent benefits across subgroups, including high- and low-volume disease [1128]. Adverse events were
similar in the two groups. Overall survival was not statistically different, but data are immature (HR, 0.81 [95% CI,
0.59 to 1.12]) (Table 6.6.6).

In summary, the addition of the new AR antagonists significantly improves clinical outcomes with no convincing
evidence of differences between subgroups. The majority of patients had de novo metastatic disease but a
proportion of patients had metachronous disease; in the subgroup analyses the effect seemed to be consistent
and therefore, a combination should also be offered for men progressing after radical local therapy [1178, 1181,
1182].

Table 6.6.3: Results from the STAMPEDE arm G and LATITUDE studies

STAMPEDE [1174] LATITUDE [1127]

ADT ADT + AA + P ADT + placebo ADT + AA + P
N 957 960 597 602
Newly diagnosed N+ 20% 19% 0 0
Newly diagnosed M+ 50% 48% 100% 100%
Key inclusion criteria Patients scheduled for long-term ADT Newly diagnosed M1 disease and 2 out
- newly diagnosed M1 or N+ situations of the 3 risk factors: ISUP GG ≥ 4,
- locally advanced (at least two of cT3 ≥ 3 bone lesions, measurable visceral
cT4, ISUP grade ≥ 4, PSA ≥ 40 ng/mL) metastasis
- r elapsing locally treated disease with a
PSA > 4 ng/mL and a PSA-DT < 6 mo.

or PSA > 20 ng/mL

or nodal
or metastatic relapse
Primary objective OS OS; rPFS
Median follow up 40 mo 30.4 mo
3-yr. OS 83% (ADT + AA + P) 66% (ADT + AA + P)
76% (ADT) 49% (ADT + placebo)
HR (95% CI) 0.63 (0.52-0.76) 0.62 (0.51-0.76)
M1 only
N 1,002 1,199
3-yr. OS NA 66% (ADT + AA + P)
49% (ADT + placebo)

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HR (95% CI) 0.61 (0.49-0.75) 0.62 (0.51-0.76)
HR FFS (biological, radiological, clinical or rPFS:
death): 0.29 (0.25-0.34) 0.49 (0.39-0.53)
AA = abiraterone acetate; ADT = androgen deprivation therapy; CI = confidence interval; FFS = failure-free
survival; HR = hazard ratio; ISUP = International Society of Urological Pathology; mo = month; n = number of
patients; NA = not available; OS = overall survival; P = prednisone; rPFS = radiographic progression-free survival;
PSA = prostate-specific antigen; yr. = year.

Table 6.6.4: Results from the ENZAMET and TITAN studies with OS as primary endpoint

ENZAMET [1172, 1178] TITAN [1125, 1179]

ADT+ older ADT + enzalutamide ADT + placebo ADT +
antagonist ± docetaxel apalutamide
± docetaxel (SOC)
N 562 563 527 525
Newly diagnosed M+ 72.1% 72.5% 83.7% 78.3%
Low volume 47% 48% 36% 38%
Primary objective OS OS; rPFS
Median follow up (mo) 68 mo 30.4 mo
OS 5-year survival: 2-yr survival:
67% (ADT + enzalutamide) 84% (ADT + apalutamide)
57% (SOC) 74% (ADT + placebo)
HR (95% CI) for OS 0.70 (0.58–0.84) 0.67 (0.51-0.89)
ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; mo = month; n = number of
patients; OS = overall survival; SOC = standard of care; rPFS = radiographic progression-free survival; yr = year.

Table 6.6.5: Results from the ARCHES and CHART studies

ARCHES [1126, 1177] CHART [1173]

ADT ± docetaxel ADT + enzalutamide ADT + ADT +
± docetaxel bicalutamide rezvilutamide
N 576 574 328 326
Newly diagnosed M+ 63% 70% 100% 100%
Low volume 35% 38% 0% 0%
Use of early docetaxel 18% (previous) 18% (previous) 0% 0%
Primary endpoint(s) rPFS OS; rPFS
Median follow up 44.6 mo 29.3 mo
Median rPFS (mo.) 38.9 mo 49.8 mo 23.5 mo Not reached
HR (95% CI) for rPFS HR: 0.63 (0.52–0.76) HR: 0.46 (0.36–0.60)
Median OS Not reached Not reached Not reached Not reached
HR (95% CI) for OS 0.66 (0.53–0.81): Main secondary endpoint 0.58 (0.44–0.77)
HR = hazard ratio; mo = month; n = number of patients; OS = overall survival; rPFS = radiographic progression-
free survival; yr = year.

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Table 6.6.6: Results from ARANOTE study with rPFS as the first endpoint

ARANOTE [1128]
ADT+darolutamide ADT + placebo
N 448 223
Newly diagnosed M+ 71.1% 75.3%
Low volume 29.4% 29.6%
Use of early docetaxel 0 0
Primary endpoint(s) rPFS
Median follow-up 25.3 mo 25.0 mo
Median rPFS Not reached 25.0 mo
HR (95% CI) for rPFS 0.54 (0.41 - 0.71); P < .0001)
Median OS Not reached Not reached
HR (95% CI) for OS 0.81 (0.59 - 1.12]): immature
HR = hazard ratio; mo = month; OS = overall survival; rPFS = radiographic progression-free survival.

6.6.4.2.2 Androgen deprivation therapy combined with chemotherapy

Three large RCTs were conducted [775, 1088, 1114]. All trials compared ADT alone as the SOC with ADT
combined with immediate docetaxel (75 mg/sqm, every three weeks within three months of ADT initiation). The
primary objective in all three studies was to assess OS.
In the GETUG 15 trial, all patients had M1 PCa, either de novo or after a primary treatment [1183].
They were stratified based on previous treatment and Glass risk factors [1146]. In the CHAARTED trial the same
inclusion criteria applied, and patients were stratified according to disease volume [1149].

STAMPEDE is a multi-arm multi-stage trial in which the reference arm (ADT monotherapy) included 1,184
patients. One of the experimental arms was docetaxel combined with ADT (n = 593), another was docetaxel
combined with zoledronic acid (n = 593). Patients were included with either M1 or N1 or having two of the
following 3 criteria: T3/4, PSA ≥ 40 ng/mL or ISUP grade group 4–5. Also relapsed patients after local treatment
were included if they met one of the following criteria: PSA ≥ 4 ng/mL with a PSA-DT < six months or a PSA ≥
20 ng/mL, N1 or M1. No stratification was used regarding metastatic disease volume (high/low volume) [839].
In all 3 trials toxicity was mainly haematological with around 12–15% grade 3–4 neutropenia, and 6–12% grade
3–4 febrile neutropenia. The use of granulocyte colony-stimulating factor receptor (GCSF) was shown to be
beneficial in reducing febrile neutropenia. Primary or secondary prophylaxis with GCSF should be based on
available guidelines [1184, 1185].

Docetaxel in all three trials was used at the standard dose of 75 mg/sqm every three weeks, 6 cycles in
CHAARTED and STAMPEDE and up to 9 cycles in GETUG-AFU-15. In subgroup analyses from GETUG-AFU 15
and CHAARTED the beneficial effect of the addition of docetaxel to ADT was most evident in men with de novo
metastatic high-volume disease [1150, 1151], while it was in the same range whatever the volume in the post-
hoc analysis from STAMPEDE [1186]. The effect of adding docetaxel was less apparent in men who had prior
local radical treatment although the numbers were small and the event rates low. A SR and meta-analysis which
included these 3 trials showed that the addition of docetaxel to SOC improved survival [1185]. The HR of 0.77
(95% CI: 0.68–0.87, p < 0.0001) translates into an absolute improvement in four-year survival of 9% (95% CI:
5–14). In a SR and meta-analysis of individual participant data from the three trials it has been shown that there
is no meaningful beneficial effect of addition of docetaxel to ADT for patients with metachronous low volume
disease. Interestingly the largest absolute improvement at five years was observed for the patients with high
volume and clinical stage 4 disease [1187]. Therefore adding docetaxel alone to ADT should only be considered
if no ARPI is available or all available ARPIs are contraindicated.

The addition of abiraterone to ADT and docetaxel has been reported to have a benefit in rPFS and in OS in the
PEACE-1 trial [1188, 1189]. The trial has a 2x2 factorial design and participants with de novo (synchronous)
metastatic PCa were randomised to SOC; at the beginning of the trial ADT, later ADT plus docetaxel for 6
cycles if chemotherapy-fit) vs. SOC plus radiotherapy vs. SOC plus abiraterone vs. SOC plus radiotherapy plus
abiraterone. Co-primary endpoints were rPFS and OS, both were statistically significantly improved in the total
population. Also in the group of patients who received ADT plus docetaxel as SOC (n = 710) both rPFS and OS
were increased with a HR: 0.5 (0.34–0.71) and 0.75 (0.59–0.95), respectively. Of note; in this population about
35% had low-volume disease. Toxicity was modestly increased, mostly hypertension.

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 In the ARASENS Phase III trial all patients received ADT and docetaxel for 6 cycles as SOC plus
darolutamide or placebo [1190]. 1,306 metastatic patients were included, 14 % of them with relapsed disease
after radical local treatment (metachronous). Primary endpoint was OS and this was statistically significantly
increased by the addition of darolutamide with a HR of 0.68 (0.57–0.8).
Interestingly, in this trial the occurrence of AEs was similar in both arms. In both trials docetaxel
and the ARPI have been given concomitantly. Of the included patients 77% had high volume and 70% high-risk
disease. In an unplanned subgroup analysis the beneficial effect of adding darolutamide vs. placebo for OS
was seen in the patients with high-volume (HR 0.69; 0.57-0.82), with high-risk (HR 0.71; 0.58-0.86) and in low-
risk disease (HR 0.62; 0.42-0.9), for the small subgroup of patients with low-volume disease the results were
suggestive of an OS benefit (HR 0.68; 0.41-1.13) [1191].
Also in ENZAMET, TITAN and ARCHES there were patients who received docetaxel as a part of SOC,
thus not all concomitantly, but the percentage of patients receiving docetaxel in these trials was much lower
[1125, 1126, 1172, 1177-1179].
There are also SRs and network meta-analysis for systemic triplet therapies and they confirm that
the triplets are more effective than ADT and docetaxel alone [1192], in one analysis looking into subgroups
statistically significant for patients with high volume disease and de novo disease [1193].
A SR and network MA for the different systemic treatments of mHSPC confirms triplets to be more
effective than a doublet of ADT and docetaxel but not necessarily better than ADT plus ARPI. For patients
with metachronous low-volume PCa, ARPI doublet therapies were ranked as the potentially most efficacious
treatment options and the expected outcomes were not significantly different from those achieved by triplet
regimens [1194]. In addition, in a MA of individual patient trial data of patients with metachronous low volume
prostate cancer did not benefit from receiving docetaxel [1187].

6.6.5 Treatment selection and patient selection

There have been several network meta-analyses of the published data concluding that combination therapy is
more efficient than ADT alone, but none of the doublet combination therapies has been convincingly proven
to be superior over another [1194-1199]. In a SR and meta-analysis looking at association between age and
efficacy of combination therapy patients seemed to profit from combination therapy irrespective of age [1199].
As a consequence, patients should be offered combination treatment unless there are clear contra-indications
or they present with asymptomatic disease and a very short life expectancy (based on frailty assessment or
non-cancer co-morbidities).

Since the data of the above mentioned phase III triplet therapy trials have been reported, docetaxel as
sole addition to ADT is no longer a valid option in the majority of patients if an androgen receptor pathway
inhibitor (ARPI) is available and there are no contra-indications to use one. From subgroup analysis of all
the above-mentioned RCTs we know that probably all subgroups (high vs. low volume/risk and synchronous
vs. metachronous) can profit from the addition of an ARPI to ADT. Therefore, in view of the current data the
recommendation is using ADT plus ARPI as the sole additional therapy or the triplet with an ARPI plus docetaxel.
Formally the question what the added value of adding docetaxel to ADT plus an ARPI has not been evaluated.
The data should be discussed with patients who are fit for chemotherapy and an ARPI, realising that most of
the toxicity is caused by adding the chemotherapy. There is more evidence for using the triplet in synchronous
disease and the OS benefit in PEACE-1 seemed to be driven mostly by the high volume patients at the time point
of the analysis for the publication, in ARASENS only few patients had low volume disease. A living SR and MA,
providing continuously automated updates is recommended for review [1194].

The choice of treatment will most likely be driven by fitness for docetaxel, the nature of the disease (low/high
volume; synchronous/metachronous), patient preference, the specific side effects, availability, logistics and
cost. The lack of high-level evidence for the benefit of triplet (ADT+ARPI+docetaxel) vs. doublet (ADT+ARPI)
makes it difficult to make a strong recommendation for one option over the other including for patients with
synchronous high-volume mHSPC.

6.6.6 Treatment of the primary tumour in newly diagnosed metastatic disease

The first reported trial evaluating prostate RT in men with metastatic castration-sensitive disease was the
HORRAD trial. Four hundred and thirty-two patients were randomised to ADT alone or ADT plus IMRT with
IGRT to the prostate. Overall survival was not significantly different (HR: 0.9 [0.7–1.14]), median time to PSA
progression was significantly improved in the RT arm (HR: 0.78 [0.63–0.97]) [1200]. The STAMPEDE trial
evaluated 2,061 men with metastatic castration-sensitive PCa (mCSPC) who were randomised to ADT alone vs.
ADT plus RT to the prostate. This trial confirmed that RT to the primary tumour did not improve OS in unselected
patients [1152]. However, following the results from CHAARTED and prior to analysing the data, the original
screening investigations were retrieved, and patients categorised as low- or high volume. In the low-volume

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subgroup (n = 819) there was a significant OS benefit by the addition of prostate RT. This was confirmed by the
latest analysis of long-term follow-up (median follow-up of 61 months [HR: 0.64 for OS benefit in the low-volume
group]) [1201].
A secondary, not pre-planned analysis of the STAMPEDE trial confirmed the benefit of prostate RT in
patients with ≤ 3 bone metastases, but also showed a benefit in patients with M1a disease [1202]. No evidence
of difference in time to symptomatic local events was found with median follow-up of over five years [1201].
The dose used in these indications should be equivalent of up to 72 Gy in 2 Gy fractions. Therefore, RT of the
prostate only in patients with low-volume metastatic disease should be considered.
A network meta-analysis demonstrates that adding prostate RT to ADT alone results in 27%
reduction in the hazard for death (pooled HR: 0.73; 95% credible interval [CrI]: 0.62–0.87), while ADT plus ARPI
was associated with a 32% reduction (pooled HR: 0.68; 95% CrI: 0.60–0.78) and ADT plus ARPI plus RT was
associated with a 47% reduction (pooled HR: 0.53; 95% CrI: 0.34–0.81) in the hazard for death (in risk of death)
[1203]. It is not clear if these data can be extrapolated to RP as local treatment as results of ongoing trials are
awaited.
In a SR and meta-analysis including the above two RCTs, the authors found that, overall, there was
no evidence that the addition of prostate RT to ADT improved survival in unselected patients (HR: 0.92, 95% CI:
0.81–1.04, p = 0.195) [1204]. However, there was a clear difference in the effect of metastatic burden on survival
with an absolute improvement of 7% in three-year survival in men who had four or fewer bone metastases.

The randomised phase-III trial with a 2 × 2 factorial design PEACE-1 (SOC, SOC+Abiraterone, SOC+RT and
SOC+Abiraterone+RT) including 1,172 patients demonstrated that adding prostate radiotherapy (total dose 74
Gy in 37 fractions) significantly prolonged the co-primary endpoint of PFS from 4.4 years to 7.5 years in the
low-volume metastatic burden group treated with SOC+ARPI. Additionally, a significant delay in the time to
castration resistance was observed, although there was no improvement in OS in this group [1205].
PEACE-1 also reported a significant reduction in the incidence of serious genitourinary events such
as obstruction, bleeding, insertion of double-J stent and TURP for patients treated with local RT to the prostate.
This was an important secondary endpoint in the PEACE-1 study where the preventive effect of radiotherapy
was observed both in the cohort of patients with low-volume metastatic disease (26% vs. 11%; delay in the time
to first serious genitourinary event p = 0·0002;) and the overall cohort (22.3% vs 12.2%; p = 0·0001) [1205].

6.6.7 Metastasis-directed therapy in M1-patients

In patients relapsing after a local treatment, a metastases-targeting therapy has been proposed, with the aim to
delay systemic treatment. In a retrospective analysis on 211 patients treated with MDT, Milenkovic et al. aimed
at defining prognostic factors for MFS, palliative ADT-free (pADT) survival and cause-specific survival (CSS).
With a median follow-up of 42 months after MDT, patients with cN1 only had significantly superior five-years
MFS, pADT and CSS when compared to patients with M1 disease (p<0.02). Of interest, 23% of patients were
free of biochemical recurrence at five years [1206]. There are two randomised phase II trials testing metastasis-
directed therapy (MDT) using surgery ± SABR vs. surveillance [1207] or SABR vs. surveillance in men with oligo-
recurrent PCa [1208]. Oligo-recurrence was defined as < 3 lesions on choline-PET/CT only [1207] or conventional
imaging with MRI/CT and/or bone scan [1208]. The sample size was small with 62 and 54 patients, respectively,
and a substantial proportion of them had nodal disease only [1207]. Androgen deprivation therapy-free survival
was the primary endpoint in one study which was longer with MDT than with surveillance [1207]. The primary
endpoint in the ORIOLE trial was progression after six months which was significantly lower with SBRT than with
surveillance (19% vs. 61%, p = 0.005) [1208].

Recently the combined results of STOMP and ORIOLE confirmed the significant improvement in PFS
in favour of MDT (HR: 0.44, p < 0.001) [1209].

A phase II trial assessed the biochemical response after 18F-DCFPyL PET/MRI and subsequent MDT. Overall
biochemical response rate, defined as ≥ 50% PSA decline, was 60%, including 22% of patients with complete
biochemical response [1210].

The phase II randomised EXTEND trial investigated whether MDT when added to standard-of-care systemic
treatment improved PFS when compared to standard-of-care systemic treatment alone in oligometastatic
prostate cancer patients, with oligometastatic being defined as maximally 5 lesions. In total, 87 patients were
randomized and the vast majority presented with 1 or 2 metastatic lesions. In total, 51 patients received ADT
alone, while 36 patients also received ARPI. The addition of MDT significantly improved both PFS (15.8 months
vs. not reached; HR: 0.25; p<0.001) and eugonadal PFS (6.1 months vs. not reached; HR: 0.32; p = 0.03). This
significant benefit was observed both in the patient group receiving ADT alone or ADT + ARPI [1211]. In analogy,
the SATURN trial, which included 28 oligo-recurrent metastatic prostate cancer patients, looked at the PFS

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of adding dual ARPI and MDT to existing ADT. The median PFS in SATURN was 19.3 months and 50% of the
patients still had an undetectable PSA six months after testosterone recovery. While MDT-induced toxicity was
very low, adding dual ARPI induced grade 3 toxicity in 20% of the patients [1212].

Currently there are no data to suggest an improvement in OS. Two comprehensive reviews highlighted MDT
(SABR) as a promising therapeutic approach that must still be considered as investigational until the results of
the ongoing RCT are available [1213, 1214]. The toxicity of MDT is low, with nearly no grade ≥ 3 toxicity [1215-
1217].

6.6.8 Recommendations for the first-line treatment of hormone-sensitive metastatic disease*

Recommendations Strength rating

First-line treatment
Discuss all patients with hormone-sensitive metastatic disease in a multidisciplinary team. Strong
Offer immediate systemic treatment with androgen deprivation therapy (ADT) to palliate Strong
symptoms and reduce the risk for potentially serious sequelae of advanced disease (spinal
cord compression, pathological fractures, ureteral obstruction) to M1 symptomatic patients.
Offer short-term administration of an older generation androgen receptor (AR) antagonist to Weak
M1 patients starting luteinising hormone-releasing hormone (LHRH) agonist to reduce the
risk of the ‘flare-up’ phenomenon.
At the start of ADT offer LHRH antagonists or orchiectomy to patients with impending Strong
clinical complications such as spinal cord compression or bladder outlet obstruction.
Do not offer AR antagonist monotherapy to patients with M1 disease. Strong
Do not offer ADT monotherapy to patients whose first presentation is M1 disease if they Strong
have no contra-indications for combination therapy and have a sufficient life expectancy to
benefit from combination therapy (≥ 1 year) and are willing to accept the increased risk of
side effects.
Offer ADT combined with abiraterone acetate plus prednisone or apalutamide or enzalutamide Strong
to patients with M1 disease who are fit for the regimen.
Offer darolutamide to patients with M1 disease who are fit for the regimen. Weak
Offer docetaxel only in combination with ADT plus abiraterone or darolutamide to patients Strong
with M1 disease who are fit for docetaxel.
Offer ADT combined with prostate radiotherapy (using doses up to the equivalent of 72 Gy in Strong
2 Gy fractions) to patients whose first presentation is M1 disease and who have low volume
of disease by CHAARTED criteria.
Do not offer ADT combined with surgery to M1 patients outside of clinical trials. Strong
Only offer metastasis-directed therapy to M1 patients within a clinical trial setting or a well- Strong
designed prospective cohort study.
Supportive care
Assess osteoporosis risk factors and perform a dexa scan when commencing long-term Strong
ADT, to mitigate osseous complications.
Offer bone protection to avoid fractures in patients receiving combination treatment. Strong
Offer calcium and vitamin D supplementation when prescribing either denosumab or Strong
bisphosphonates and monitor serum calcium.
Treat painful bone metastases early on with palliative measures such as intensity-modulated Strong
radiation therapy/volumetric arc radiation therapy plus image-guided radiation therapy and
adequate use of analgesics.
In patients with spinal cord compression start immediate high-dose cortico-steroids and Strong
assess for spinal surgery potentially followed by radiation. Offer radiation therapy alone if
surgery is not appropriate.
*All the following statements are based on metastatic disease defined by bone scintigraphy and CT scan/MRI.

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6.7 Treatment: Castration-resistant PCa (CRPC)
6.7.1 Definition of CRPC
Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either:
a. Biochemical progression: Three consecutive rises in PSA at least one week apart resulting in two 50%
increases over the nadir, and a PSA > 2 ng/mL; or
b. Radiological progression: The appearance of new lesions: either two or more new bone lesions on bone
scan, ideally confirmed [1218], or a soft tissue lesion using RECIST (Response Evaluation Criteria in Solid
Tumours) [1219]. Symptomatic progression alone must be questioned and subject to further investigation.
It is not sufficient to diagnose CRPC.
c. Unequivocal clinical progression.

6.7.2 Management of mCRPC - general aspects

Selection of treatment for mCRPC is multifactorial and in general dependent on:
• previous treatment for mHSPC and for non-mHSPC;
• previous treatment for nmCRPC and mCRPC;
• quality of response and pace of progression on previous treatment;
• known cross resistance between androgen receptor pathway inhibitor (ARPI);
• co-medication and known drug interactions (see approved summary of product characteristics);
• known genetic alterations and microsatellite instability–high (MSI-H)/mismatch repair-deficient (dMMR)
status;
• known histological variants and DNA repair deficiency (to consider platinum or targeted therapy like
PARPi);
• local approval status of drugs and reimbursement situation;
• available clinical trials;
• the patient and his co-morbidities.

6.7.2.1 Molecular diagnostics

All metastatic patients should be offered somatic genomic testing for homologous repair and MMR defects
early on, preferably before first-line mCRPC treatment is established. Testing should preferably be performed
on metastatic carcinoma tissue but testing on primary tumour may also be performed. Alternatively, but still
less common, genetic testing on circulating tumour DNA (ctDNA) is an option and has been used in some trials.
One test, the FoundationOne® Liquid CDx, has been FDA approved [1220]. Defective MMR assessment can be
performed by IHC for MMR proteins (MSH2, MSH6, MLH1 and PMS2) and/or by next generation sequencing
(NGS) assays [1221]. Germline testing for BRCA1/2, ATM and MMR is recommended for high-risk- and
particularly for metastatic PCa if clinically indicated.
Molecular diagnostics should be performed by a certified (accredited) institution using a standard
NGS multiplication procedure (minimum depth of coverage of 200 X). The genes and respective exons should be
listed; not only DNA for mutations but RNA needs to be examined for fusions and protein expression to obtain all
clinically relevant information. A critical asset is the decision support helping to rate the mutations according to
their clinical relevance [1222, 1223]. Ideally, a molecular tumour board is involved to support interpretation of the
report and clinical decision taking.
Level 1 evidence for the use of PARP-inhibitors has been reported [273, 1224-1235]. Microsatellite
instability (MSI)-high (or MMR deficiency) is rare in PCa, but for those patients, pembrolizumab has been
approved by the FDA and could be a valuable additional treatment option [1141, 1236]. Germline molecular
testing is discussed in section 5.1.7 and recommendations for germline testing are provided in section 5.1.8.

6.7.3 Treatment decisions and sequence of available options

Approved agents for the treatment of mCRPC in Europe are docetaxel, abiraterone/prednisolone (AAP),
enzalutamide, cabazitaxel, olaparib, niraparib/AAP, talazoparib/enzalutamide, radium-223 and lutetium (177Lu)
vipivotide tetraxetan. Regarding CRPC, darolutamide and apalutamide have been approved only for nmCRPC.
In general, sequencing of ARPIs like abiraterone and enzalutamide is not recommended particularly if the time
of response to ADT and to the first ARPI was short (≤ six to twelve months) and high-risk features of rapid
progression are present (see detailed discussion in section 6.7.7) [1237-1239].
The use of chemotherapy with docetaxel and subsequent cabazitaxel in the treatment sequence
is recommended and should be applied early enough when the patient is still fit for chemotherapy. This is
supported by high-level evidence [1237].
In case of a known BRCA alteration, the use of a PARP inhibitor should always be prioritised as its
use improves rPFS and OS [1240-1243].

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6.7.4 Non-metastatic CRPC
Frequent PSA testing in men treated with ADT has resulted in earlier detection of biochemical progression. Of
these men approximately one-third will develop bone metastases within two years, detected by conventional
imaging [952].
In men with CRPC and no detectable clinical metastases using bone scan and CT-scan, baseline PSA
level, PSA velocity and PSA-DT have been associated with time to first bone metastasis, bone MFS and OS [952,
1244]. These factors may be used when deciding which patients should be evaluated for metastatic disease. A
consensus statement by the PCa Radiographic Assessments for Detection of Advanced Recurrence (RADAR)
group suggested a bone scan and a CT scan when the PSA reached 2 ng/mL and if this was negative, it should
be repeated when the PSA reached 5 ng/mL, and again after every doubling of the PSA based on PSA testing
every three months in asymptomatic men [1245]. Symptomatic patients should undergo relevant investigations
regardless of PSA level. With more sensitive imaging techniques like PSMA PET/CT or whole-body MRI, more
patients are diagnosed with early mCRPC [1246]. It remains unclear if the use of PSMA PET/CT in this setting
improves outcome.

Three large phase III RCTs, PROSPER [1247], SPARTAN [1248] and ARAMIS [1249], evaluated MFS as the primary
endpoint in patients with nmCRPC (M0 CRPC) treated with enzalutamide (PROSPER) vs. placebo or apalutamide
(SPARTAN) vs. placebo or darolutamide (ARAMIS) vs. placebo, respectively (Table 6.7.1). The M0 status was
established by CT and bone scans. Only patients at high risk for the development of metastasis with a short
PSA-DT of ≤ ten months were included. Patient characteristics in the trials revealed that about two-thirds of
participants had a PSA-DT of < 6 months. All trials showed a significant MFS benefit. All three trials showed
a survival benefit after a follow-up of more than 30 months. In view of the long-term treatment with these AR
targeting agents in asymptomatic patients, potential AEs need to be taken into consideration and the patient
informed accordingly.

6.7.5 Metastatic CRPC

The remainder of this section focuses on the management of men with proven mCRPC on conventional
imaging.

6.7.5.1 Conventional androgen deprivation in CRPC

Eventually men with PCa will show evidence of disease progression despite castration. Two trials have shown
only a marginal survival benefit for patients remaining on LHRH analogues during second- and thirdline
therapies [1250, 1251]. However, in the absence of prospective data, the modest potential benefits of continuing
castration outweigh the minimal risk of treatment. In addition, all subsequent treatments have been studied in
men with ongoing androgen suppression, therefore, it should be continued in these patients.

6.7.6 First-line treatment of metastatic CRPC

6.7.6.1 Abiraterone
Abiraterone was evaluated in 1,088 chemo-naive, asymptomatic or mildly symptomatic mCRPC patients in the
phase III COU-AA-302 trial. Patients were randomised to abiraterone acetate or placebo, both combined with
prednisone [1252]. Patients with visceral metastases were excluded. The main stratification factors were ECOG
PS 0 or 1 and asymptomatic or mildly symptomatic disease. Overall survival and rPFS were the co-primary
endpoints. After a median follow-up of 22.2 months there was significant improvement of rPFS (median 16.5
vs. 8.2 months, HR: 0.52, p < 0.001) and the trial was unblinded. At the final analysis with a median follow-up
of 49.2 months, the OS endpoint was significantly positive (34.7 vs. 30.3 months, HR: 0.81, 95% CI: 0.70–0.93,
p = 0.0033) [1253]. Adverse events related to mineralocorticoid excess and liver function abnormalities were
more frequent with abiraterone, but mostly grade 1–2. Subset analysis of this trial showed the drug to be equally
effective in an elderly population (> 75 years) [1254].

6.7.6.2 Enzalutamide
A randomised phase III trial (PREVAIL) included a similar patient population and compared enzalutamide
and placebo [1255]. Men with visceral metastases were eligible but the numbers included were small.
Corticosteroids were allowed but not mandatory. PREVAIL was conducted in a chemo-naive mCRPC population
of 1,717 men and showed a significant improvement in both co-primary endpoints, rPFS (HR: 0.186, CI: 0.15–
0.23, p < 0.0001), and OS (HR: 0.706, CI: 0.6–0.84, p < 0.001). A ≥ 50% decrease in PSA was seen in 78% of
patients. The most common clinically relevant AEs were fatigue and hypertension. Enzalutamide was equally
effective and well tolerated in men > 75 years [1256] as well as in those with or without visceral metastases
[1257]. However, for men with liver metastases, there seemed to be no discernible benefit [1257, 1258].

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 Enzalutamide has also been compared with bicalutamide 50 mg/day in a randomised double-blind
phase II study (TERRAIN) showing a significant improvement in PFS (15.7 months vs. 5.8 months, HR: 0.44,
p < 0.0001) in favour of enzalutamide [1258]. With extended follow-up and final analysis the benefit in OS and
rPFS were confirmed [1259].

6.7.6.3 Docetaxel
A statistically significant improvement in median survival of 2.0–2.9 months has been shown with docetaxel
compared to mitoxantrone plus prednisone [1260, 1261]. The standard first-line chemotherapy is docetaxel
75 mg/m2, 3-weekly doses combined with prednisone 5 mg twice a day (BID), up to ten cycles. Prednisone
can be omitted if there are contra-indications or no major symptoms. The following independent prognostic
factors: visceral metastases, pain, anaemia (Hb < 13 g/dL), bone scan progression, and prior estramustine
may help stratify the response to docetaxel. Patients can be categorised into three risk groups: low risk (0 or 1
factor), intermediate (2 factors) and high risk (3 or 4 factors), and show three significantly different median OS
estimates of 25.7, 18.7 and 12.8 months, respectively [1262].
Age by itself is not a contra-indication to docetaxel [1263] but attention must be paid to careful
monitoring and co-morbidities as discussed in section 6.1 - Estimating life expectancy and health status [1264].
In men with mCRPC who are thought to be unable to tolerate the standard dose and schedule, docetaxel 50
mg/m2 every two weeks seems to be well tolerated with less grade 3–4 AEs and a prolonged time to treatment
failure [1265].

6.7.6.4 Sipuleucel-T
In 2010 a phase III trial of sipuleucel-T showed a survival benefit in 512 asymptomatic or minimally symptomatic
mCRPC patients [1266]. After a median follow-up of 34 months, the median survival was 25.8 months in the
sipuleucel-T group compared to 21.7 months in the placebo group, with a HR of 0.78 (p = 0.03). No PSA decline
was observed and PFS was similar in both arms. The overall tolerance was very good, with more cytokine-
related AEs grade 1–2 in the sipuleucel-T group, but the same grade 3–4 AEs in both arms. Sipuleucel-T is not
available in Europe.

6.7.6.5 Combinations with PARP inhibitors

Based on the suggestion that there is a synergistic antitumour effect when combining an ARPI with a PARP
inhibitor, several such combination trials were conducted in first-line mCRPC patients with different trial designs,
different patient selection and conflicting results.

Abiraterone/prednisone plus olaparib

A randomised double-blind, phase III trial (PROpel) of AAP plus olaparib (300 mg twice daily) or placebo in
patients with mCRPC in the first-line setting was conducted [1226, 1227]. Patients (n = 796) were randomly
assigned 1:1 to study treatment regardless of homologous recombination repair gene mutation (HRRm) status
which was retrospectively evaluated and determined by tumour tissue and circulating tumour DNA tests. The
primary end point was imaging-based PFS (ibPFS) by investigator assessment. The result was significantly
positive in favour of the combination with ibPFS of 24.8 vs. 16.6 mo (HR 0.66; 95% CI: 0.54 to 0.81; p = 0.001).
In the prespecified final analyses the key secondary endpoint OS had only 47.9% maturity and did not meet the
prespecified 2-sided boundary for significance (HR 0.95% CI: 0.81, 0.67-1.0, p = 0.054). The subgroup of patients
with positive HRRm status showed a rPFS HR of 0.50 (CI: 0.34 to 0.73). The BRCA mutated patients (11% of the
ITT population) had an even larger benefit for rPFS (HR 0.24; 95% CI: 0.12, 0.45) and the OS HR in these patients
was 0.30 (95% CI: 0.15, 0.59), suggesting that the improvement in rPFS observed in the ITT population was
primarily driven by patients with a BRCA mutation [1228].
The most common AEs in patients receiving olaparib plus AAP were anaemia (48%; ≥ G3 15%),
fatigue (38%), nausea (30%), diarrhoea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%),
and abdominal pain (13%); 18% of patients required at least one blood transfusion and 12% required multiple
transfusions [1228]. The combination of olaparib plus AAP was approved by the EMA for the treatment of adult
patients with mCRPC in whom chemotherapy is not clinically indicated [1240]. In the US, the FDA has approved
olaparib with AAP for mCRPC patients with deleterious or suspected deleterious BRCA-mutations as determined
by an FDA-approved companion diagnostic test [1229]. For patients without BRCAm, the FDA determined that
the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable
risk/benefit assessment [1241].
The combination of PARP inhibitor plus ARPI in patients with BRCA1/2 (or ATM) mutations in
the first-line as opposed to the use of PARP inhibitor monotherapy or the sequential use of these agents is
supported by a randomised phase II trial albeit with low patient numbers and thus a low level of evidence [1267].

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Abiraterone/prednisone plus niraparib
In a randomised, double-blind, phase III trial (MAGNITUDE) AAP plus niraparib 200 mg once/daily or placebo,
was evaluated [1230]. The study prospectively included 2 cohorts, an HRR-negative and an HRR-positive
cohort. The HRR-negative cohort was closed early for futility after enrolling 200 patients. In the overall HRR-
positive cohort, the addition of Niraparib to AAP resulted in a significant improvement in the first endpoint rPFS
compared to AAP plus placebo (HR = 0.73; 95% CI 0.56-0.96; p = 0.0217) and the median rPFS was 16.5 vs.
13.7 months in favour of the combination. In particular, the 113 patients with BRCA 1/ 2 mutations [1231] who
received AAP plus niraparib [1231] derived a major rPFS benefit (19.5 vs. 10.9 months; HR = 0.55 [95% CI 0.39-
0.78]; nominal p = 0.0007). The OS data is still immature. The most common side effects with Niraparib plus
AAP in the ITT population were anemia (46.2%), fatigue (26.4%), hypertension (31.6%) and constipation (30.7%).
The combination of niraparib plus AAP in a dual-action tablet has been approved by the EMA and the FDA for
patients with mCRPC and BRCA 1/2 mutations in whom chemotherapy is not clinically indicated [1232].

Enzalutamide plus Talazoparib

A randomised double-blind, phase III trial (TALAPRO-2) of the PARP inhibitor talazoparib (0.5mg daily) plus
enzalutamide versus enzalutamide/placebo showed a significantly better median rPFS (first endpoint) in favour
of the combintion regardless of the HRR pathway status [1233].
The median rPFS was not yet reached for the combination as compared to 21.9 mo in the control
arm (95% CI 16.6-25.1). The HR for rPFS was 0.63 (0.51-0.78) with p<0.0001. For the subgroups of patients with
HRR mutations the benefit of the combination was much more pronounced. The HRR gene-mutated population
showed a median rPFS of 27.9 (16.6–not reached) for the talazoparib combination versus 16.4 (10.9–24.6)
for the placebo group (0.46; 95% CI: 0.30–0.70; p = 0.0003 ) and 0.70 (0.54–0.89; p = 0.0039) in patients with a
status of non-deficient or unknown. In an exploratory analysis, the HR for rPFS in patients with BRCA-mutated
mCRPC was 0.23 (0.10–0.53; p = 0.0002) and, in patients with non-BRCAm HRR gene-mutated mCRPC, it was
0.66 (0.39–1.12; p = 0.12) in favour of the talazoparib combination [1233]. The OS data were still immature.
The expected clinical benefit in the subgroups needs to be weighed against the potential burden of side effects
[1240].
The most common treatment-emergent AEs with the addition of talazoparib were anaemia,
neutropenia, and fatigue; the most common grade 3–4 event was anaemia (46%), which improved after dose
reduction, however, 39% required a blood transfusion, including 22% who required multiple transfusions,
8% discontinued treatment due to anaemia and two patients on the combination were diagnosed with
myelodysplastic syndrome/acute myeloid leukaemia [1233]. In TALAPRO-2 an HRR-deficient-only cohort (cohort
2; n = 230) was recruited. The primary analysis for the combined HRR-deficient population (n = 399) met the
rPFS endpoint with a HR 0.45 (95% CI, 0.33 to 0.61; p < 0.0001; median not reached at the time of the analysis
for the talazoparib group versus 13.8 months for the placebo group). Also for this cohort data for OS were
immature but favour talazoparib (HR 0.69; 95% confidence interval, 0.46 to 1.03; p = 0.07) [1234].
The FDA approved talazoparib with enzalutamide only for HRR gene-mutated mCRPC [1235, 1240,
1268]. The EMA has approved the combination of talazoparib and enzalutamide for the treatment of patients
with mCRPC in whom chemotherapy is not clinically indicated [1269].

Regarding additional side effects of special interest, there seems to be a doubling of the risk of thromboembolic
events with the use of PARPis. In a meta-analysis of 2,210 and 1,662 patients with PC and PARPi treatment vs.
control, PARPi had a statistically significant increased risk of thrombosis in PCa patients (OR = 1.98, 95 % CI:
1.06–3.70, p = 0.030) with 96 (4.3 %) and 37 (2.2 %) in the PARPi and control groups, respectively [1270].
Based on eighteen placebo-controlled RCTs (n = 7,307 patients, tumour agnostic), PARPis
significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with
placebo treatment (Peto OR 2·63 [95% CI 1·13–6·14], p = 0·026) with no between-study heterogeneity (I2=0%,
χ2 p = 0·91). Median treatment duration was 9.8 months (IQR 3·6–17·4; n = 96) and median latency period since
first exposure to a PARPi was 17.8 months (8·4–29·2; n = 58). Of 104 cases that reported outcomes, 47 (45%)
resulted in death [1271].

6.7.7 Second-line treatment for mCRPC

All patients who receive treatment for mCRPC will eventually progress. All treatment options in this setting are
presented in Table 6.7.3. There is a paucity of high-level data with regards to the sequence of treatments in case
of pretreatment with ARPI and/or docetaxel for mHSPC.

6.7.7.1 Cabazitaxel
Cabazitaxel is a taxane with activity in docetaxel-resistant cancers. It was studied in a large prospective,
randomised, phase III trial (TROPIC) comparing cabazitaxel plus prednisone vs. mitoxantrone plus prednisone in
755 patients with mCRPC, who had progressed after or during docetaxel-based chemotherapy [1272]. Patients

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received a maximum of ten cycles of cabazitaxel (25 mg/m2) or mitoxantrone (12 mg/m2) plus prednisone (10
mg/day). Overall survival was the primary endpoint which was significantly longer with cabazitaxel (median:
15.1 vs. 12.7 months, p < 0.0001). There was also a significant improvement in PFS (median: 2.8 vs. 1.4 months,
p < 0.0001), objective RECIST response (14.4% vs. 4.4%, p < 0.005), and PSA response rate (39.2% vs. 17.8%,
p < 0.0002). Treatment-associated WHO grade 3–4 AEs developed significantly more often in the cabazitaxel
arm, particularly haematological (68.2% vs. 47.3%, p < 0.0002) but also non-haematological (57.4 vs. 39.8%, p <
0.0002) toxicity. In two post-marketing randomised phase III trials, cabazitaxel was shown not to be superior to
docetaxel in the first-line setting; in the second-line setting in terms of OS, 20 mg/m2 cabazitaxel was not inferior
to 25 mg/m2, but less toxic. Therefore, the lower dose should be preferred [1273, 1274]. Cabazitaxel should
preferably be given with prophylactic granulocyte colonystimulating factor (G-CSF) and should be administered
by physicians with expertise in handling neutropenia and sepsis [1275].

6.7.7.2 Abiraterone acetate after docetaxel for mCRPC

Positive results of the large phase III trial (COU-AA-301) were reported after a median follow-up of 12.8 months
[1276] and confirmed by the final analysis [1277]. A total of 1,195 patients with mCRPC were randomised
2:1 to AAP or placebo plus prednisone. All patients had progressive disease based on the Prostate Cancer
Clinical Trials Working Group 2 (PCWG2) criteria after docetaxel therapy (with a maximum of two previous
chemotherapeutic regimens). The primary endpoint was OS, with a planned HR of 0.8 in favour of AAP. After
a median follow-up of 20.2 months, the median survival in the AAP group was 15.8 months compared to
11.2 months in the placebo arm (HR: 0.74, p < 0.0001). The benefit was observed in all subgroups and all
the secondary objectives were in favour of AAP (PSA, radiologic tissue response, time to PSA or objective
progression). The incidence of the most common grade 3–4 AEs did not differ significantly between arms, but
mineralocorticoid-related side effects were more frequent in the AAP group, mainly grade 1–2 (fluid retention,
oedema and hypokalaemia).

6.7.7.3 Enzalutamide after docetaxel for mCRPC

The planned interim analysis of the AFFIRM study was published in 2012 [1278]. This trial randomised 1,199
patients with mCRPC in a 2:1 fashion to enzalutamide or placebo. The patients had progressed after docetaxel
treatment, according to the PCWG2 criteria. Corticosteroids were not mandatory, but could be prescribed, and
were received by about 30% of the patients. The primary endpoint was OS, with an expected HR benefit of 0.76
in favour of enzalutamide. After a median follow-up of 14.4 months, the median survival in the enzalutamide
group was 18.4 months compared to 13.6 months in the placebo arm (HR: 0.63, p < 0.001). This led to the
recommendation to halt and unblind the study. The benefit was observed irrespective of age, baseline pain
intensity, and type of progression. In the final analysis with longer follow-up the OS results were confirmed
despite crossover and extensive post-progression therapies [1223]. Enzalutamide was active also in patients
with visceral metastases.
All the secondary objectives were in favour of enzalutamide (PSA, soft tissue response, QoL, time
to PSA, or objective progression). No difference in terms of side effects was observed in the two groups, with
a lower incidence of grade 3–4 AEs in the enzalutamide arm. There was a 0.6% incidence of seizures in the
enzalutamide group compared to none in the placebo arm.

6.7.7.4 Radium-223 after ARPI or both ARPI and docetaxel for mCRPC
The only bone-specific drug that is associated with a survival benefit is the α-emitter radium-223. In a large
phase III trial (ALSYMPCA) 921 patients with symptomatic mCRPC, who failed or were unfit for docetaxel, were
randomised to six injections of 50 kBq/kg radium-223 or placebo plus SOC. The primary endpoint was OS.
Radium-223 significantly improved median OS by 3.6 months (HR: 0.70, p < 0.001) and was also associated
with prolonged time to first skeletal event, improvement in pain scores and improvement in QoL [1279]. The
associated toxicity was mild and, apart from slightly more haematologic toxicity and diarrhoea with radium-223,
did not differ significantly from that in the placebo arm [1279]. Radium-223 was effective and safe whether or
not patients were docetaxel pre-treated [1280]. Due to safety concerns, use of radium-223 was restricted to after
docetaxel and at least one AR targeted agent [1281]. In particular, the use of radium-223 in combination with
AAP showed significant safety risks related to fractures and more deaths. This was most striking in patients
without the concurrent use of bone health agents [1282] so that radium-223 should always be used together
with bone health agents (see section 6.7.11.2)

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6.7.7.5 Rucaparib after ARPI [1243]
In a 2:1 randomised, controlled, phase III trial (TRITON-3) 405 mCRPC patients were included. Patients were
selected for a BRCA1, BRCA2, or ATM alteration and disease progression after treatment with an ARPI for
mCRPC. Treatment was as follows: rucaparib 600 mg twice daily or a physician’s choice control, either second
line docetaxel or the ARPI which had not been given previously. The first endpoint rPFS in the intention-to-treat
group was significantly better with rucaparib (median, 10.2 months and 6.4 months, respectively; HR 0.61;
95% CI, 0.47 to 0.80; p < 0.001). The small ATM subgroup did not derive a benefit. An interim analysis revealed
OS to be immature. The study design allowed for cross-over and 60% of patients received a PARP inhibitor at
progression (47% rucaparib). With regards to the control arms, the median rPFS was longer with rucaparib than
with docetaxel (11.2 months vs. 8.3 months; hazard ratio, 0.53; 95% CI, 0.37 to 0.77) and it was also longer than
with an ARPI (11.2 months vs. 4.5 months; hazard ratio, 0.38; 95% CI, 0.25 to 0.58). The most frequent AEs with
rucaparib were fatigue, nausea and anaemia, including 24% Grade ≥ 3 anaemia and 29% of patients on rucaparib
required at least one blood transfusion [1283]. Rucaparib has been approved by the FDA.

6.7.7.6 Olaparib after ARPI

See section 6.7.8.3 PARP inhibitors for mCRPC.

6.7.7.7 177Lu-PSMA-617 after ARPI

Primary and updated analyses of rPFS for the phase III, multicenter RCT, PSMAfore, investigating taxane-naive
patients with PSMA-positive mCRPC who had progressed on ARPI, have been published. Patients were 1:1
randomised between open-label, intravenous ¹⁷⁷Lu-PSMA-617 (7.4 GBq intravenously, every 6 weeks, for up to
6 cycles) and a change of ARPI. A total of 468 patients met all eligibility criteria and were randomly assigned to
receive ¹⁷⁷Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Of the 234 patients assigned to ARPI
change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the updated analysis at time of the third data
cut-off (median time from randomisation to third data cut-off 24.11 months [IQR 20.24–27.40]), median rPFS
was 11.60 months (95% CI: 9.30–14.19) in the ¹⁷⁷Lu-PSMA-617 group vs. 5.59 months (4.21–5.95) in the ARPI
change group (HR 0.49 [95% CI: 0.39–0.61]). The incidence of grade 3–5 AEs was lower in the ¹⁷⁷Lu-PSMA-617
group compared to the ARPI change group. The key secondary endpoint OS was similar in both groups [1284].

6.7.8 Treatment after docetaxel and one line of hormonal treatment for mCRPC
6.7.8.1 General considerations
For men progressing quickly on AR targeted therapy (< 12 months) it is now clear that cabazitaxel is the
treatment supported by the best data. The CARD trial, an open label randomised phase III trial, evaluated
cabazitaxel after docetaxel and one line of ARPI (either AAP or enzalutamide) [1237]. It included patients
progressing in less than twelve months on previous abiraterone or enzalutamide for mCRPC. Cabazitaxel more
than doubled rPFS vs. another ARPI and reduced the risk of death by 36% vs. ARPI. The rPFS with cabazitaxel
remained superior regardless of the ARPI sequence and if docetaxel was given before, or after, the first ARPI.
The choice of further treatment after docetaxel and one line of HT for mCRPC is open for patients
who have a > twelve months response to first-line abiraterone or enzalutamide for mCRPC [1259]. Either second-
line chemotherapy (cabazitaxel), radium-223 (if bone-only metastases), 177Lu–PSMA-617 radioligand therapy
[1285, 1286] and PARP inhibitors (if BRCA mutation) are valuable options.
Men previously treated with at least one ARPI or both an ARPI and docetaxel and whose tumours
demonstrated homozygous deletions or deleterious mutations in DNA-repair genes showed an 88% response
rate to olaparib [1287] and in another confirmatory trial a composite response of 54.3% (95% CI: 39.0–69.1) in
the 400 mg cohort and in 18 of 46 (39.1%; 25.1–54.6) evaluable patients in the 300 mg cohort [1288]. See also
section ‘Second-line management’). In general, subsequent treatments in unselected patients are expected
to have less benefit than with earlier use [1289, 1290] and there is evidence of cross-resistance between
enzalutamide and abiraterone [1291, 1292].

6.7.8.2 Radiopharmaceuticals
6.7.8.2.1 Introduction
Historically, several radiopharmaceuticals including phosphorous-32, strontium-89, yttrium-90, samarium-153,
and rhenium-186 were developed for the treatment of bone pain secondary to metastases from PCa [1293].
They proved effective in a palliation setting, by relieving pain and improving QoL, especially in the setting
of diffuse bone metastases. However, they never gained widespread adoption. The first radioisotope to
demonstrate a survival benefit was radium-223 (see Section 6.7.7.4).

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6.7.8.2.2 PSMA-based therapy
The increasing use of PSMA PET as a diagnostic tracer and the realisation that this allowed identification
of a greater number of metastatic deposits led to attempts to treat cancer by replacing the imaging isotope
with a therapeutic isotope which accumulates where the tumour is demonstrated (theranostics) [1294].
Therefore, after identification of the target, usually with diagnostic 68Gallium-labelled PSMA, therapeutic
radiopharmaceuticals labelled with β(lutetium-177 or yttrium-90) or α(actinium-225)-emitting isotopes could be
used to treat metastatic PCa.

The PSMA therapeutic radiopharmaceutical supported by the most robust data is 177Lu-PSMA-617. The
first patient was treated in 2014 and early clinical studies evaluating the safety and efficacy of 177Lu-PSMA
therapy have demonstrated promising results, despite the fact that a significant proportion of men had already
progressed on multiple therapies [1295]. The early data were based on single-centre experience [1296]. Data
from uncontrolled prospective phase II trials reported high response rates with low toxic effects [1297, 1298].
Positive signals are also coming from a randomised phase II trial (TheraP) [1299].

In TheraP patients for whom cabazitaxel was considered the next appropriate standard treatment after
docetaxel and who were highly selected by 68Ga-PSMA-11 and 18FDG PET-CT scans, were randomised to receive
177Lu-PSMA-617 (6.0–8.5 GBq intravenously, every 6 weeks, for up to 6 cycles) or cabazitaxel (20 mg/m2 for up

to ten cycles). The primary endpoint was a reduction of at least 50% in PSA. The first endpoint was met (66% vs.
37% for 177Lu–PSMA-617 vs. cabazitaxel, respectively, by intention to treat; difference 29% (95% CI: 16–42; p <
0.0001; and 66% vs. 44% by treatment received; difference 23% [9–37]; p = 0.0016) [1299]. Secondary outcomes
of the TheraP trial, including survival after a median follow-up of 35.7 months (IQR 31.1 to 39.2) showed that 77
(78%) participants had died in the 177Lu-PSMA-617 group and 70 (69%) participants in the cabazitaxel group.
Overall survival was similar between randomly assigned patients in the two groups (19.1 vs. 19.6 months;
difference -0.5, 95% CI: -3.7 to 2.7]; p = 0.77) [1300, 1301].

An open-label phase III trial (VISION) compared 177Lutetium Vipivotid tetraxetan (177Lu-PSMA-617 radioligand
therapy) with protocol-permitted SOC (i.e., excluded chemotherapy, immunotherapy, radium-223 and
investigational drugs) in mCRPC patients, with PSMA expressing metastases on PET/CT, previously treated with
at least one ARPI and one (around 53%) or two taxanes. Imaging-based PFS and OS were the alternate primary
endpoints. More than 800 patients were randomised. 177Lu-PSMA-617 plus SOC significantly prolonged both
imaging-based PFS and OS, as compared with SOC alone (see Table 6.6.3). Grade 3 or above AEs were higher
with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but QoL was not adversely affected. 177Lu–PSMA-617 has
shown to be an additional treatment option in this mCRPC population [1302].

A SR and updated meta-analysis, investigated the proportion of patients with any or more than 50% PSA
decrease, and OS. The review, including 69 articles and a total of 4,157 patients, showed that patients treated
with 177Lu–PSMA 617 had a significantly higher response to therapy compared to controls, based on ≥ 50%
PSA decrease (OR = 5.33, 95% CI: 1.24–22.90, p < 0.05). Meta-analysis revealed an OS of 0.26 according to
pooled HRs for any PSA decline, which was significant after 177Lu–PSMA-617 therapy (95% CI: 0.18–0.37, p <
0.00001) and an OS of 0.52 for ≥ 50% PSA decrease, also significant after radioligand (RLT) (95% CI: 0.40–0.67,
p < 0.00001) [1303].

The earlier use of ¹⁷⁷Lu-PSMA-617 was studied in patients progressing on the first ARPI for mCRPC (PSMAfore),
see section 6.7.7.7.

There is an increasing interest for PSMA-targeted alpha therapy (225Ac-PSMA) due to the ability to deliver potent
higher local radiation more selectively to cancer cells than PSMA-targeted beta therapy, while minimising
unwanted damage to the surrounding normal tissues. Additionally, the intensive radiation to cancer cells results
in more effective DNA strand breakage and reduces the development of treatment resistance. A meta-analysis,
including nine studies with 263 patients, investigated the therapeutic effects of 225Ac-PSMA RLT in patients
with metastatic CRPC, pre-treated with chemotherapy, 177Lu-PSMA and/or radium-223. The pooled proportions
of patients with more than 50% PSA decline and any PSA decline were 60.99% (95% CI: 54.92%– 66.83%) and
83.57% (95% CI: 78.62%–87.77%), respectively. The estimated mean PFS and mean OS were 9.15 months
(95% CI: 6.69–11.03 months) and 11.77 months (95% CI: 9.51–13.49 months), respectively. These findings
suggest that 225Ac-PSMA RLT may be an effective treatment option for patients with mCRPC [1304]. Despite
the encouraging therapeutic response and survival of patients who received 225Ac-PSMA RLT, major AEs like
xerostomia and severe haematotoxicity have to be considered as possible reasons for dose reduction or
discontinuation of the therapy.

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A retrospective, multicentre international study, WARMTH Act, pooled data of 488 men with mCRPC, who
received one or more cycles of 8 MBq 225Ac-PSMA RLT, across 7 international centres [1305]. Patients were
heavily pretreated (docetaxel 66%, cabazitaxel 21%, abiraterone 39%, enzalutamide 39%, ¹⁷⁷Lu-PSMA RLT
32%, and 223Ra-dichloride 4%). The median follow-up was 9.0 months. The median OS was 15.5 months (95%
CI: 13.4–18.3) and median PFS was 7.9 months (CI: 6.8–8.9). In 347 (71%) out of 488 patients, information
regarding treatment-induced xerostomia was available, with 236 (68%) of the 347 patients reporting xerostomia
after the first cycle of 225Ac-PSMA RLT. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients,
leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious AEs or treatment-
related deaths were recorded. This study supports previous data showing that 225Ac-PSMA RLT has a
substantial antitumour effect, being a viable therapy option in heavily pretreated mCRPC patients, including
patients after ¹⁷⁷Lu-PSMA RLT. Comparable results, with a median OS of 15 months (95% CI: 10-19) for a median
follow-up was of 22 months, were reported in a series of patients with mCRPC treated with 225Ac-PSMA (100-
150 kBq/kg at least 2 cycles, at 8 weeks), after becoming resistant to all previous anti-cancer agents [1306]. The
side effect profile remains to be elucidated. So far, 225Ac-PSMA RLT for mCRPC has not been approved.

Combined therapies, including 177Lu-PSMA-RLT, in mCRPC have moved into the focus of clinical research.
In an open-label, multicentre, randomised, phase II trial, EnzaP, participants were randomly assigned (1:1)
between getting oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) 7.5 GBq
¹⁷⁷Lu-PSMA-617 intravenous, every 6–8 weeks, based on a 12-week interim PSMA PET/CT [1307]. The primary
endpoint was PSA PFS. Overall, 83 men were assigned to the enzalutamide plus 177Lu-PSMA-RLT group,
and 79 were assigned to enzalutamide alone. Median PSA PFS was 13.0 months (95% CI: 11.0–17.0) in the
enzalutamide plus RLT group and 7.8 months (95% CI: 4·3–11·0) in the enzalutamide group (HR 0.43, 95%
CI: 0.29–0.63, p < 0·0001). The most common AEs were fatigue (75%), nausea (47%), and dry mouth (40%)
in the enzalutamide plus RLT and fatigue (70%), nausea (27%], and constipation (23%) in the enzalutamide
group. EnzaP suggests that the addition of ¹⁷⁷Lu-PSMA-617 to enzalutamide improved PFS by enhanced
anticancer activity in patients with mCRPC [1307]. The actual benefit of the combined use in particular in
patients pretreated by one or two ARPIs is still to be proven in larger prospective controlled trials and a firm
recommendation would be premature.

6.7.8.3 PARP inhibitors for mCRPC

So far, two PARP inhibitors as monotherapy, olaparib and rucaparib, are licenced by the FDA (EMA only approved
olaparib) and several other PARP inhibitors are under investigation or were approved only in combination with an
ARPI (see section 6.7.6.5 e.g., talazoparib, niraparib).

A randomised phase III trial (PROfound) compared the PARP inhibitor olaparib to an alternative ARPI in mCRPC
with alterations in ≥ 1 of any qualifying gene with a role in HRR and progression on an ARPI. Most patients
were heavily pre-treated with 1–2 chemotherapies and up to 2 ARPIs [273, 1225]. Radiographic PFS by blinded
independent central review in the BRCA1/2 or ATM mutated population (Cohort A) was the first endpoint and
significantly favoured olaparib (HR: 0.49, 95% CI: 0.38–0.63). The final results for OS demonstrated a significant
improvement among men with BRCA1/2 or ATM mutations (Cohort A) (p = 0.0175; HR: 0.69, 95% CI: 0.50–
0.97). This was not significant in men with any (other) HRR alteration (Cohort B) (HR: 0.96, 95% CI: 0.63–1.49).
Of note, patients in the physician’s choice of enzalutamide/abiraterone-arm who progressed, 66% (n = 86/131)
crossed over to olaparib.
The most common AEs were anaemia (46.1% vs. 15.4%), nausea (41.4% vs. 19.2%), decreased
appetite (30.1% vs. 17.7%) and fatigue (26.2% vs. 20.8%) for olaparib vs. enzalutamide/abiraterone. Among
patients receiving olaparib 16.4% discontinued treatment secondary to an AEs, compared to 8.5% of patients
receiving enzalutamide/abiraterone. Interestingly, 4.3% of patients receiving olaparib had a pulmonary
embolism, compared to 0.8% among those receiving enzalutamide/abiraterone, none of which were fatal. There
were no reports of myelodysplastic syndrome or acute myeloid leukaemia. This was the first trial to show a
benefit for genetic testing and precision medicine in mCRPC.

The olaparib approval by the FDA is for patients with deleterious or suspected deleterious germline- or somatic
HRR gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.
The EMA approved olaparib for patients with BRCA1 and BRCA2 alterations [1308]. The recommended olaparib
dose is 600 mg daily (300 mg taken orally twice daily), with or without food.

132 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Rucaparib has been approved by the FDA for patients with deleterious BRCA mutations (germline and/or
somatic) who have been treated with ARPI and a taxane-based chemotherapy [1309]. Approval was based on
the results of the single-arm TRITON2 trial (NCT02952534). The confirmed ORR per independent radiology
review in 62 patients with deleterious BRCA mutations was 43.5% (95% CI: 31–57) [1310]. Rucaparib second line
after ARPI was studied in the TRITON 3 trial and is discussed in section 6.7.7.5

The combination of ARPI plus a PARP inhibitor in first-line mCRPC was studied in several RCT including AAP
plus Olaparib [1226], AAP plus Niraparib [1230] and Enzalutamide plus Talazoparib [1233]. See Table 6.7.2.

6.7.8.4 Sequencing treatment

6.7.8.4.1 ARPI -> ARPI (chemotherapy-naïve mCRPC patients)
The use of sequential ARPIs in mCRPC showed limited benefit in retrospective series as well as in one
prospective trial [1311-1318]. In particular in patients who had a short response to the first ARPI for mCRPC
(< twelve months), this sequence should be avoided because of known cross resistance and the availability of
chemotherapy and PARP inhibitors (if a relevant mutation is present). In the control arm of the contemporary
PSMAfore trial, the ARPI-switch showed an rPFS of 5·59 mo (4.21–5.95) [1284].
In highly selected patients treated for more than 24 weeks with AAP, the sequence with enzalutamide
showed some activity with a median rPFS of 8.1 months (95% CI: 6.1–8.3) and an unconfirmed PSA response
rate of 27% [1239]. In case the patient is unfit for chemotherapy and a PARP inhibitor, best supportive care
should be considered in case no other appropriate treatment option is available (clinical trial or immunotherapy
if MSI-high). An ARPI-ARPI sequence should never be the preferred option but might be considered in such
patients if the PS still allows for active treatment and the potential side effects seem manageable.
First prospective cross-over data on an ARPI-ARPI sequence [1311] and a SR and meta-analysis
suggest that for the endpoints PFS and PSA PFS, but not for OS, abiraterone followed by enzalutamide is the
preferred choice [1319].

6.7.8.4.2 ARPI -> PARP inhibitor

This sequence in patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated
mCRPC is supported by data from the randomised phase III PROfound trial studying olaparib [1225] and TRITON
3 studying rucaparib [1243]. A subgroup of patients in pROfound was pre-treated with one or two ARPIs and no
chemotherapy (35%).
The ARPI-PARP inhibitor sequence versus ARPI-ARPI or ARPI-docetaxel in patients with BRCA 1/
2 (and ATM) altered tumours was studied in TRITON-3 and showed a significant rPFS benefit in favour of the
PARP inhibitor following the first ARPI. These data underscore the importance of early genomic testing in
mCRPC patients. (see also chapter 6.7.7.5)

6.7.8.4.3 Docetaxel for mHSPC -> docetaxel rechallenge

There is limited evidence for second- or third-line use of docetaxel after treatment with docetaxel for mHSPC.
Docetaxel seems to be less active than ARPI at progression to mCRPC following docetaxel for mHSPC [1320].

6.7.8.4.4 ARPI -> docetaxel or docetaxel -> ARPI followed by PARP inhibitor
Both olaparib and rucaparib are active in biomarker-selected mCRPC patients after ARPI and docetaxel in either
sequence [1225, 1309].

6.7.8.4.5 ARPI before or after docetaxel

There is level 1 evidence for both sequences (see Table 6.7.3).

6.7.8.4.6 ARPI –> docetaxel -> cabazitaxel or docetaxel –> ARPI -> cabazitaxel
Both third-line treatment Both third-line treatment sequences are supported by level 1 evidence. Of note, there
is high-level evidence favouring cabazitaxel vs. a second ARPI after docetaxel and one ARPI in particular in
patients progressing ≤ 12 months on a prior ARPI. CARD is the first prospective randomised phase III trial
addressing this question (Table 6.7.3) [1237].

6.7.8.5 Platinum chemotherapy

Cisplatin or carboplatin as monotherapy or combinations have shown limited activity in unselected patients in the
pre-docetaxel era [1321]. The combination of cabazitaxel and carboplatin was evaluated in pre-treated mCRPC
patients in a randomised phase I/II trial. The combination improved the median PFS from 4.5 months (95% CI:
3.5–5.7) to 7.3 months (95% CI: 5.5–8.2; HR: 0.69, 95% CI: 0.50–0.95, p = 0.018) and the combination was well
tolerated [1322]. On a histopathological and molecular level, there is preliminary evidence that platinum adds
efficacy in patients with aggressive variant PCa molecular signatures including TP53, RB1, and PTEN [1323].

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Patients with mCRPC and alterations in DDR genes are more sensitive to platinum chemotherapy than
unselected patients [1324], also after progression on PARP inhibitors. Interestingly, in contemporary
retrospective series, unselected patients as well as patients without DDR gene alterations also showed a 50%
PSA decline when treated with platinum in up to 36% of patients [1297].

In a MA of 23 studies with 901 BRCA-positive mCRPC patients the PSA 50 response rates for PARPi and
platinum were 69% (CI: 53–82%), and 74% (CI: 49–90%), respectively. Analyses of OS data showed no difference
between PARPi and platinum treatments (HR: 0.86; CI: 0.49-1.52; p = 0.6) [1325]. This analysis supports the use
of platinum in patients with BRCA alterations in particular after progression on PARPi or if PARPi are unavailable
or suspended due to AEs

In view of the excellent tolerability of e.g., carboplatin monotherapy, platinum could be offered to patients with
far advanced mCRPC harbouring DDR gene aberrations after having progressed on standard treatment options.
Prospective controlled trials are ongoing.

Table 6.7.1: Randomised phase III controlled trials – nmCRPC

Study Intervention Comparison Selection criteria Main outcomes

ARAMIS ADT + ADT + placebo nmCRPC; baseline 59% reduction of distant
2019, 2020 darolutamide PSA ≥ 2 ng/mL progression or death
[1249, 1326] PSA-DT ≤ 10 mo Median MFS: darolutamide
40.4 vs. placebo 18.4 mo;
31% reduction in risk of death
HR = 0.69 (95% CI: 0.53–0.88)
p = 0.003
PROSPER ADT + ADT + placebo nmCRPC; baseline 71% reduction of distant
2018, 2020 enzalutamide PSA ≥ 2 ng/mL progression or death
[1247, 1327] PSA-DT ≤ 10 mo Median MFS: enzalutamide
36.6 vs. placebo 14.7 months;
27% reduction in risk of death
HR = 0.73 (95% CI: 0.61–0.89)
p = 0.001
SPARTAN ADT + ADT + placebo nmCRPC; baseline 72% reduction of distant
2018, 2021 apalutamide PSA ≥2 ng/mL progression or death
[1248, 1328] PSA-DT ≤ 10 mo Median MFS: apalutamide
40.5 vs. placebo 16.2 months;
22% reduction in risk of death
HR = 0.78 (95% CI: 0.64–0.96)
p = 0.0161
ADT = androgen-deprivation therapy; CI = confidence interval; HR = hazard ratio; MFS = metastasis-free survival;
nmCRPC = non-metastatic castrate-resistent prostate cancer; PSA-DT = prostate-specific antigen doubling time.

Table 6.7.2: Randomised phase III controlled trials - first-line treatment of mCRPC

Study Intervention Comparison Selection criteria Main outcomes

DOCETAXEL
SWOG 99-16 docetaxel/EMP, mitoxantrone, OS: 17.52 vs. 15.6 mo.
2004 [1329] every 3 weeks, every 3 weeks, (p = 0.02, HR: 0.80; 95% CI: 0.67–
60 mg/m2, EMP 12 mg/m2 0.97)
3 x 280 mg/day prednisone 5 mg PFS: 6.3 vs. 3.2 mo.
BID (p < 0.001)

134 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

TAX 327 docetaxel, every mitoxantrone, OS: 19.2 for 3-weekly vs. 17.8 mo.
2004, 2008 3 weeks, 75 mg/ every 3 weeks, 4-weekly and 16.3 in the control
[1260, 1261] m2 prednisone 5 12 mg/m2, group.
mg BID prednisone 5 mg (p = 0.004, HR: 0.79, 95% CI:
or BID 0.67–0.93)
docetaxel,
weekly, 30 mg/
m2 prednisone 5
mg BID
ABIRATERONE
COU-AA-302 abiraterone + placebo + - No previous OS: 34.7 vs. 30.3 mo.
2013, 2014, prednisone prednisone docetaxel (HR: 0.81, p = 0.0033)
2015 [1252, - ECOG 0–1 FU: 49.2 mo. rPFS: 16.5 vs. 8.3
1253, 1330] - PSA or radiographic mo.
progression (p < 0.0001)
- No or mild
symptoms.
- No visceral
metastases
ENZALUTAMIDE
PREVAIL enzalutamide placebo - No previous OS: 32.4 vs. 30.2 mo.
2014 [1255] docetaxel (p < 0.001). FU: 22 mo. (p < 0.001
- ECOG 0–1 HR: 0.71, 95% CI: 0.60–0.84)
- PSA or radiographic rPFS: 20.0 mo. vs. 5.4 mo.
progression HR: 0.186 (95% CI: 0.15–0.23)
- No or mild p < 0.0001)
symptoms
- 10% had visceral
mets
SIPULEUCEL-T
IMPACT 2010 sipuleucel-T placebo - Some with previous OS: 25.8 vs. 21.7 mo.
[1266] docetaxel (p = 0.03 HR: 0.78, 95% CI: 0.61–
- ECOG 0–1 0.98).
- Asymptomatic FU: 34.1 mo. PFS: 3.7 vs. 3.6 mo.
or minimally (no difference)
symptomatic
2006 [1331] sipuleucel-T - ECOG 0–1 OS: 25.9 vs. 21.4 mo.
- No visceral met. (p = 0.1)
- No corticosteroids FU: 36 mo. PFS: 11.7 vs. 10.0 wk.
COMBINATIONS
PROpel [1226, olaparib (300mg placebo + - ECOG 0-1 ibPFS in ITT population: 24.8 vs.
1227] BID) abiraterone + - regardless of HRRm 16.6 mo;
+ abiraterone prednisone (retrospective HR: 0.66; 95% CI: 0.54–0.81; (p =
(1000 mg/d) + testing) 0.001)
prednisone (5 - prior taxane for ibPFS in BRCA+: HR 0.24; 95% CI:
mg BID) mHSPC allowed 0.12- 0.45
OS in ITT population: 42.1 vs. 38.9
mo;
HR 0.81; 0.95% CI: 0.81, 0.67-1.0;
(p= 0,054)OS in BRCA+: HR 0.30;
95% CI: 0.15- 0.59

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 135

MAGNITUDE niraparib placebo + - ECOG 0-1 rPFS (central review) in HRR+:
[1231, 1332] 200 mg/d + abiraterone -A  AP ≤ 4mo allowed 16.5 vs. 13.7 mo
abiraterone (1,000 mg/d plus for mCRPC HR = 0.73; 95% CI: 0.56-0.96;
(1,000 mg/d plus prednisone 5 mg - HRR-biomarker (p = 0.022)
prednisone 5 mg BID) positive cohort rPFS (central review) in BRCA 1/
BID) - prior docetaxel for 2+:
mHSPC allowed rPFS 19.5 versus 10.9 months;
- prior ARPI for HR= 0.55; 95% CI 0.39-0.78;
mHSPC allowed (nominal p= 0.0007)
- prior ARPI for
mCRPC allowed
TALAPRO-2 talazoparib enzalutamide + - ECOG 0-1 rPFS in ITT: NR (27.5-NR) vs. 21.9
[1233, 1240, (0.5mg/d) + placebo - All-comers: HHR mo;
1268] enzalutamide deficient and HRR HR 0.63; 95% CI: 0.51-0.78
160mg/d non-deficient or (p<0.0001);
unknown rPFS in BRCA+:
- prior AAP or HR 0.23; 95% CI: 0.10- 0.53
docetaxel allowed p=0.0002
for mHSPC
BID = twice a day; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; EMP = estramustine;
FU = follow-up; HR = hazard ratio; mets. = metastases; mo = month; ib (imaging based); (r)PFS = (radiographic)
progression-free survival; OS = overall survival; IHC = immunohistochemistry ; HRRm = homologour recombination
repair genes mutation; BRCA+ = BRCA gene mutated; ITT = intention to treat; BICR = blinded independent central
review.

Table 6.7.3: Randomised controlled phase II/III - second-line/third-line trials in mCRPC

Study Intervention Comparison Selection criteria Main outcomes

ABIRATERONE
COU-AA-301 abiraterone + placebo + - Previous docetaxel OS: 15.8 vs. 11.2 mo.
2012 [1277] prednisone HR prednisone - ECOG 0–2 (p < 0.0001, HR: 0.74; 95% CI:
- PSA or radiographic 0.64–0.86; p < 0.0001). FU: 20.2
progression mo.
rPFS: no change
COU-AA-301 OS: 14.8 vs. 10.9 mo.
2011 [1276] (p < 0.001 HR: 0.65; 95% CI:
0.54–0.77).
FU: 12.8 mo.
rPFS: 5.6 vs. 3.6 mo.
Radium-223
ALSYMPCA radium-223 placebo - Previous or no OS: 14.9 vs. 11.3 mo.
2013 [1279] previous docetaxel (p = 0.002, HR: 0.61; 95% CI:
- ECOG 0–2 0.46–0.81).
- Two or more All secondary endpoints show a
symptomatic bone benefit over best SOC.
metastases
- No visceral
metastases
CABAZITAXEL
TROPIC cabazitaxel + mitoxantrone + - Previous docetaxel OS: 318/378 vs. 346/377 events
2013 [1333] prednisone prednisone - ECOG 0–2 (OR: 2.11; 95% CI: 1.33–3.33).
FU: 25.5 months OS ≥ 2 yr. 27%
vs. 16% PFS

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TROPIC OS: 15.1 vs. 12.7 mo.
2010 [1272] (p < 0.0001, HR: 0.70; 95% CI:
0.59–0.83). FU: 12.8 mo.
PFS: 2.8 vs. 1.4 mo.
(p < 0.0001, HR: 0.74, 95% CI:
0.64–0.86)
CARD cabazitaxel ARPI: - Previous docetaxel Med OS 13.6 vs. 11.0 mo.
2019 [1237] (25 mg/m2 Q3W) abiraterone + - Progression ≤ (p = 0.008, HR: 0.64, 95% CI:
+ prednisone prednisone 12 mo. on prior 0.46–0.89).
+ G-CSF OR alternative ARPI rPFS 8.0 vs. 3.7 mo.
Enzalutamide (either before or (p < 0.001, HR: 0.54, 95% CI:
after docetaxel) 0.40–0.73).
FU: 9.2 mo.
ENZALUTAMIDE
AFFIRM enzalutamide Placebo - Previous docetaxel. OS: 18.4 vs. 13.6 mo.
2012 [1278] - ECOG 0–2. (p < 0.001, HR: 0.63; 95% CI:
0.53–0.75).
FU: 14.4 mo.
rPFS: 8.3 vs. 2.9 mo.
(HR: 0.40; 95% CI: 0.35–0.47,
p < 0.0001).
PARP inhibitor
PROfound olaparib abiraterone + - Previous ARPI, rPFS: 7.39 vs. 3.55 mo.
2020 [273, prednisolone alterations in HRR (p < 0.0001, HR: 0.34; 95% CI:
1225, 1288] or enzalutamide; genes 0.25–0.47), conf. ORR 33.3% vs.
cross-over 2.3% (OR 20.86, 95%
allowed at CI: 4.18–379.18).
progression OS: 19.1 mo vs. 14.7 mo
(in patients with BRCA1/2, ATM
alterations)
(p = 0.0175; HR 0.69; 95% CI:
0.5–0.97).
TRITON-3 rucaparib docetaxel or - EOCG 0-1 rPFS: ITT 10.2 mo vs. 6.4 mo,
[1243] (600 mg BID) abiraterone - Previous one ARPI (HR 0.61; 95% CI, 0.47 to 0.80; p <
acetate or - BRCA 1/2 or ATM 0.001 for both comparisons)
enzalutamide alteration
Radioligand therapy
VISION 177Lu-PSMA-617 SOC alone - Previous at least 1 Imaging-based PFS: 8.7 vs. 3.4
2021 [1302] SOC ARPI and one or two mo.
taxane regimens; (p < 0.001; HR 0.40; 99.2% CI:
- Mandatory: PSMA- 0.29–0.57)
positive gallium-68 OS: 15.3 vs. 11.3 mo. (p < 0.001;
(68Ga)–labelled HR 0.62; 95% CI: 0.5–0.74)
PSMA-PET scan
TheraP 177Lu-PSMA-617 177Lu-PSMA-617 - Post docetaxel, First endpoint PSA reduction of
2021 [1299, (8.5 GBq 1:1 - Suitable for > 50%:
1300] i.v.q 6-weekly, randomisation cabaziaxel 66 vs. 37 PSA responses; 66% vs.
decreasing cabazitaxel (20 37% by ITT; difference 29% (95%
0.5 GBq/cycle; mg/m2 i.v.q CI: 16–42; p < 0.0001; and 66%
up to 6 cycles) 3-weekly, up to vs. 44% by treatment received;
10 cycles) difference 23% [9–37];
p = 0.0016).
Secondary endpoint OS:
19.1 vs. 19.6 mo (177Lu-PSMA vs.
cabazitaxel).
HR: 0.97, 95% CI: 0.7-1.4 (p = 0.99)

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PSMAfore 177Lu-PSMA-617 177Lu-PSMA-617 - One previous ARPI First endpoint: rPFS 3rd data-cut-
2023 [1284] at a dosage of 1:1 for mCRPC off :
7·4 GBq (200 randomisation - No previous taxane 11·60 mo (95% CI 9·30–14·19)
mCi) ± 10%; to ARPI- change in CRPC or HSPCb vs 5·59 mo (4·21–5·95) (HR 0·49
6 cycles (abiraterone or [95% CI 0·39–0·61])
enzalutamide)
*Only studies reporting survival outcomes as primary endpoints have been included.
ARPI = androgen receptor pathway inhibitor; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group;
FU = follow-up; GBq = gigabecquerel; HR = hazard ratio; Lu = lutetium; mo = months OS = overall survival; OR =
odds ratio; ORR = objective response rate; PSA = prostate-specific antigen; PSMA = prostatespecific membrane
antigen; (r)PFS = (radiographic) progression-free survival; SOC = standard of care; yr = year; HRR= homologous
recombination repair.

6.7.9 Monitoring of treatment

Baseline examinations should include a medical history, clinical examination as well as baseline blood
tests (PSA, total testosterone level, full blood count, renal function, baseline liver function tests, alkaline
phosphatase), bone scan and CT of chest, abdomen and pelvis [1334, 1335]. The use of choline or PSMA PET/
CT scans for progressing CRPC is unclear and most likely not as beneficial as for patients with BCR or hormone-
naive disease. Flares, PSMA upregulation and discordant results compared with PSA response or progression
on ARPI have been described [1336]. Prostate-specific antigen alone is not reliable enough [1337] for monitoring
disease activity in advanced CRPC since visceral metastases may develop in men without rising PSA [1338].
Instead, the PCWG2 recommends a combination of bone scintigraphy and CT scans, PSA measurements
and clinical benefit in assessing men with CRPC [1218]. A majority of experts at the 2015 Advanced Prostate
Cancer Consensus Conference (APCCC) suggested regular review and repeating blood profile every two
to three months with bone scintigraphy and CT scans at least every six months, even in the absence of a
clinical indication [1334]. This reflects that the agents with a proven OS benefit all have potential toxicity and
considerable cost and patients with no objective benefit should have their treatment modified. The APCCC
participants stressed that such treatments should not be stopped for PSA progression alone. Instead, at least
two of the three criteria (PSA progression, radiographic progression and clinical deterioration) should be fulfilled
to stop treatment. For trial purposes, the updated PCWG3 put more weight on the importance of documenting
progression in existing lesions and introduced the concept of no longer ‘clinically benefiting‘ to underscore the
distinction between first evidence of progression and the clinical need to terminate or change treatment [1218].
These recommendations also seem valid for clinical practice outside trials.

6.7.10 When to change treatment

The timing of treatment change for men with metastatic prostate cancer remains a matter of debate in although
it is clearly advisable to start or change treatment immediately in men with symptomatic progressing metastatic
disease. Preferably, any treatment change should precede development of de novo symptoms or worsening of
existing symptoms. Although, the number of effective treatments is increasing, head-to-head comparisons are
still rare, as are prospective data assessing the sequencing of available agents. Therefore it is not clear how
to select the most appropriate ‘second-line‘ treatment, in particular in patients without HRR alterations or other
biomarkers. A positive example, however, is the CARD trial which clearly established cabazitaxel as the better
third-line treatment in docetaxel pre-treated patients after one ARPI compared to the use of a second ARPI
[1237].
The ECOG PS has been used to stratify patients. Generally men with a PS of 0–1 are likely to
tolerate treatments and those with a PS of > 2 are less likely to benefit. However, it is important that treatment
decisions are individualised, in particular when symptoms related to disease progression are impacting on PS.
In such cases, a trial of active life-prolonging agents to establish if a given treatment will improve the PS may
be appropriate. Sequencing of treatment is discussed in the summary papers published following the 2019 and
2022 APCCC Conferences [1339, 1340].

6.7.11 Symptomatic management in metastatic castration-resistant prostate cancer

Castration-resistant PCa is usually a debilitating disease often affecting the elderly male. A multidisciplinary
approach is required with input from urologists, medical oncologists, radiation oncologists, nurses,
psychologists and social workers [1339, 1341]. Critical issues of palliation must be addressed when considering
additional systemic treatment, including management of pain, constipation, anorexia, nausea, fatigue and
depression.

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6.7.11.1 Common complications due to bone metastases
Most patients with CRPC have painful bone metastases. External beam RT is highly effective, even as a single
fraction [1342, 1343]. A single infusion of a third-generation bisphosphonate could be considered when RT is
not available [1344]. Common complications due to bone metastases include vertebral collapse or deformity,
pathological fractures and spinal cord compression. Cementation can be an effective treatment for painful
spinal fracture whatever its origin, clearly improving both pain and QoL [1345]. It is important to offer standard
palliative surgery, which can be effective for managing osteoblastic metastases [1346, 1347]. Impending spinal
cord compression is an emergency. It must be recognised early and patients should be educated to recognise
the warning signs. Once suspected, high-dose corticosteroids must be given and MRI performed as soon as
possible. A systematic neurosurgery or orthopaedic surgeon consultation should be planned to discuss a
possible decompression, followed by EBRT [1348]. Otherwise, EBRT with, or without, systemic therapy, is the
treatment of choice.

6.7.11.2 Preventing skeletal-related events

6.7.11.2.1 Bisphosphonates
Zoledronic acid has been evaluated in mCRPC to reduce skeletal-related events (SRE). This study was
conducted when no active anti-cancer treatments, but for docetaxel, were available. Six hundred and forty three
patients who had CRPC with bone metastases were randomised to receive zoledronic acid, 4 or 8 mg every three
weeks for fifteen consecutive months, or placebo [1349]. The 8 mg dose was poorly tolerated and reduced to
4 mg but did not show a significant benefit. However, at fifteen and 24 months of follow-up, patients treated with
4 mg zoledronic acid had fewer SREs compared to the placebo group (44 vs. 33%, p = 0.021) and in particular
fewer pathological fractures (13.1 vs. 22.1%, p = 0.015). Furthermore, the time to first SRE was longer in the
zoledronic acid group. No survival benefit has been seen in any prospective trial with bisphosphonates.

6.7.11.2.2 RANK ligand inhibitors

Denosumab is a fully human monoclonal antibody directed against RANKL (receptor activator of nuclear factor
κ-B ligand), a key mediator of osteoclast formation, function, and survival. In M0 CRPC, denosumab has been
associated with increased bone-MFS compared to placebo (median benefit: 4.2 months, HR: 0.85, p = 0.028)
[1342]. This benefit did not translate into a survival difference (43.9 compared to 44.8 months, respectively) and
neither the FDA or the EMA have approved denosumab for this indication [1350].
The efficacy and safety of denosumab (n = 950) compared with zoledronic acid (n = 951) in patients
with mCRPC was assessed in a phase III trial. Denosumab was superior to zoledronic acid in delaying or
preventing SREs as shown by time to first on-study SRE (pathological fracture, radiation or surgery to bone, or
spinal cord compression) of 20.7 vs. 17.1 months, respectively (HR: 0.82, p = 0.008). Both urinary N-telopeptide
and bone-specific alkaline phosphatase were significantly suppressed in the denosumab arm compared with
the zoledronic acid arm (p < 0.0001 for both). However, these findings were not associated with any survival
benefit and in a post-hoc re-evaluation of endpoints, denosumab showed identical results when comparing SREs
and symptomatic skeletal events [1351].

The potential toxicity (e.g., osteonecrosis of the jaw, hypocalcaemia) of these drugs must always be kept in
mind (5–8.2% in M0 CRPC and mCRPC, respectively) [1352, 1353]. Patients should have a dental examination
before starting therapy as the risk of jaw necrosis is increased by several risk factors including a history
of trauma, dental surgery or dental infection [1354]. Also, the risk for osteonecrosis of the jaw increased
numerically with the duration of use in a pivotal trial [1355] (one year vs. two years with denosumab), but this
was not statistically significant when compared to zoledronic acid [1350]. According to the EMA, hypocalcaemia
is a concern in patients treated with denosumab and zoledronic acid. Hypocalcaemia must be avoided by
adequate intake of calcium and vitamin D before initiating therapy [1356]. Hypocalcaemia should be identified
and prevented during treatment with bone protective agents (risk of severe hypocalcaemia is 8% and 5% for
denosumab and zoledronic acid, respectively) [1353]. Serum calcium should be measured in patients starting
therapy and monitored during treatment, especially during the first weeks and in patients with risk factors for
hypocalcaemia or on other medication affecting serum calcium. Daily calcium (> 500 mg) and vitamin D (> 400
IU equivalent) are recommended in all patients, unless in case of hypercalcaemia [1353, 1357, 1358].

6.7.12 Summary of evidence and recommendations for life-prolonging treatments of castrate-resistant

disease

Summary of evidence LE
Treatment for mCRPC will be influenced by which treatments patients have already been exposed to. 4

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Recommendations Strength rating
Ensure that testosterone levels are confirmed to be < 50 ng/dL before diagnosing castrate- Strong
resistant PCa (CRPC).
Counsel, manage and treat patients with metastatic CRPC (mCRPC) in a multidisciplinary Strong
team.
Treat patients with mCRPC with life-prolonging agents. Strong
Offer mCRPC patients somatic and/or germline molecular testing as well as testing for Strong
mismatch repair deficiencies or microsatellite instability.

6.7.13 Recommendations for systemic treatments of castrate-resistant disease

Summary statement for mCRPC first line combination therapy:

The combination of ARPI plus PARP inhibitors showed a significant rPFS benefit in RCTs for unselected patients.
However, this benefit is mainly driven by HRR- and even more pronounced by BRCA 1/2- altered patients. So
far, no clear OS benefit was seen, and the side effects of PARP inhibitors add substantial toxicity to ARPI
monotherapy. Therefore, no recommendation is given for patients without HRR or BRCA 1/2 -mutations and the
data will be re-evaluated after longer follow-up.

Recommendations Strength rating

Base the choice of treatment on the performance status (PS), symptoms, co-morbidities, Strong
location and extent of disease, genomic profile, patient preference, and on previous
treatment for hormone-sensitive metastatic PCa (mHSPC) (alphabetical order: abiraterone,
cabazitaxel, docetaxel, enzalutamide, 177lutetium-PSMA-617-radioligand therapy, radium-223,
sipuleucel-T, and for patients with DNA homologous recombination repair (HRR) alterations
olaparib, olaparib/abiraterone, niraparib/abiraterone, rucaparib, talazoparib/enzalutamide).
Avoid sequencing of androgen receptor targeted agents. Strong
Offer chemotherapy to patients previously treated with abiraterone or enzalutamide. Strong
Offer patients with metastatic castrate-resistant PCa (mCRPC) who are candidates for Strong
cytotoxic therapy and are chemotherapy naïve docetaxel with 75 mg/m2 every three weeks.
Offer patients previously untreated for mCRPC and harbouring an HRR or BRCA mutation Strong
abiraterone in combination with olaparib if the patient is fit for both agents and did not
previously receive an ARPI.
Offer patients previously untreated for mCRPC and harbouring a BRCA mutation abiraterone Strong
in combination with niraparib if the patient is fit for both agents and did not previously receive
an ARPI.
Offer patients previously untreated for mCRPC and harbouring an HRR-mutation Strong
enzalutamide in combination with talazoparib if the patient is fit for both agents and did not
previously receive an ARPI.
Offer poly(ADP-ribose) polymerase (PARP) inhibitors to pre-treated mCRPC patients with Strong
relevant DNA repair gene mutations.
Offer patients with mCRPC and progression following docetaxel chemotherapy further Strong
life-prolonging treatment options, which include abiraterone, cabazitaxel, enzalutamide,
radium-223 and olaparib in case of DNA HRR alterations.
Base further treatment decisions of mCRPC on PS, previous treatments, symptoms, Strong
co-morbidities, genomic profile, extent of disease and patient preference.
Offer abiraterone or enzalutamide to patients previously treated with one or two lines of Strong
chemotherapy.
Offer cabazitaxel to patients previously treated with docetaxel. Strong
Offer cabazitaxel to patients previously treated with docetaxel who have progressed within Strong
twelve months of treatment with abiraterone or enzalutamide for mCRPC.
Offer 177Lu-PSMA-617 to pre-treated mCRPC patients with one or more metastatic lesions, Strong
highly expressing PSMA (exceeding the uptake in the liver) on the diagnostic radiolabelled
PSMA PET/CT scan.

140 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

6.7.14 Guideline for non-metastatic castrate-resistant disease

Recommendation Strength rating

Offer apalutamide, darolutamide or enzalutamide to patients with M0 CRPC and a high risk Strong
of developing metastasis (PSA-DT < 10 months) to prolong time to metastases and overall
survival.

Figure 6.4: Treatment non-metastasized (M0) – asymptomatic disease

* Rule of thumb: Life expectancy ten years.

** Recommendation based on clinical staging using digital rectal examination, not imaging.
*** Recommendation based on staging using combination of bone scan and CT.
**** See text, dependent on GG and (biopsy) volume.

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1 EBRT:IMRT/VMAT + IGRT of the prostate.
= weak recommendation.
ADT = androgen deprivation therapy; EBRT =external beam radiotherapy; ECE = extracapsular extension; ePLND =
extended pelvic lymph node dissection; GG = grade group; HDR = high-dose rate; IDC = intraducal carcinoma; IGRT
= image-guided radiotherapy; IMRT = intensity-modulated radiotherapy; LDR = low-dose rate; VMAT = volumetric
modulated arc therapy.

Figure 6.5: Treatment of metastasized (M1*) – disease, M+HSPC

Adding EBRT 1 on the primary

(If no previous local therapy)

tumour

* Based on staging using combination of bone scan and CT.

** Alphabetical order.
***not for low volume, metachronous disease.
1 EBRT: IMRT/VMAT + IGRT of the prostate (equivalent of up to 72 Gy in 2 Gy fractions).

= weak recommendation.
EBRT = external beam radiotherapy; IGRT = image-guided radiotherapy; IMRT = intensity-modulated radiotherapy.
#Note: Please be aware that the various options in the following flowcharts present a generalised approach only,
and cannot take the management of individual patients into account, nor the availability of resources.

142 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

7. FOLLOW-UP
The rationale for following up patients is to assess immediate- and long-term oncological results, to ensure
treatment compliance and allow initiation of further therapy, when appropriate. In addition, follow-up allows
monitoring of side effects or complications of therapy, functional outcomes and an opportunity to provide
psychological support to PCa survivors, all of which is covered in Chapter 8.
For patients the most critical aspect of PCa is the diagnosis, the ensuing treatment, and follow-up.
These must be discussed between the patient and the clinician to make a shared-decision on the treatment and
the planned follow-up, including modalities, periodicity and how this will be communicated to the patient. The
patient must be prepared for different potential outcomes of the follow-up, e.g., PSA levels, and what to expect
from these. Otherwise, even a very small increase in PSA levels can cause unnecessary fear, even panic.

7.1 Watchful waiting

Watchful waiting refers to conservative management for patients deemed unsuitable for curative treatment from
the outset. Patients are clinically ‘watched’ for the development of local or systemic progression with (imminent)
disease-related complaints, at which stage they are then treated palliatively according to their symptoms in
order to maintain QoL (see section 6.2.1.)

7.2 Active surveillance strategy

Patients included in an AS programme should be monitored according to the recommendations presented in
section 6.2.3.1.

7.3 Follow-up: After local treatment with curative intent

7.3.1 Definition
Local treatment is defined as RP or RT, either by IMRT plus IGRT or LDR- or HDR-BT, or any combination of these,
including neoadjuvant and adjuvant hormonal therapy. Unestablished alternative treatments such as HIFU,
cryosurgery and focal therapy options do follow the general principles as presented in this section. In general, a
confirmed rising PSA is considered a sign of disease recurrence.

7.3.2 Why follow-up?

The first post-treatment clinic visit focuses on detecting treatment-related complications and assisting patients
in coping with their new situation, as well as providing information on the pathological analysis. Men with PCa
are at increased risk of depression and attention for mental health status is required [1359, 1360]. Tumour or
patient characteristics may prompt changing the follow-up schedule. Follow-up also allows the introduction of
additional/salvage treatments that should be considered necessary in light of the anticipated life-expectancy,
patients symptoms and EAU risk categories for biochemical recurrence (see 6.1 and Table 4.3).

7.3.3 How to follow-up?

The procedures indicated at follow-up visits vary according to the clinical situation. A disease-specific history
is mandatory at every follow-up visit and includes psychological aspects, signs of disease progression, and
treatment-related complications. Evaluation of treatment-related complications in the post-treatment period is
highlighted in section 8.2. The examinations used for cancer-related follow-up after curative surgery or RT are
discussed below.

7.3.3.1 Prostate-specific antigen monitoring

Measurement of PSA is the cornerstone of follow-up after local treatment. While PSA thresholds depend on the
local treatment used, PSA recurrence almost always precedes clinical recurrence [1361, 1362]. The key question
is to establish when a PSA rise is clinically significant since not all PSA increases have the same clinical value
(see section 6.4.2) [933]. No prospective studies are available on the optimal timing for PSA testing and the
impact on oncological outcomes.

7.3.3.1.1 Prostate-specific antigen monitoring after radical prostatectomy

Following RP, the PSA level is expected to be undetectable. Biochemical recurrence is any rising PSA after
prostatectomy as defined in section 6.3.6. Prostate-specific antigen level is expected to be undetectable two
months after a RP [1363]. Prostate-specific antigen is generally determined every six months until three years
and yearly thereafter but the evidence for a specific interval is low [551] and mainly based on the observation
that early recurrences are more likely to be associated with more rapid progression [933, 1364, 1365]. A rising
PSA may occur after longer intervals up to 20 years after treatment and depends on the initial risk group [879].
A yearly PSA after three years is considered adequate considering the fact that a longer interval to BCR is
correlated with a lower EAU-BCR risk score but around 50% of recurrence should be expected beyond 3 years,

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follow-up should be terminated if life expectancy drops < 10 years. As mentioned in Section 6.4.2 no definitive
threshold can be given for relapse after RP. Persistently measurable PSA in patients treated with RP is discussed
in section 6.3.6.

Ultrasensitive PSA assays remain controversial for routine follow-up after RP. Men with a PSA nadir < 0.01 ng/
mL have a high (96%) likelihood of remaining relapse-free within two years [1366]. In addition, post-RP PSA
levels > 0.01 ng/mL in combination with clinical characteristics such as ISUP GG and surgical margin status
may predict PSA progression and can be useful to establish follow-up intervals [1365]. However, up to 86% of
men were reported to have PSA values below 0.2 ng/mL at five years after an initial PSA nadir below 0.1 ng/mL
within six months after surgery [1367].

7.3.3.1.2 Prostate-specific antigen monitoring after radiotherapy

Following RT, PSA drops more slowly as compared to post RP. A PSA nadir < 0.5 ng/mL is associated with a
favourable outcome after RT although the optimal cut-off value remains controversial [1368]. The interval before
reaching the PSA nadir can be up to three years, or more. At the 2006 RTOG-ASTRO Consensus Conference the
Phoenix definition of radiation failure was proposed to establish a better correlation between definition and
clinical outcome (mainly metastases), namely, an increase of 2 ng/mL above the post-treatment PSA nadir
[954]. This definition also applies to patients who received ADT [954].

7.3.3.2 Digital rectal examination

Local recurrence after curative treatment is possible without a concomitant rise in PSA level although very rarely
[1369]. This has only been proven in patients with unfavourable undifferentiated tumours. Prostate specific
antigen and DRE comprise the most useful combination for first-line examination in follow-up after RT but the
role of DRE was questioned since it failed to detect any local recurrence in the absence of a rising PSA in a series
of 899 patients [1370]. In a series of 1,118 prostatectomy patients, no local histologically proven recurrence was
found by DRE alone and PSA measurement may be the most efficient test needed after RP [1371, 1372].

7.3.3.3 Transrectal ultrasound, bone scintigraphy, CT, MRI and PET/CT

Imaging techniques have no place in routine follow-up of localised PCa as long as the PSA is not rising. Imaging
is only justified in patients for whom the findings will affect treatment decisions, either in case of BCR or in
patients with symptoms (see section 6.4.4.3 for a more detailed discussion).

7.3.3.4 Functional follow-up

All local treatments for PCa may cause short- and long-term side effect of various degree that will affect the
patients’ QoL. For quality control, and in order to help the patient in choosing the optimal treatment for him, it
is essential that the functional outcomes of any treatment given is measured and registered by validated and
reproducible methods. In order to address side effects and their impact of QoL specific tools or ‘patient-reported
outcome measures’ (PROMs) have been developed and validated for men with PCa. These questionnaires
assess common issues after PCa diagnosis and treatment and generate scores which reflect the impact on
perceptions of HRQoL. For further discussion on this see section 8.3.

7.3.4 How long to follow-up?

Most patients who fail treatment for PCa do so within seven years after local therapy [1373]. Patients should be
followed more closely during the initial post-treatment period when risk of failure is highest. PSA measurement,
disease-specific history and DRE (if considered) are recommended every six months until three years and then
annually. Whether follow-up should be stopped if PSA remains undetectable (after RP) or stable (after RT)
remains an unanswered question, but it seems fair that follow-up is only done to the point that if a recurrence is
found the patient is fit enough for salvage therapy.
Risk assessment to predict metastases-free and PCa-specific survival after recurrence after primary
treatment may guide individual decisions on a need for longer follow-up [884, 933, 1374]. Even in men with a
PSA-DT less than ten months after RP who choose to defer treatment, a median MFS of 192 months and OS of
204 months from RP was observed, indicating the relatively long disease-free intervals observed in men with a
rising PSA after local treatment [1375].
Symptomatic recurrence without a PSA rise is extremely rare; however, the symptoms typical for
recurrent disease may vary and are poorly defined by published data. In case of the following symptoms PSA
testing should be performed to exclude a possible cancer recurrence in particular in men not followed up by
regular testing of their PSA levels: pelvic/skeletal pain, haematuria, progressive LUTS, progressive lower body
oedema, progressive bowel complaints or complaints of fatigue, sarcopenia or unexplained weight loss [1376].

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7.3.5 Summary of evidence and recommendations for follow-up after treatment with curative intent

Summary of evidence LE
A detectable PSA, indicating a relapse of the disease, must be differentiated from a clinically 3
meaningful relapse. The PSA threshold that best predicts further metastases after RP is > 0.4 ng/mL
and > NADIR + 2 ng/mL after IMRT/VMAT plus IGRT (± ADT].

Recommendations Strength rating

Routinely follow-up asymptomatic patients by obtaining at least a disease-specific history Strong
and a prostate-specific antigen measurement.
At recurrence, only perform imaging if the result will affect treatment planning. Strong

7.4 Follow-up: During first line hormonal treatment (androgen sensitive period)
7.4.1 Introduction
Androgen deprivation therapy is used in various situations: combined with RT for localised or locally-advanced
disease, as monotherapy for a relapse after a local treatment, or in the presence of metastatic disease often in
combination with other treatments. All these situations are based on the benefits of testosterone blockage or
suppression either by drugs (LHRH agonists or antagonists) or orchidectomy. In the majority of patients with
metastatic PCa, castrate resistance will develop, defined as PCa progression despite a testosterone level < 50
ng/dL during maintained ADT, which is usually maintained during the entire mHSPC and mCRPC phases.
This section addresses the general principles of follow-up of patients on ADT alone. Section 6.5.3
includes further information on other drug treatments. Furthermore, the specific follow-up needed for every
single drug is outside the scope of this text, as is follow-up after chemotherapy.
To detect disease- and treatment-related complaints, regular clinical follow-up is mandatory and
cannot be replaced by imaging or laboratory tests alone.

7.4.2 Purpose of follow-up

The main objectives of follow-up in patients receiving ADT are to ensure treatment compliance, to monitor
treatment response, to detect side effects early, and to guide treatment at the time point of clinical progression.
After the initiation of ADT, it is recommended that patients are evaluated every three to six months. This must
be individualised and each patient should be advised to contact his physician in the event of troublesome
symptoms. This is even more important for patients who receive a combination of ADT and other potent
medication, e.g., ARPI where the frequency of follow-up is monthly for the first three months, for their disease.

7.4.3 General follow-up of men on ADT

Patients under ADT require regular follow-up, including monitoring of serum testosterone, creatinine, liver
function and metabolic parameters at three to six month intervals. Men on ADT can experience toxicity
independent of their disease stage. Androgen deprivation therapy induced bone density loss increases the risk
of fractures [1377]. Therefore, assessment of bone density before and during treatment with ADT with or without
a combination with other drugs is essential.
As the consequences of ADT are so varying, a structured follow-up including lab results, radiology
and QoL, may be of value both for the patient and for the treating physician [1378].

7.4.3.1 Testosterone monitoring

Testosterone monitoring should be considered standard clinical practice in men on ADT. Many men receiving
medical castration will achieve a castrate testosterone level (< 20 ng/dL), and most a testosterone level < 50
ng/dL. However, approximately 13–38% of patients fail to achieve these levels and up to 24% of men may
experience temporary testosterone surges (testosterone > 50 ng/dL) during long-term treatment [1363] referred
to as ‘acute on-chronic effect’ or ‘breakthrough response’ [1379]. Breakthrough rates for the < 20 ng/dL threshold
were found to be more frequent (41.3%) and an association with worse clinical outcomes was suggested [1379].
The timing of measurements is not clearly defined. A three to six month testosterone level
assessment has been suggested to ensure castration is achieved (especially during medical castration) and
maintained. In case a castrate testosterone level is not reached, switching to another agonist or antagonist or
to an orchiectomy should be considered. In patients with a confirmed rising PSA and/or clinical progression,
serum testosterone must be evaluated in all cases to confirm a castration-resistant state. Ideally, suboptimal
testosterone castrate levels should be confirmed with an appropriate assay [1380, 1381]. After ADT cessation
(intermittent treatment or temporary ADT use as with EBRT) testosterone recovery is dependent on patients age
and the duration of ADT [1382, 1383].

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7.4.3.2 Liver function monitoring
Liver function tests will detect treatment toxicity (especially applicable for NSAA), but rarely indicate disease
progression. Men on combined ADT should have their transaminase levels checked at least yearly but in
particular in the first six months of treatment initiation since liver function disorders were observed relatively
early in the majority of patients in larger trials [1384]. In view of potential liver toxicity a more frequent check is
needed with some drugs (including abiraterone acetate) [1385].

7.4.3.3 Serum creatinine and haematological parameters

Estimated glomerular filtration rate monitoring is good clinical practice as an increase may be linked to ureteral
obstruction or bladder retention. A decline in haemoglobin is a known side effect of ADT. A significant decline
after three months of ADT is independently associated with shorter progression-free and OS rates and might
explain significant fatigue although other causes should be considered [1386]. Anaemia is often multi-factorial
and other possible aetiologies should be excluded. An early decrease in haemoglobin three months after
ADT initiation predicted better survival whereas a decrease beyond six months was associated with poor
outcome in the SPCG-5 population [1387]. Radiotherapy to extensive bone metastases locations may result in
myelosuppression and haematological toxicity [1388, 1389].

7.4.3.4 Monitoring of metabolic complications

The most severe complications of androgen suppression are metabolic syndrome, cardiovascular morbidity,
mental health problems, and bone resorption (see Section 8.2.5).

All patients should be screened for diabetes by checking fasting glucose and HbA1c (at baseline and routinely)
in addition to checking blood lipid levels. Men with impaired glucose tolerance and/or diabetes should be
referred for an endocrine consultation. Prior to starting ADT an ECG should be done. A cardiology consultation
is recommended, as a minimum, in men with a history of cardiovascular disease and depending on the
combination drug planned also an ECHO. Men on ADT are at increased risk of cardiovascular problems and
hypertension and regular checks are required [1390]. More profound androgen ablation resulted in a higher
cardiovascular toxicity [1391] and cardio-respiratory fitness decreased even after six months of ADT [1392].

7.4.3.5 Monitoring bone problems

Androgen deprivation therapy increases the risk of osteoporosis. A combination of ADT with apalutamide,
darolutamide, enzalutamide, abiraterone plus prednisone or docetaxel increases the fracture risk even more
[1179, 1393, 1394]. Administration of ADT for more than a year, as compared to less than one year, showed
a higher risk of osteoporosis (HR: 1.77 and 1.38, respectively) [1395]. Several scores (e.g., Fracture Risk
Assessment Tool [FRAX score], Osteoporosis Self-Assessment Tool [OST], Osteoporosis Risk Assessment
Instrument [ORAI], Osteoporosis Index of Risk [OSIRIS], Osteoporosis Risk Estimation [SCORE]) can help identify
men at risk of osteoporotic complications but validation of these scores in the ADT setting is required (see
section 8.3.2.2) [1285, 1396, 1397].
Vitamin D and calcium levels should be regularly monitored when patients receive ADT and patients
should be supplemented if needed (see Section 8.3.2.2).

Routine bone monitoring for osteoporosis should be performed at the start of ADT using dual emission X-ray
absorptiometry (DEXA) scan [1286, 1398, 1399]. Presence of osteoporosis should prompt the use of bone
protective agents. The criteria for initiation of bone protective agents are mentioned in Section 8.3.2.2. If no
bone protective agents are given, a DEXA scan should be done regularly, at least every two years [1400].
A review summarising the incidence of bone fractures showed an almost doubling of the risk of
fractures when using ADT depending on patients’ age and duration and type of ADT with the highest incidence in
older men and men on additional novel ARPI medication across the entire spectrum of disease [1401]. In case of
an osteoporotic fracture a bone protective agent is mandatory.

7.4.3.6 Monitoring lifestyle, cognition, fatigue and sexual function

Lifestyle (e.g., diet, exercise, smoking status, etc.) affects QoL and potentially outcome [1402]. During follow-
up men should be counselled on the beneficial effects of exercise to decrease ADT-related toxicity [1403].
Androgen deprivation therapy may affect mental and cognitive health and men on ADT are three times more
likely to report depression [1404]. Attention to mental health should therefore be an integral part of the follow-up
scheme. Men on ADT may experience complaints of fatigue possibly related to systemic inflammation [1405].
Reduced cognitive performance and fatigue may arise within six months after initiation of ADT but can improve
over time [1406]. Another aspect of starting ADT is that it leads to sexual dysfunction, causing > 80% of couples
to cease sexual activity completely. This aspect affects patients as well as their partners and couple counselling
should be considered [1407].

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7.4.4 Methods of follow-up in men on ADT without metastases
7.4.4.1 Prostate-specific antigen monitoring
Prostate-specific antigen is a key marker for following the course of androgen-sensitive non-metastasized PCa.
Imaging should be considered when PSA is rising > 2 ng/mL or in case of symptoms suggestive of metastasis.

7.4.4.2 Imaging
The choice of imaging modality is between PSMA-PET/CT, with higher sensitivity, and conventional imaging with
CT or MRI and bone-scan on which almost all clinical studies and guideline recommendations are based (see
section 5.8). Next generation imaging with its higher sensitivity may detect progression earlier. Imaging should
be scheduled regularly, also in asymptomatic patients with stable PSA, as the earlier recommendation that
asymptomatic patients with a stable PSA level do not require further imaging may no longer hold true. This is
especially true in patients with aggressive variants when PSA levels may not reflect tumour progression [1408].
New bone pain requires at least targeted imaging and potentially a bone scan. When PSA progression suggests
CRPC status and treatment modification is considered, imaging, by means of a bone and CT scan, is currently
recommended for restaging.

7.4.5 Methods for follow-up in men under ADT for hormone-sensitive metastatic PCa
In metastatic patients it is of the utmost importance to counsel about early signs of spinal cord compression,
urinary tract complications (ureteral obstruction, bladder outlet obstruction) or bone lesions that are at an
increased fracture risk. Since most men will receive another anti-cancer therapy combined with ADT such as
ARPI, chemotherapy, local RT, or combinations, follow-up frequency should also be dependent on the treatment
modality. A secondary analysis of the Titan study found that nearly half of the patients developing subsequent
radiographic progression had no concomitant PSA progression, suggesting that heavy reliance on PSA
monitoring may be inadequate for assessing disease activity in this context [1180]. The specific points related
to follow-up during the castrate-resistant situation are detailed in section 6.7.9.

7.4.5.1 PSA monitoring

In men on ADT alone, a PSA decline to < 4 ng/mL suggests a likely prolonged response and follow-up visits
may be scheduled every three to six months provided the patient is asymptomatic or clinically improving. This
applied to men on ADT monotherapy as well as after ADT plus docetaxel [1155]. Depending on symptoms
and risk assessment, more frequent visits may be indicated. Treatment response may be evaluated based on
a change in serum PSA level [1154, 1155] and bone- and CT scan, although there is no consensus about how
frequently these should be performed [1339]. A rise in PSA level usually precedes the onset of clinical symptoms
by several months. A rising PSA should prompt assessment of testosterone level, which is mandatory to define
CRPC status, as well as restaging using imaging. However, it is now recognised that a stable PSA during ADT
is not enough to characterise a non-progressive situation [1409]. During the combination treatment with ADT
and ARPI treatment, reliance on PSA without regular imaging might miss early detection of progressive PCa as
a secondary analysis of the Titan study found that nearly half of patients developing subsequent radiographic
progression had no concomitant PSA [1180].

7.4.5.2 Imaging as a marker of response in metastatic PCa

Treatment response in soft-tissue metastases can be assessed by morphological imaging methods using the
Response Evaluation Criteria in Solid Tumours (RECIST) criteria. However, these criteria cannot be used for bone
metastases where response assessment is difficult [1410, 1411].
When bone scan is used to follow bone metastases, a quantitative estimation of tracer uptake at
bone scan can be obtained through automated methods such as the Bone Scan Index [1412]. Nonetheless,
bone scan is challenging due to the so-called ‘flare’ phenomenon which is defined by the treatment-induced
demasking of earlier invisible metastases. This “flare” actually represents a favourable response when observed
within eight to twelve weeks of treatment initiation. The differentiation between progression of bone metastases
and this “flare” requires repeated bone scans. Computed tomography cannot be used to monitor sclerotic
bone lesions because bone sclerosis can occur under effective treatment and reflects bone healing. Magnetic
resonance imaging can directly assess the bone marrow and demonstrate progression based on morphologic
criteria or changes in apparent diffusion coefficient. A standardisation for reporting is available [1413]. The
ability of PET/CT to assess response has been evaluated in a few studies. Until further data are available, MRI
and PET/CT should not be used outside trials for treatment monitoring in metastatic patients [1414].
Men with metastasized PCa on ADT should also, in the absence of a PSA rise, be followed up with
regular imaging since twenty-five percent of men with, or without, docetaxel in the CHAARTED trial developed
clinical progression without a PSA rise [1409]. One in eight men with a PSA < 2 ng/mL showed clinical
progression [1409]. The addition of docetaxel to ADT in the CHAARTED trial population did not reduce the
incidence of clinical progression at low PSA values and this rate was similar for both low- and high-volume

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disease as per CHAARTED criteria [1409]. Also during the combination of ADT and ARPI treatment in mHSPC,
reliance on PSA without regular imaging might miss early detection of progressive PCa as a secondary analysis
of the Titan study found that nearly half of the patients developing subsequent radiographic progression
had no concomitant PSA progression [1180]. In the Prevail study, nearly one-quarter of mCRPC patients on
enzalutamide had radiographic progression without increasing PSA [1415]. However, the optimal timing and
image modality to be used remain unclear, as is the real clinical value of any findings.

7.4.6 Recommendations for follow-up during hormonal treatment

Recommendations Strength rating

The follow-up strategy must be individualised based on stage of disease, prior symptoms, Strong
prognostic factors and the treatment given.
In patients on long-term androgen deprivation therapy (ADT), measure initial bone mineral Strong
density to assess fracture risk.
In patients receiving combination treatment offer bone protection to avoid fractures. Strong
In patients with stage M0 disease, schedule follow-up at least every six months. As a Strong
minimum requirement, include a disease-specific history, serum prostate-specific antigen
(PSA) determination, as well as liver and renal function in the diagnostic work-up.
In M1 patients, schedule follow-up at least every three to six months including imaging at Strong
regular intervals.
During follow-up of patients receiving ADT, check PSA and testosterone levels and monitor Strong
patients for symptoms associated with metabolic syndrome as a side effect of ADT.
In patients on long-term ADT, as a minimum requirement, include a medical history including Strong
assessment of ADT-induced complications, haemoglobin, serum creatinine, alkaline
phosphatase, lipid profiles and HbA1c level measurements.
Counsel patients (especially with M1b status) about the clinical signs suggestive of spinal Strong
cord compression.
When disease progression is suspected, restaging is needed and the subsequent follow-up Strong
adapted/individualised.
In patients with suspected progression, assess the testosterone level. By definition, Strong
castration-resistant PCa requires a testosterone level < 50 ng/dL (< 1.7 nmol/L).

8. QUALITY OF LIFE OUTCOMES IN PROSTATE

CANCER
This chapter is presented in two parts. The first (Section 8.2) will summarise long-term consequences (≥
twelve months) of therapies for PCa. Based on two SRs, the second (Section 8.3) provides evidence-based
recommendations for supporting patients when selecting primary treatment options for localised disease and
also supportive interventions aimed at improving disease-specific QoL across all stages of disease.

8.1 Introduction
Quality of life and personalised care go hand in hand. Treating PCa can affect an individual both physically
and mentally, as well as close relations and work or vocation. These multi-faceted issues all have a bearing
on an individual‘s perception of QoL [1416, 1417]. Approaching care from a holistic point of view requires
the intervention of a multi-disciplinary team including urologists, medical oncologists, radiation oncologists,
oncology nurses, behavioural practitioners and many others including fellow patients. Attention to the
psychosocial concerns of people with PCa is integral to quality clinical care, and this can include the needs of
carers and partners [1418]. Prostate cancer care should not be reduced to focusing on the organ in isolation:
side effects or late adverse effects of treatment can manifest systemically and have a major influence on the
patient’s QoL. Psychological distress can be caused by the cancer diagnosis itself, cancer symptoms and/or
treatment side effects [1419]. Taking QoL into consideration relies on understanding the patient’s values and
preferences so that optimal treatment proposals can be formulated and discussed. Cross-sectional patient
reported outcomes studies in general PCa populations show the impact of treatment on global and disease

148 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

specific QoL is greater than that described in clinical trial populations who often have less co-morbidity and
belong to higher socio-economic groups. Individuals undergoing two or more treatments have more symptoms
and greater impact on QoL [1420, 1421]. Subgroups of people including those with poor general health, being
unmarried, older age and/or pre-existing depressive symptoms are more at risk of long-term mental health
issues following treatment for PCa [1422].

8.2 Adverse effects of PCa therapies

8.2.1 Active surveillance
In a SR [1423] on the long-term (> five year) health-related QoL in patients on AS, it was observed that there
were differences in specific functional outcomes between patients on AS and surgery or radiotherapy, ≥ five
year after treatment. In patients on AS, the overall HRQoL and psychological well-being outcomes were good.
All studies comparing AS with active treatment found no substantial or consistent difference in general HRQoL
PROMs between groups. In preservation of continence there is a clear advantage for AS over, active treatment,
particularly to RP. Results suggest that even after extended periods, continence is still considerably superior in
AS to that in RP. Obstructive voiding symptoms were more common in patients on AS than in post-operative
patients. In the domain of sexual function, it is seen that AS group has better than or comparable sexual
function to that in the active treatment group. Studies comparing AS with that of PCa-free patients had mixed
results with papers observing no statistically significant difference and others reporting that sexual function
was, at least numerically, worse in patients on AS than in PCa-free patients. All patients on AS report good QoL,
similar to that in individuals without prostate cancer [1424]. Regarding anxiety it was seen in a registry on AS
in the USA that men undergoing AS, had a moderate risk of cancer-specific anxiety that significantly decreases
over time. Patients considering active surveillance can be informed that, although it is common experience
some anxiety initially, most men rapidly adjust and report low levels of anxiety within two years [1424].

8.2.2 Surgery
A lack of clear consensus in reporting surgical complications following RP, specifically urinary incontinence
and stricture rates, and the introduction of different techniques has resulted in a wide variation in the types of
complications reported, as well as variation in the overall incidence of complications [1425-1428]. The most
common post-operative complication is ED but other related issues to consider include dry ejaculation, which
occurs with removal of the prostate, change in the quality of orgasm and occasional pain on orgasm. Men
also complain of loss of penile length (3.73%, 19/510 men) [1429]. The second most commonly occurring
complication is long-term incontinence [1425-1428] but voiding difficulties may also occur associated with
bladder neck contracture (e.g., 1.1% after RALP) [1430].
A key consideration is whether long-term consequences of surgery are reduced by using newer
techniques such as RALP. Systematic reviews have documented complication rates after RALP [681, 683-686],
and can be compared with contemporaneous reports after RRP [687]. From these reports, the mean continence
rates at twelve months were 89–100% for patients treated with RALP and 80–97% for patients treated with
RRP. A prospective controlled non-randomised trial of patients undergoing RP in fourteen centres using RALP
or RRP demonstrated that at twelve months after RALP, 21.3% were incontinent, as were 20.2% after RRP.
The unadjusted OR was 1.08 (95% CI: 0.87–1.34). Erectile dysfunction was observed in 70.4% after RALP and
74.7% after RRP. The unadjusted OR was 0.81 (95% CI: 0.66–0.98) [688, 1431]. Further follow-up demonstrates
similar functional outcomes with both techniques at 24 months [1431, 1432]. A single-centre randomised
phase III study comparing RALP and RRP (n = 326) also demonstrates similar functional outcomes with both
techniques at 24 months [1433]. Prostatectomy was found to increase the risk of complaints from an inguinal
hernia, in particular after an open procedure when compared to minimally-invasive approaches [1434, 1435].
For those undergoing minimally-invasive procedures port site hernia has been reported in 0.66% after inserting
12 mm bladeless trocar and can occur more rarely with 8 mm and 5 mm trocars [1436]. Another complication
after primary treatment is lower limb and genital lymphedema. A SR found a prevalence of (0-14%) lower limb
and (0-1%) genital lymphedema after radical prostatectomy with PLND [1437] and between 0-9% and 0-8% in
patients after irradiation on the LNs. In the subgroup that underwent pelvic irradiation after staging pelvic LNs
dissections the prevalence of lower limb (18-29%) and genital (2-22%) is substantially elevated.

8.2.3 Radiotherapy
8.2.3.1 Side effects of external beam radiotherapy
Analysis of the toxicity outcomes of the ProtecT trial shows that patients treated with EBRT and six months of
ADT report bowel toxicity including persistent diarrhoea, bowel urgency and/or incontinence and rectal bleeding
(described in detail in Section 8.3.1.1 below) [1438]. Participants in the ProtecT study were treated with 3D-CRT
and studies using IMRT demonstrate less bowel toxicity than noted previously with 3D-CRT [1439].

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 149

 A SR and meta-analysis of observational studies comparing patients exposed or unexposed to RT in
the course of treatment for PCa demonstrates an increased risk of developing second cancers for bladder (OR:
1.39), colorectal (OR: 1.68) and rectum (OR: 1.62) with similar risks over lag times of five and ten years. Absolute
excess risks over ten years are small (1–4%) but should be discussed with younger patients in particular [1440].
Patient-reported outcomes suggest a temporary drop in the EPIC hormonal and sexual domains
when six months of ADT was added to radiotherapy, with a disappearance of any clinical relevant difference at
one year [1206, 1441].

8.2.3.2 Side effects from brachytherapy

Some patients experience significant urinary complications following implantation such as urinary retention
(1.5-22%), with post-implantation TURP reported as being required in up to 8.7% of cases, and incontinence
(0–19%) [1442]. Chronic urinary morbidity is more common with combined EBRT and BT and can occur in up to
20% of patients, depending on the severity of the symptoms before BT. Urethral strictures account for at least
50% of urinary complications and can be resolved with dilation in the majority [787, 794]. Prevention of morbidity
depends on careful patient selection and IPSS score, backed up by urodynamic studies.

8.2.4 Local primary whole-gland treatments other than surgery or radiotherapy

8.2.4.1 Whole-gland treatments
In a SR and meta-analysis there was evidence that the rate of urinary incontinence at one year was lower for
whole gland cryotherapy than for RP, but the size of the difference decreased with longer follow-up [807]. There
was no significant difference between cryotherapy vs. EBRT in terms of urinary incontinence at one year (< 1%);
cryotherapy had a similar ED rate (range 0–40%) to RP at one year. Whole gland HIFU on the other hand showed
lower incontinence rates at one-year than RP (OR: 0.06; 95% CI: 0.01–0.48) [807].

8.2.4.2 Focal treatments

Over the last decade, prostate cancer is detected at earlier stage with smaller tumours and with more patients
potentially suitable for focal therapy [811-813]. Focal therapy is seeking the optimal balance regarding cancer
control and functional outcome. A recent SR included data from 5,827 patients across 72 studies covering
different energy sources and found evidence that focal therapy has favourable functional outcomes and
minimises AEs [817]. For focal HIFU and cryotherapy, this SR showed pad-free continence rates above 95% and
a median decrease of erectile function of only 12%. A SR with only prospective data found that focal ablation
showed only 9% reduction in sexual function scores, compared to 43% for whole gland ablation at one year
[818].

8.2.5 Androgen deprivaton therapy

Quality of life
Androgen deprivation therapy impacts sexual function, mood, depression, cognitive function, as well as the
relationship with the patient’s partner [1443, 1444].
A small RCT evaluated the QoL at one-year follow-up in patients with PSA only relapse after primary
therapy without evidence of metastasis, between various ADT regimens, or no treatment. Patients treated
by ADT reported a significant decline in spatial reasoning, spatial abilities and working memory as well as
increased depression, tension, anxiety, fatigue, and irritability during treatment [1445]. Conversely, a prospective
observational study with follow-up out to three years failed to demonstrate any association with cognitive
decline in men on ADT when compared to men with PCa not treated with ADT and healthy controls [1446]. A
prospective observational study of locally advanced PCA or BCR after local therapy found that immediate ADT
was associated with a lower overall QoL compared to deferred treatment [1447].
Androgen deprivation therapy-induced are non-negligible and tend to increase over time, prompting
attempts to treat metastatic PCa patients while keeping intact the gonadal function, i.e., physiologic
testosterone level.
Metastasis directed therapy (MDT) for men with oligometastatic PCa is a strategy to avoid or at least
postpone the initiation of ADT. The period of ADT free survival or eugonadal PFS has been applied as end-point
for several studies and future reports on its correlation with QoL are awaited. Eugonadal PFS may be prolonged
by MDT as compared to intermittent hormone treatment alone in men with at maximum oligometastatic PCa
either at primary diagnosis or after recurrence [1211]. The EORTC-GUCG 1532 study used eugonadal PFS as
end-point as well and showed that it can be achieved with an ARPI with similar PSA response as ADT [1448].
The three-armed Embark study in men with biochemical recurrence randomised to either ADT alone,
Enzalutamid alone or ADT & Enzalutamide demonstrated that treatment with an ARPI without ADT is not without
toxicities and less effective than the combination of ADT & ARPI. The choice between the different treatment
options will depend on each patient’s preferences after thorough information by the treating physician.

150 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

Different types of ADT
A SR and meta-analysis assessed potential benefits of intermittent vs. continuous ADT [1449]. Of note, only
a minority of patients with less aggressive PCa is considered eligible for intermittent ADT. The meta-analysis
did not reveal an advantage of continuous over intermittent ADT in PCSM and did neither show a significant
reduction in non-PCa mortality of intermittent versus continuous ADT.

In men with metastatic PCa, ADT is to be applied continuously and surgical orchiectomy represents a
definitive treatment with similar outcomes as compared to LHRH analogues, as demonstrated in a SR of 15
studies comprising almost 60,000 men on medical ADT as opposed to close to 5,000 men on surgical ADT
[1450]. Surgical ADT is considered cost-effective and might prove beneficial for the patient’s well-being as a
retrospective study suggested less reported worry and physical discomfort, better overall health and a higher
likelihood of considering oneself free of cancer than men receiving LHRH agonists continuously. The stage at
diagnosis had no effect on health outcomes [1451].

ADT duration reduced the likelihood of testosterone recovery and prolongs the time to recovery significantly.
In 1,230 men with localised PCa randomised to RT without ADT or with ADT for 6, 18 or 36 months normal
testosterone was measured in 87% without ADT, 76% after 6 months, 55% after 18 months and 43% after 36
months of ADT, respectively. Further, time to testosterone recovery increased with ADT duration ranging from
0.3, 1.6, 3 to 5 years for the 0-, 6-, 18- or 36-month schedules, respectively [1031]. In general, testosterone
recovered faster in otherwise healthy men with a normal baseline testosterone.

The oral LHRH antagonist relugolix achieved a similar castration resistance-free survival as the LHRH agonist
leuprolide, with 48-week CRFS rates of 74.3% and 75.3%, respectively [1452]. After cessation of relugolix and
leuprolidetestosterone recovery after 48 weeks was achieved by a greater percentage of men (54% vs. 3.2%),
and also quicker, i.e. within 86 vs. 112, for relugolix and leuprolide, respectively.

Balancing risks and benefits

To appropriately balance the risks of PCa and non-PCa mortality the PCa aggressiveness and comorbidities of
individual patients must be taken into account. The omega score, a quantitative measure of the relative risk for
cancer-related vs. competing mortality events, might assist in assessing these risks when, for example, deciding
whether the addition of ADT to RT provides a greater benefit regarding PCa mortality than a threat regarding
non-PCa mortality [1453].
In men with metastatic PCa, balancing the intensity of continuous ADT combined with either an ARPI,
docetaxel or both is no less challenging. A SR and meta-analysis on the impact of performance status (PS) on
oncologic outcomes showed that combination systemic therapies significantly improved OS in patients with
worse PS as well as in those with good PS, while the MFS benefit from ARPI in the nmCRPC setting was more
pronounced in patients with good PS than in those with worse PS [1454]. However, as most RCTs are limited to
men with PS of either 0 or 1, these findings might not apply to men with PS of ≥ 2.

8.2.5.1 Sexual function

Cessation of sexual activity is very common in people undergoing ADT, affecting up to 93% [1455]. Androgen
deprivation therapy reduces both libido and the ability to gain and maintain erections. The management of
acquired ED is mostly non-specific [1456].

Using a specific non-validated questionnaire, bicalutamide monotherapy showed a significant advantage over
castration in the domains of physical capacity and sexual interest (not sexual function) at twelve months [1457].
A post-hoc analysis, including only patients with sexual interest suggested that bicalutamide was associated
with better sexual preservation, including maintained sexual interest, feeling sexually attractive [1458], preserved
libido and erectile function [1459].

8.2.5.2 Hot flushes

Hot flushes are a common side effect of ADT (prevalence estimated between 44–80% of men on ADT) [1455].
They appear three months after starting ADT, usually persist long-term and have a significant impact on QoL.

Serotonin re-uptake inhibitors (e.g., venlafaxine or sertraline) appear to be effective in men but less than
hormone therapies based on a prospective RCT comparing venlafaxine, 75 mg daily, with medroxyprogesterone,
20 mg daily, or cyproterone acetate, 100 mg daily [1460]. After six months of LHRH (n = 919), 311 men had
significant hot flushes and were randomised to one of the treatments. Based on median daily hot-flush score,
venlafaxine was inferior -47.2% (interquartile range -74.3 to -2.5) compared to -94.5% (-100.0 to -74.5) in
the cyproterone group, and -83.7% (-98.9 to -64.3) in the medroxyprogesterone group. Another RCT (n = 78)

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compared oestradiol (transdermal 0,9 mg or 0.1% gel) to placebo. After six months oestradiol reduced daily hot
flushes frequency (mean adjusted difference (MAD) -1.6; p=0.04) but the effect on weekly hot flushes was not
significant (MAD -19.6 p=0.11) [1461].

Considering placebo effects registered in up to 30% of patients [1462], prospective RCTs are required to
document the efficacy of clonidine, veralipride, gabapentin [1463] and acupuncture [1464].

8.2.5.3 Non-metastatic bone fractures

Due to increased bone turnover and decreased BMD in a time-dependent manner, ADT use is linked to an
increased risk of fracture (up to 45% RR with long-term ADT) [1465]. Severe fractures in men are associated
with a significant risk of death [1466]. A precise evaluation of BMD should be performed by DEXA, ideally
before starting long-term ADT. An initial low BMD (T-score < -2.5 or < -1, with other risk factors) indicates a
high risk of subsequent non-metastatic fracture and causes should be investigated. Other risk factors include
increasing age, BMI of 19 or less, history of previous fracture or parent with fractured hip, current smoking,
use of glucocorticoids, rheumatoid arthritis, alcohol consumption > two units per day, history of falls and a
number of other chronic medical conditions [1467]. Fracture risk algorithms which combine BMD and clinical
risk factors such as FRAX score can be used to guide treatment decisions, but uncertainty exists regarding the
optimal intervention threshold, therefore no specific risk algorithm can be recommended for men on ADT for
PCa. Obesity (increase in body fat mass by up to 10% and/or BMI > 30) and sarcopenia (decrease in lean tissue
mass by up to 3%) as well as weight loss are common and occur during the first year of ADT [1468, 1469]. These
changes increase the fracture risk [1470].

It is suggested that adding an ARPI to ADT further increases this risk as shown in a SR and meta-analysis of 11
studies with a total population of 11,382 men, with 6,536 receiving enzalutamide, apalutamide, or darolutamide
in combination with ADT or other enzalutamide combinations compared to the control group of 4,846 men
receiving placebo, bicalutamide, or abiraterone [1471]. The control group contained men using the ARPI
abiraterone. The incidence of fracture was 242 (4%) in the enzalutamide, apalutamide, darolutamide group
and 107 (2%) in the control group. Use of enzalutamide, apalutamide, darolutamide was associated with an
increased risk of fractures: all-grade fracture (RR: 1.59; 95% CI: 1.35-1.89; p < 0.001), and likely grade 3 or greater
fracture (RR: 1.71; 95% CI: 1.12-2.63; p = 0.01).

Bicalutamide monotherapy may have less impact on BMD but its suboptimal efficacy for M1 disease renders it
a poor option in these patients [1472, 1473]. The intermittent LHRH-agonist modality might be associated with
less bone impact [1474].

8.2.5.4 Metabolic effects

Lipid alterations are common and may occur as early as the first three months of ADT [1468]. Androgen
deprivation therapy also decreases insulin sensitivity and increases fasting plasma insulin levels, which is a
marker of insulin resistance. In diabetic patients, metformin appears to be an attractive option for protection
against metabolic effects based on retrospective analysis [1475], but there is insufficient data to recommend its
use in non-diabetic patients.

Metabolic syndrome is an association of independent cardiovascular disease risk factors, often associated with
insulin resistance. The definition requires at least three of the following criteria [1476]:
• waist circumference > 102 cm;
• serum triglyceride > 1.7 mmol/L;
• blood pressure > 130/80 mmHg or use of medication for hypertension;
• high-density lipoprotein (HDL) cholesterol < 1 mmol/L;
• glycaemia > 5.6 mmol/L or the use of medication for hyperglycaemia.

The prevalence of a metabolic-like syndrome is higher during ADT compared with men not receiving ADT [1477].
Androgen deprivation therapy impairs skeletal muscle health and muscular weakness is a common complaint
already during the first months of treatment. Skeletal muscle mass heavily influences basal metabolic rate and
is in turn heavily influenced by endocrine pathways [1478]. A prospective longitudinal study involving 252 men
on ADT for a median of 20.4 months reported lean body mass decreases progressively over three years; 1.0%
at one year, 2.1% at two years, and 2.4% at three years which appears more pronounced in men at ≥ 70 years of
age [1479].

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A SR on the impact of ADT on body composition revealed a quite stable body mass index (BMI) but increasing
sarcopenia and subcutaneous adipose tissue [1469]. Sarcopenia at baseline, found in 27% of 110 men with
mCRPC, significantly predicted severe toxicity and ER visits in men initiating ARPI treatment. Sarcopenia was
also a predictor of radiographic progression and overall mortality regardless of treatment type [1480].

8.2.5.5 Cardiovascular morbidity

Cardiovascular mortality is a common cause of death in PCa patients [1098, 1481, 1482]. Several studies
showed that ADT after only six months was associated with an increased risk of diabetes mellitus,
cardiovascular disease, and myocardial infarction [1483]. The RTOG 92-02 [1484] and 94-08 [1485] trials
confirmed an increased cardiovascular risk, unrelated to the duration of ADT and not accompanied by an
overall increased cardiovascular mortality. This was confirmed in the 20-year update of the NRG/RTOG 9202
RCT investigating the long-term relationship between ADT and CVM which showed the increased myocardial
infarction mortality was found after long-term vs. short-term ADT, especially in men with baseline CVD [1486].
No increase in cardiovascular mortality has been reported in both a secondary analysis of PLCO trial, even
among subgroups with pre-existing cardiovascular disease [1487] and a meta-analysis of trials RTOG 8531,
8610, 9202, EORTC 30891 and EORTC 22863 [1488]. However, serious concerns about the conclusions of this
meta-analysis have been raised due to poor consideration of bias in the included studies [1489, 1490]. A meta-
analysis of observational data reports consistent links between ADT and the risk of cardiovascular disease
patients treated for PCa, e.g., the associations between LHRH agonists and non-fatal or fatal myocardial
infarction or stroke RR: 1.57 (95% CI: 1.26–1.94) and RR: 1.51 (95% CI: 1.24–1.84), respectively [1491]. In an
updated meta-analysis on cardiometabolic effects of ADT, ADT was not significantly associated with metabolic
syndrome RR: 1.60 (95% CI: 1.06-2.42), had a lower association with diabetes RR 1.43 (95% CI: 1.28-1.59) as
previously reported, and an increased risk of hypertension by 30%, RR: 1.30 (95% CI: 1.08-1.55). After adjustment
for publication bias ADT was associated with a 25% increased risk for diabetes but was not found to be
associated with metabolic syndrome [1492].

An increase in cardiovascular mortality has been reported in patients suffering from previous congestive heart
failure or myocardial infarction in a retrospective database analysis [1493] or presenting with a metabolic
syndrome [1494]. It has been suggested that antagonists might be associated with less CMV compared to
agonists, but, as yet there is no definite evidence [1495, 1496]. In a phase III RCT the use of relugolix, an oral
LHRH antagonist, was associated with a reduced risk of major adverse cardiovascular events when compared
to leuprolide, an injectable LHRH agonists, at 2.9% vs. 6.2%, respectively, over a follow-up time of 48 weeks (HR:
0.46, 95% CI: 0.24–0.88) [1114]. A SR, including the above RCT, assessing major cardiovascular events in 11
studies comprising approximately 4,200 patients showed a significantly lower risk (HR: 0.57 (95% CI: 0.37-0.86)
for the antagonist as compared to different agonists, whereas there was no significant difference in all-cause
mortality (HR: 0.58, 95% CI: 0.32-1.08) [1497].
Concerns about LHRH agonists resulted in an FDA warning and consensus paper from the American
Heart, Cancer Society and Urological Associations [1097]. Preventive advice includes non-specific measures
such as loss of weight, increased exercise, minimising alcohol intake, improved nutrition and smoking cessation
[93, 1498].
The AEs of different ARPIs (abiraterone, apalutamide, darolutamide, enzalutamide) in the treatment
of mCRPC, nmCRPC, and mHSPC were systematically reviewed in a multi-variate network meta-analysis. Here
it is suggested that the ARTAs adverse effect profiles do not significantly differ from each other, except that
enzalutamide was ranked the most toxic regarding hypertension in mCRPC and nmCRPC, and the most toxic
regarding headache across all prostate cancer settings [1499].

8.2.5.6 Fatigue
Fatigue often develops as a side effect of ADT. Regular exercise appears to be the best protective measure.
Reporting clinically significant fatigue is associated with severe psychological distress and should prompt
screening for anxiety and/or depression [1500]. Anaemia may be a cause of fatigue [1455, 1501]. Anaemia
requires an aetiological diagnosis (medullar invasion, renal insufficiency, iron deficiency, chronic bleeding) and
individualised treatment. Regular blood transfusions may be required in patients with severe anaemia.

8.2.5.7 Neurological side effects

Castration seems also to be associated with an increased risk of stroke [1502], and is suspected to be
associated with an increased risk for depression and cognitive decline such as Alzheimer disease [1503].

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8.2.6 Osteonecrosis during bisphosphonates or denosumab
Bisphosphonates are synthetic pyrophosphate analogues and used in conditions such as malignancy and
osteoporosis. Infrequent side effects associated with bisphosphonate use include pyrexia, renal function
impairment, hypocalcemia, and avascular osteonecrosis of the jaw. Denosumab is a human monoclonal
antibody that is used in the treatment of osteoporosis and bone metastasis [1504, 1505]. It acts by inhibiting
osteoclast activity, reducing bone resorption, and increasing bone density [1504]. Its highly specific mechanism
of action is the inhibition of receptor activator of nuclear factor-kappa B ligand (RANKL). It has been shown to be
effective at increasing bone mineral density and decreasing the risk of fractures in men with prostate cancer on
ADT [1506].
Both drugs are associated with osteonecrosis of the jaw (ONJ) According to the American Society
of Bone and Mineral Research, ONJ is described as exposed bone in the maxillofacial region that does not
heal within eight weeks of being identified by a healthcare provider in a patient that is currently or has been
on bisphosphonates who does not have a history of radiation therapy in the craniofacial region [1507]. The
incidence of ONJ is related to the dose and duration of treatment. The risk ranges from greater than 1%
at twelve months to 11% after four years of treatment - taking zoledronic acid alone increases the risk of
osteonecrosis to 21% after the third year. A SR on denosumab [1508] showed in a total of 8,963 patients with
a variety of solid tumours in seven randomised controlled trials (RCTs) that the overall incidence of ONJ in
patients with cancer receiving denosumab was 1.7% [95% CI: 0.9–3.1%]. The use of denosumab was associated
with a significantly increased risk of ONJ in comparison with bisphosphonates (BPs)/placebo treatment
(RR: 1.61, 95% CI: 1.05–2.48, p = 0.029). Subgroup analysis based on controlled therapies demonstrated an
increased risk of ONJ in denosumab therapy, when compared with BPs (RR: 1.48, 95% CI: 0.96–2.29, p = 0.078)
or placebo (RR: 16.28, 95% CI: 1.68–158.05, p = 0.017). Similar results were observed for prostate cancer (RR
3.358, 95% CI: 1.573–7.166, p = 0.002). Denosumab combined with risk factors such as dental extraction, poor
oral hygiene, use of removable apparatus, and chemotherapy may favour the development of ONJ. Therefore,
before starting these drugs the patients should undergo a dental examination and maintain good oral hygiene.

8.3 Overall quality of life in men with PCa

Living longer with PCa does not necessarily equate to living well [1416, 1418]. There is clear evidence of
unmet needs and ongoing support requirements for some individuals and partners after diagnosis and
treatment for PCa [1509, 1510]. Fear of cancer recurrence and PSA anxiety has a prevalence of 16% and 22%,
respectively, across studies [1511]. Combined cognitive- and education-based psychological interventions
improve depression, anxiety, and distress [1512]. Cancer impacts on the wider family and cognitive behavioural
therapy can help reduce depression, anxiety, and stress in caregivers [1513]. Radical treatment for PCa can
negatively impact long-term QoL (e.g., sexual, urinary and bowel dysfunction) as can ADT used in short- or
long-term treatment, e.g., sexual problems, fatigue, psychological morbidity, adverse metabolic sequelae and
increased cardiovascular and bone fracture risk [1444, 1514]. Direct symptoms from advanced or metastatic
cancer, e.g., pain, hypercalcaemia, spinal cord compression and pathological fractures, also adversely affect
health [1515, 1516]. Patients’ QoL including domains such as sexual function, urinary function and bowel
function is worse after treatment for PCa compared to non-cancer controls [1517, 1518]. A PCa diagnosis
commonly results in financial strain both for the individual and their families. This financial toxicity is associated
with younger age at diagnosis, black race, low socio-economic status, low educational attainment and living
in a rural area. Clinicians should discuss financial strains and signpost to support services so that QoL and
adherence to treatment can be maintained [1519].

As QoL is subjective and can mean different things to different people it can be difficult to measure and
compare. Nevertheless, there are some generally common features across virtually all patients. Drawing
from these common features, specific tools or PROMs have been developed and validated for men with PCa.
These questionnaires assess common issues after PCa diagnosis and treatment and generate scores which
reflect the impact on perceptions of HRQoL. During the process of undertaking two dedicated SRs around
cancer-specific QoL outcomes in patients with PCa as the foundation for our guideline recommendations, the
following validated PROMs were found in our searches (see Table 8.3.1). The tools with the best evidence for
psychometric properties and feasibility for use in routine practice and research settings to assess PROMs in
patients with localised PCa were EORTC QLQ-C30 and QLQ-PR25. Since EORTC QLQ-C30 is a general module
that does not directly assess PCa-specific issues, it should be adopted in conjunction with the QLQ-PR25
module [1520].

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Table 8.3.1: PROMs assessing cancer specific quality of life [1520]

Questionnaire Domains/items
European Organisation for Research and Treatment of Five functional scales (physical, role, cognitive,
Cancer QLQ-C30 (EORTC QLQ-C30) [1521] emotional, and social); three symptom scales
(fatigue, pain, and nausea and vomiting); global
health status/QoL scale; and a number of single
items assessing additional symptoms commonly
reported by cancer patients (dyspnoea, loss of
appetite, insomnia, consti-pation and diarrhoea)
and perceived financial impact of the disease.
European Organisation for Research and Treatment of Urinary, bowel and treatment-related symptoms,
Cancer QLQ-PR 25 (EORTC QLQ-PR 25) [1522] as well as sexual activity and sexual function.
Functional Assessment of Cancer Therapy-General Physical well-being, social/family well-being,
(FACT-G) [1523] emotional well-being, and functional well-being.
Functional Assessment of Cancer Therapy-Prostate Twelve cancer site specific items to assess for
(FACT-P) [1524] prostate-related symptoms. Can be combined with
FACT-G or reported separately.
Expanded prostate cancer index compo-site (EPIC) [1525] Urinary, bowel, sexual, and hormonal symptoms.
Expanded prostate cancer index compo-site short form Urinary, sexual, bowel, and hormonal domains.
26 (EPIC 26) [1526]
UCLA Prostate Cancer Index (UCLA PCI) [1527] Urinary, bowel, and sexual domains.
Prostate Cancer Quality of Life Instru-ment (PCQoL) Urinary, sexual, and bowel domains, supplemented
[1528] by a scale assessing anxiety.
Prostate Cancer Outcome Study Instru-ment [1518] Urinary, bowel, and sexual domains.

8.3.1 Long-term (> twelve months) quality of life outcomes in men with localised disease
8.3.1.1 Men undergoing local treatments
In the updated results of the ProtecT trial [1529] treatment-received analyses revealed different impacts of
treatments over six years. Men remaining on AM experienced gradual declines in sexual and urinary function
with age with increases in ED from 35% at baseline to 53% at six years and nocturia from 20% to 38%. Radical
treatment impacts were immediate and continued over six years. After RP, 95% reported ED persisting for 85% at
six years, after EBRT this was 69% and 74%, respectively (p < 0.001 compared with AM). After RP, 36% reported
urinary leakage requiring at least one pad/day, persisting for 20% at six years, compared with no change in men
receiving EBRT or AM (p < 0.001). Worse bowel function and bother such as bloody stools 6% at six years and
faecal incontinence 10%, was experienced by more men after EBRT than after RP or AM (p < 0.001) with lesser
effects after BT. No treatment affected mental or physical QoL. In another paper on the twelve years outcome
this trial [1438], it was seen that the generic QoL scores were similar in randomised groups over seven to twelve
years, urinary leakage requiring pads occurred in 18-24% of patients In the prostatectomy group over seven to
twelve years, compared with 9-11% in the AM group and 3-8% in the radiotherapy group. Erections sufficient for
intercourse were reported in 18% at seven years in the prostatectomy group, compared with 30% in the AM and
27% in the radiotherapy groups; all converged to low levels of potency by year twelve. Nocturia (voiding at least
twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and
47% in the AM group at twelve years. Faecal leakage affected 12% in the radiotherapy group compared with 6%
in the other groups by year twelve. The AM group experienced gradual age-related declines in sexual and urinary
function, avoiding radical treatment effects unless they changed management. The PACE-A Trial randomised
123 patients over ten years to prostatectomy or SBRT [1530]. At 24 months, only 32 patients in the surgery group
and 46 of the RT group were available for analysis. Each group has one patient with more than one security
pad per day. In summary, the authors show an equal urinary bother score, with more imitative symptoms and
bowel symptoms for SBRT. The overall sexual function is better in the SBRT group. However, this study showed
a differential dropout with only 50% patients of the surgery group in the final readout, an extremely show
recruitment and an unmet target size.

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Other observational studies [738, 1373, 1428, 1531-1534] also report findings regarding RP and RT. The Prostate
Cancer Outcomes Study (PCOS) studied a cohort of 1,655 men, of whom 1,164 had undergone RP and 491 RT
[1428]. The study reported that at five years of follow-up, men who underwent RP had a higher prevalence of
urinary incontinence and ED, while men treated with RT had a higher prevalence of bowel dysfunction. However,
despite these differences detected at five years, there were no significant differences in the adjusted odds of
urinary incontinence, bowel dysfunction or ED between RP and RT at fifteen years. Investigators have reported
that although EBRT was associated with a negative effect in bowel function, the difference in bowel domain
score was below the threshold for clinical significance twelve months after treatment [1439]. As 81% of patients
in the EBRT arm of the study received IMRT, these data suggest that the risk of side effects is reduced with IMRT
compared to older 3D-CRT techniques. This is supported by five-year prospective, population-based cohort
study where PROMs were compared in men with favourable- and unfavourable-risk localised disease [1533]. In
the 1,386 men with favourable risk, comparison between AS and nerve-sparing prostatectomy, EBRT or LDR BT
demonstrates that surgery is associated with worse urinary incontinence at five years and sexual dysfunction
at three years when compared to AS. External beam RT is associated with changes not clinically different from
AS, and LDR BT is associated with worse irritative urinary-, bowel- and sexual symptoms at one year. In 619 men
with high-risk localised disease, comparison between non-nerve sparing RP and EBRT with ADT demonstrates
that surgery is associated with worse urinary incontinence and sexual function through five years. A SR
demonstrates that the risk of post-radiotherapy ED has reduced to a median of 25% at two years with utilisation
of IMRT and is now similar to that noted after LDR BT [1535].

Some prospective studies have reported specific long-term urinary functional outcomes after RP and RT even
if the studies are not comparative between the two treatment modalities. Considering incontinence and ED
after RP the prospective randomised PIVOT trial, comparing RP to observation, reported that 40% of men wore
pads, of which 20% wore more than > one pad/day, and an increased rate of ED in the RP group as compared to
observation from 70% to approximately 87%, after a median follow-up of 12.7 years [1373]. The corresponding
figures from the prospective non-randomised LAPPRO-trial, comparing open- to robot-assisted RP, were 27–29%
of the patients reporting urinary incontinence of some degree after eight years and 66–70% reporting ED [1534].
Data on urinary, sexual and bowel function after RT has been reported from the HYPO-RT-PC-trial, a prospective
randomised non-inferiority trial comparing ultra-HFX to conventional fractionation RT. In this trial 52–55% of the
patients reported urinary problems (RTOG toxicity grade ≥ 1) at five years, of which 4.2–4.7% reported a RTOG
grade ≥ 3 urinary morbidity and 7–8% reported moderate-to-severe incontinence at six years. Bowel toxicity
of any level (RTOG toxicity grade ≥ 1) was reported in 53–54% of the patients at five years, of which 1.5–1.9%
reported a RTOG grade ≥ 3 bowel morbidity, and 66–71% reported to have little or no erection without aids after
six years follow-up [738, 1532].

8.3.1.2 Recommendations for quality of life in men undergoing local treatments

Recommendations Strength rating

Advise eligible patients for active surveillance that global quality of life is equivalent for up to Strong
five years compared to radical prostatectomy or external beam radiotherapy (RT).
Discuss the negative impact of surgery and radiotherapy on urinary and sexual function, as Strong
well as the negative impact of RT on bowel function with patients.
Advise patients treated with brachytherapy of the negative impact on irritative urinary Weak
symptomatology at one year but not after five years.

8.3.2 Improving quality of life in men who have been diagnosed with PCa
8.3.2.1 Men undergoing local treatments
In men with localised disease, nurse-led multi-disciplinary rehabilitation (addressing sexual functioning, cancer
worry, relationship issues, depression, managing bowel and urinary function problems) provided positive short-
term effects (four months) on sexual function (effect size 0.45) and long-term (twelve months) positive effects
on sexual limitation (effect size 0.5) and cancer worry (effect size 0.51) [1536].
Exercise programs during RT combined with ADT result in consistent benefits for cardiovascular
fitness (standardised mean difference [SMD], 0.83; 95% CI: 0.31–1.36; p < 0.01) and muscle function (SMD,
1.30; 95% CI: 0.53–2.07; p < 0.01) with a reduction in urinary toxicity (SMD, -0.71; 95% CI: -1.25 to -0.18; p <
0.01) [1537]. In men undergoing AS, twelve weeks of high-intensity interval training may improve cardiovascular
fitness and suppress PSA progression [1538].

156 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

In men with post-surgical urinary incontinence, conservative management options include pelvic floor muscle
training with or without biofeedback, electrical stimulation, extra-corporeal magnetic innervation (ExMI),
compression devices (penile clamps), lifestyle changes, or a combination of methods. Uncertainty around the
effectiveness and value of these conservative interventions remains [1539]. Surgical interventions including
sling and artificial urinary sphincter (AUS) significantly decrease the number of pads used per day and increase
the QoL compared with before intervention. The overall cure rate is around 60% and results in improvement
in incontinence by about 25% [1540]. Other alternatives, such as the Adjustable Transobturator Male System
(ATOMS) and the Adjustable Continence Therapy (proACT) may be an option but seems less efficacious than
AUS [1541]. For a more detailed overview of management of urinary incontinence in these men see Chapter 5.6
in the EAU Guidelines for Management of Non-neurogenic Male LUTS [1542].

The use of PDE5 inhibitors in penile rehabilitation has been subject to some debate. A single-centre, double-blind
RCT of 100 men undergoing nerve-sparing surgery reported no benefit of nightly sildenafil (50 mg) compared to
on-demand use [1543]. However, a multi-centre double-blind RCT (n = 423) in men aged < 68 years, with normal
pre-treatment erectile function undergoing either open, conventional or robot-assisted laparoscopic nerve-
sparing RP, tadalafil (5 mg) once per day improved participants EPIC sexual domain-scores (least squares mean
difference +9.6, 95% CI: 3.1–16.0) when compared to 20 mg ‘on demand’ or placebo at nine months of follow-
up, even though the difference vanished after the end of study [1544]. Therefore, based on discordant results,
no clear recommendation is possible, even if a trend exists for early use of PDE5 inhibitors after RP for penile
rehabilitation [1545]. A detailed discussion can be found in the EAU Guidelines for Sexual and Reproductive
Health [1546].

In a SR of genitourinary cancers with mostly prostate cancers it is evident that sexual well-being concerns for
men and their partners are evident from diagnosis and into survivorship. Both (patient and partners) benefited
from interventions but many articulated difficulties with initiating the topic due to embarrassment and limited
access to interventions in cancer services [1547].

Testosterone supplementation
Although the evidence is limited, men who are managed expectantly for PCa, or who received radical local
therapy, do not have worse outcomes when receiving testosterone supplementation [86]. Currently the panel see
no contraindication to give testosterone substitution to symptomatic hypogonadal men with prostate cancer
where ADT is not the treatment of choice.

8.3.2.2 Men undergoing systemic treatments

Similar to men treated with a radical approach, in men with T1-T3 disease undergoing RT and ADT, a
combined nurse-led psychological support and physiotherapist-led multi-disciplinary rehabilitation has reported
improvements in QoL. Specifically, this intervention involved action planning around patients’ needs related to
lifestyle changes, weight control, toilet habits, sexuality, and psychological problems. This was complemented
with pelvic floor muscle therapy. Improvements in urinary (adjusted mean 4.5, 95% CI: 0.6–8.4), irritative
(adjusted mean 5.8, 95% CI: 1.4–10.3) and hormonal (adjusted mean 4.8, 95% CI: 0.8–8.8) EPIC domains were
found up to 22 weeks of follow-up [1548]. In a three-year follow-up with 92% response rate from the initial study,
fewer participants had moderate-severe bowel problems in the intervention (n = 2; 3%) vs. control group (n = 10;
14%) (p = 0.016) but the benefits in terms of urinary function were maintained only in those participants with
moderate-severe urinary problems at baseline [1549].
Providing supervised aerobic and resistance exercise training of a moderate intensity improves
EORTC QLQ-C30 role (adjusted mean 15.8, 95% CI: 6.6–24.9) and cognitive domain outcomes (adjusted mean
11.4, 95% CI: 3.3–19.6) as well as symptom scales for fatigue (adjusted mean 11.0, 95% CI: 20.2–1.7), nausea
(adjusted mean 4.0, 95% CI: 7.4–0.25), and dyspnoea (adjusted mean 12.4, 95% CI: 22.5–2.3) up to three
months in men treated with ADT [1550]. Such interventions have also reported clinically relevant improvements
in FACT-P (mean difference 8.9, 95% CI: 3.7–14.2) in men on long-term ADT [1551, 1552]. These findings are
supported by a SR which reported improvements up to twelve weeks in cancer-specific QoL in a meta-analysis
of high-quality trials (SMD 0.33, 95%, CI: 0.08–0.58) [1501]. Supervised exercise interventions delivered over
twelve months are effective in reducing psychological distress; particularly in those men with highest levels of
baseline anxiety and depression [1553]. In untrained older men, SR suggests lower volume exercise programs at
moderate-to-high intensity are as effective as higher volume resistance training for enhancing body composition,
functional capacity and muscle strength and may reduce barriers to exercise and enhance adherence [1554].

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Another SR and meta-analysis of randomised trials shows that exercise interventions for patients on ADT result
in higher lean body mass (mean difference: 0.88, 95% CI: 0.4 to 1.36, p < 0.01), a lower body fat mass (mean
difference: -0.93, 95% CI: -1.10 to -0.10, p < 0.05), and a lower body fat rate (mean difference:-0.93, 95% CI:
-1.39 to -0.47, p < 0.01). Greater efficacy was noted for exercise duration of ≥ six months (vs. < six months) and
exercise immediately after starting ADT (vs. delayed exercise) [1555]. A SR and meta-analysis in patients with
prostate cancer undergoing ADT, on supervised exercise therapy vs. no therapy shows that supervised exercise
therapy is probably superior to no exercise therapy in improving ‘disease-specific QoL’ 0.43 (95%CI: 0.29, 0.58)
and ‘walking performance’ −0.41 (95% CI: −0.60, −0.22) with a moderate certainty of evidence [1556]. A SR and
meta-analysis on determining the factors that affect adherence to exercise programs, found that exercise had
no effects (p < 0.05) on QoL and fatigue. For aerobic fitness, and upper- and lower-body strength significant
effects (all p < 0.05) were observed. Adherence to exercise-based interventions was 80.38%, with improvements
observed in aerobic fitness and strength. Subgroup analysis revealed exercise adherence impacted fatigue and
strength, with greater improvements observed in programs > 12 weeks [1557].

If dietary intake is not adequate, vitamin D and calcium supplementation should be offered, as there is evidence
that vitamin D and calcium have modest effects on bone in men on ADT [1543]. Online tools are available to
calculate daily calcium intake for individual patients. For vitamin D deficiency a dose of at least 800 IU/day
colecalciferol can be recommended. Use of a 25(OH) assay may be helpful to measure vitamin D levels [1558,
1559].

Anti-resorptive therapy is recommended for men on ADT for > six months with either a BMD T-score of < -2.5
or with an additional risk factor for osteoporosis or annual bone loss confirmed to exceed 5%, or in cases of
severe fracture. Referral to a bone specialist should be considered in complex cases with severe fracture and/
or multiple risk factors. Alendronate, risedronate, zoledronate and denosumab have all been shown to prevent
bone loss in men with hormone-sensitive locally-advanced and metastatic PCa on ADT [1560-1563]. Patients
should be warned about the < 5% risk of osteonecrosis of the jaw and/or atypical femoral fractures associated
with these drugs. Bisphosphonates increase BMD in the hip and spine by up to 7% in one year [1562, 1564]. The
optimal regimen for zoledronic acid for men on ADT with hormone-sensitive locally-advanced and metastatic
PCa remains unclear: quarterly [1565] or yearly [1566] injections. The question is relevant as the risk of jaw
necrosis is both dose- and time-related [1567]. A quarterly regimen should be considered for a BMD ≤ 2.5 as a
yearly injection is unlikely to provide sufficient protection [1568, 1569]. Care should be taken when discontinuing
treatment as rebound increased bone resorption can occur.

In M0 patients, denosumab has been shown to increase the lumbar BMD by 5.6% compared to a 1% decrease
in the placebo arm after two years, using 60 mg subcutaneous regimen every six months [1506]. This was
associated with a significant decrease in vertebral fracture risk (1.5% vs. 3.9%, p = 0.006). The benefits were
similar whatever the age (< or > 70 years), the duration or type of ADT, the initial BMD, the patient’s weight, or
the initial BMI. This benefit was not associated with any significant toxicity, e.g., jaw osteonecrosis or delayed
healing in vertebral fractures. In M0 patients, with the use of a higher dosage (120 mg every four weeks), a delay
in bone metastases of 4.2 months has been shown [1351] without any impact on OS, but with an increase in
side effects. Therefore, this later regimen cannot be recommended.

In the SPARTAN phase III study (apalutamide in nmCRPC) [1570], patients receiving apalutamide experienced
falls more frequently vs. those receiving placebo (15.6% vs. 9.0%). In the final multi-variable model, the baseline
patient characteristics of older age, poor ECOG, history of neuropathy, and α-blocker use before study treatment,
remained significantly associated with fall. After-baseline clinical characteristics significantly associated with
time to fall were development of neuropathy, arthralgia, and weight loss before fall. Preventive interventions
should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or
weight decrease are present, to reduce risk of fall.

8.3.2.3 Decision regret

Several treatments with curative intent for localised PCa are available, all with comparable ten-year OS [551].
They vary in terms of the incidence of major side effects, including urinary symptoms, bowel symptoms and
compromised sexual functioning [1438, 1439, 1571]. For this reason, patients’ treatment preferences, in which
they weigh expected benefits against likely side effects, are a central consideration in shared decision-making
and in making informed treatment decisions [1572-1574].

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 It remains challenging, however, to evaluate whether the decision-making process can be viewed
as successful; that is, whether the choice of treatment best reflects the patient’s preferences and expectations
[1575, 1576]. According to Decision Justification Theory (DJT) two main components of decision-related
regret exist; one is associated with the (comparative) evaluation of the outcome and the second with the
feeling of self-blame for having made a poor choice [1577]. About 25% of men with PCa undergoing either
single or combined modality treatments report experiencing worse side effects than expected [1578]. Urinary
incontinence most strongly correlates with regret after prostatectomy [1579].
Unmet expectations are comparable among the treatment groups, except for fatigue. Fatigue is
less frequently reported as worse than expected by patients who received BT when compared to patients who
received RP or EBRT. This could be explained by the less invasive treatment course of BT in comparison to EBRT
with or without ADT and RP [1580]. Unmet expectations were more frequently reported by patients with positive
surgical margins following surgery; having had a passive role in the decision-making process; and who had
higher scores on the decisional conflict scale (i.e., more uncertainty about the treatment decision). Interestingly,
positive surgical margins are not directly associated with an increased risk of Ca-related mortality [1019]. Active
participation and support in the process of forming a preference increases the chance of choosing a treatment
that is in line with patients’ expectations [1574, 1581-1583].
While it may seem desirable to tailor the patients’ role in decision-making to their initial preference,
and particularly to a preference for deferring to the advice of the clinician, this does not result in less decisional
conflict or regret. Increasing patients’ knowledge regardless of initial preference may actually be preferable
[1579].

8.3.2.4 Decision aids in prostate cancer

Shared decision-making can increase patients’ comfort when confronted with management decisions but has
been shown to improve health outcome [1584] and more training seems needed for health care professionals
guiding patients [1585]. Patient education decreased PSA testing [1586] and increased adherence to AS
protocols [1587, 1588]. Autonomous active decision-making by patients was associated with less regret after
prostatectomy regardless of the method chosen and decision aids reduce decisional conflict [1589]. Still,
guidance is needed to optimise patients’ understanding of the options [1590]. Patients prioritised effectiveness
and pain control over mode of administration and risk of fatigue when confronted with treatment choice in
metastasized PCa [1591]. When implementing decision aids clinical validity and utility should be carefully
evaluated and distinguished [1592]. A decision aid should educate as well as promote shared decision-making
to optimise efficacy [1593] and pay attention to communicative aspects [1594].

8.3.2.5 Recommendations for quality of life in men undergoing systemic treatments

Recommendations Strength rating

Offer men on androgen deprivation therapy (ADT), twelve weeks of supervised (by trained Strong
exercise specialists) combined aerobic and resistance exercise.
Advise men on ADT to maintain a healthy weight and diet, to stop smoking, reduce alcohol to Strong
≤ 2 units daily and have yearly screening for diabetes and hypercholesterolemia. Ensure that
calcium and vitamin D meet recommended levels.
Offer men after any radical treatment specialist nurse-led, multi-disciplinary rehabilitation Strong
based on the patients’ personal goals addressing incontinence, sexuality, depression and
fear of recurrence, social support and positive lifestyle changes.
Offer men starting on long-term ADT dual emission X-ray absorptiometry (DEXA) scanning to Strong
assess bone mineral density.
Offer anti-resorptive therapy to men on long term ADT with either a BMD T-score of < -2.5 or Strong
with an additional clinical risk factor for fracture or annual bone loss on ADT is confirmed to
exceed 5%.

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9. REFERENCES
1. Cornford, P., et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update.
Part I: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol, 2024. 86: 148.
https://www.ncbi.nlm.nih.gov/pubmed/38614820
2. Tilki, D., et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II-2024
Update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur Urol, 2024. 86: 164.
https://www.ncbi.nlm.nih.gov/pubmed/38688773
3. Phillips, B., et al. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by Jeremy
Howick March Updated 2009. 1998.
https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-
medicine-levels-of-evidence-march-2009
4. Guyatt, G.H., et al. Going from evidence to recommendations. BMJ, 2008. 336: 1049.
https://www.ncbi.nlm.nih.gov/pubmed/18467413
5. Culp, M.B., et al. Recent Global Patterns in Prostate Cancer Incidence and Mortality Rates. Eur Urol,
2020. 77: 38.
https://www.ncbi.nlm.nih.gov/pubmed/31493960
6. W.H.O. Data visualization tools for exploring the global cancer burden in 2020. 2020. 2021.
https://gco.iarc.fr/today/home
7. Bergengren, O., et al. 2022 Update on Prostate Cancer Epidemiology and Risk Factors-A Systematic
Review. Eur Urol, 2023. 84: 191.
https://www.ncbi.nlm.nih.gov/pubmed/37202314
8. European Commission. Prostate cancer burden in EU-27. 2021.
https://ecis.jrc.ec.europa.eu
9. Bell, K.J., et al. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J
Cancer, 2015. 137: 1749.
https://www.ncbi.nlm.nih.gov/pubmed/25821151
10. Haas, G.P., et al. The worldwide epidemiology of prostate cancer: perspectives from autopsy studies.
Can J Urol, 2008. 15: 3866.
https://www.ncbi.nlm.nih.gov/pubmed/18304396
11. Fleshner, K., et al. The effect of the USPSTF PSA screening recommendation on prostate cancer
incidence patterns in the USA. Nat Rev Urol, 2017. 14: 26.
https://www.ncbi.nlm.nih.gov/pubmed/27995937
12. Kimura, T., et al. Global Trends of Latent Prostate Cancer in Autopsy Studies. Cancers (Basel), 2021.
13.
https://www.ncbi.nlm.nih.gov/pubmed/33478075
13. James, N.D., et al. The Lancet Commission on prostate cancer: planning for the surge in cases.
Lancet, 2024. 403: 1683.
https://www.ncbi.nlm.nih.gov/pubmed/38583453
14. Leitzmann, M.F., et al. Risk factors for the onset of prostatic cancer: age, location, and behavioral
correlates. Clin Epidemiol, 2012. 4: 1.
https://www.ncbi.nlm.nih.gov/pubmed/22291478
15. Cook, L.S., et al. Incidence of adenocarcinoma of the prostate in Asian immigrants to the United
States and their descendants. J Urol, 1999. 161: 152.
https://www.ncbi.nlm.nih.gov/pubmed/10037388
16. Nyame, Y.A., et al. Deconstructing, Addressing, and Eliminating Racial and Ethnic Inequities in
Prostate Cancer Care. Eur Urol, 2022. 82: 341.
https://www.ncbi.nlm.nih.gov/pubmed/35367082
17. Karami, S., et al. Earlier age at diagnosis: another dimension in cancer disparity? Cancer Detect Prev,
2007. 31: 29.
https://www.ncbi.nlm.nih.gov/pubmed/17303347
18. Sanchez-Ortiz, R.F., et al. African-American men with nonpalpable prostate cancer exhibit greater
tumor volume than matched white men. Cancer, 2006. 107: 75.
https://www.ncbi.nlm.nih.gov/pubmed/16736511
19. Chen, F., et al. Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry
Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry. Eur Urol, 2023.
84: 13.
https://www.ncbi.nlm.nih.gov/pubmed/36872133

160 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

20. Freedland, S.J., et al. The impact of race on survival in metastatic prostate cancer: a systematic
literature review. Prostate Cancer Prostatic Dis, 2023. 26: 461.
https://www.ncbi.nlm.nih.gov/pubmed/37592001
21. Patki, S., et al. A Systematic Review of Patient Race, Ethnicity, Socioeconomic Status, and
Educational Attainment in Prostate Cancer Treatment Randomised Trials-Is the Evidence Base
Applicable to the General Patient Population? Eur Urol Open Sci, 2023. 54: 56.
https://www.ncbi.nlm.nih.gov/pubmed/37545851
22. Mahal, B.A., et al. Prostate Cancer Racial Disparities: A Systematic Review by the Prostate Cancer
Foundation Panel. Eur Urol Oncol, 2022. 5: 18.
https://www.ncbi.nlm.nih.gov/pubmed/34446369
23. Ma, T.M., et al. Race-dependent association of clinical trial participation with improved outcomes for
high-risk prostate cancer patients treated in the modern era. Prostate Cancer Prostatic Dis, 2023. 26:
625.
https://www.ncbi.nlm.nih.gov/pubmed/36966268
24. Barlow, M., et al. Ethnic differences in prostate-specific antigen levels in men without prostate
cancer: a systematic review. Prostate Cancer Prostatic Dis, 2023. 26: 249.
https://www.ncbi.nlm.nih.gov/pubmed/36456698
25. Bratt, O., et al. Family History and Probability of Prostate Cancer, Differentiated by Risk Category: A
Nationwide Population-Based Study. J Natl Cancer Inst, 2016. 108.
https://www.ncbi.nlm.nih.gov/pubmed/27400876
26. Beebe-Dimmer, J.L., et al. Risk of Prostate Cancer Associated With Familial and Hereditary Cancer
Syndromes. J Clin Oncol, 2020. 38: 1807.
https://www.ncbi.nlm.nih.gov/pubmed/32208047
27. Brook, M.N., et al. Family History of Prostate Cancer and Survival Outcomes in the UK Genetic
Prostate Cancer Study. Eur Urol, 2023. 83: 257.
https://www.ncbi.nlm.nih.gov/pubmed/36528478
28. Breast Cancer Association Consortium. et al. Breast Cancer Risk Genes - Association Analysis in
More than 113,000 Women. N Engl J Med, 2021. 384: 428.
https://www.ncbi.nlm.nih.gov/pubmed/33471991
29. Nicolosi, P., et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current
Genetic Testing Guidelines. JAMA Oncol, 2019. 5: 523.
https://www.ncbi.nlm.nih.gov/pubmed/30730552
30. Giri, V.N., et al. Germline genetic testing for inherited prostate cancer in practice: Implications for
genetic testing, precision therapy, and cascade testing. Prostate, 2019. 79: 333.
https://www.ncbi.nlm.nih.gov/pubmed/30450585
31. Pritchard, C.C., et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N
Engl J Med, 2016. 375: 443.
https://www.ncbi.nlm.nih.gov/pubmed/27433846
32. Castro, E., et al. PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair
Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin
Oncol, 2019. 37: 490.
https://www.ncbi.nlm.nih.gov/pubmed/30625039
33. Ewing, C.M., et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med, 2012. 366:
141.
https://www.ncbi.nlm.nih.gov/pubmed/22236224
34. Lynch, H.T., et al. Screening for familial and hereditary prostate cancer. Int J Cancer, 2016. 138: 2579.
https://www.ncbi.nlm.nih.gov/pubmed/26638190
35. Nyberg, T., et al. Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective
Cohort Study. Eur Urol, 2020. 77: 24.
https://www.ncbi.nlm.nih.gov/pubmed/31495749
36. Castro, E., et al. Germline BRCA mutations are associated with higher risk of nodal involvement,
distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol, 2013. 31: 1748.
https://www.ncbi.nlm.nih.gov/pubmed/23569316
37. Castro, E., et al. Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After
Radical Treatment for Localised Prostate Cancer. Eur Urol, 2015. 68: 186.
https://www.ncbi.nlm.nih.gov/pubmed/25454609
38. Na, R., et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent
Prostate Cancer and are Associated with Early Age at Death. Eur Urol, 2017. 71: 740.
https://www.ncbi.nlm.nih.gov/pubmed/27989354

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 161

39. Mano, R., et al. Malignant Abnormalities in Male BRCA Mutation Carriers: Results From a
Prospectively Screened Cohort. JAMA Oncol, 2018. 4: 872.
https://www.ncbi.nlm.nih.gov/pubmed/29710070
40. Wang, Y., et al. CHEK2 mutation and risk of prostate cancer: a systematic review and meta-analysis.
Int J Clin Exp Med, 2015. 8: 15708.
https://www.ncbi.nlm.nih.gov/pubmed/26629066
41. Zhen, J.T., et al. Genetic testing for hereditary prostate cancer: Current status and limitations. Cancer,
2018. 124: 3105.
https://www.ncbi.nlm.nih.gov/pubmed/29669169
42. Edwards, S.M., et al. Two percent of men with early-onset prostate cancer harbor germline mutations
in the BRCA2 gene. Am J Hum Genet, 2003. 72: 1.
https://www.ncbi.nlm.nih.gov/pubmed/12474142
43. Agalliu, I., et al. Rare germline mutations in the BRCA2 gene are associated with early-onset prostate
cancer. Br J Cancer, 2007. 97: 826.
https://www.ncbi.nlm.nih.gov/pubmed/17700570
44. Leongamornlert, D., et al. Frequent germline deleterious mutations in DNA repair genes in familial
prostate cancer cases are associated with advanced disease. Br J Cancer, 2014. 110: 1663.
https://www.ncbi.nlm.nih.gov/pubmed/24556621
45. Karlsson, R., et al. A population-based assessment of germline HOXB13 G84E mutation and prostate
cancer risk. Eur Urol, 2014. 65: 169.
https://www.ncbi.nlm.nih.gov/pubmed/22841674
46. Storebjerg, T.M., et al. Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical
prostatectomy and its correlations with prostate cancer risk and aggressiveness. BJU Int, 2016. 118:
646.
https://www.ncbi.nlm.nih.gov/pubmed/26779768
47. Leongamornlert, D., et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer,
2012. 106: 1697.
https://www.ncbi.nlm.nih.gov/pubmed/22516946
48. Thompson, D., et al. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst, 2002. 94: 1358.
https://www.ncbi.nlm.nih.gov/pubmed/12237281
49. Ryan, S., et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis.
Cancer Epidemiol Biomarkers Prev, 2014. 23: 437.
https://www.ncbi.nlm.nih.gov/pubmed/24425144
50. Carlsson, S., et al. Influence of blood prostate specific antigen levels at age 60 on benefits and harms
of prostate cancer screening: population based cohort study. BMJ, 2014. 348: g2296.
https://www.ncbi.nlm.nih.gov/pubmed/24682399
51. Rosty, C., et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in
mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer, 2014. 13:
573.
https://www.ncbi.nlm.nih.gov/pubmed/25117503
52. Siltari, A., et al. How Well do Polygenic Risk Scores Identify Men at High Risk for Prostate Cancer?
Systematic Review and Meta-Analysis. Clin Genitourin Cancer, 2023. 21: 316 e1.
https://www.ncbi.nlm.nih.gov/pubmed/36243664
53. Klein, R.J., et al. Prostate cancer polygenic risk score and prediction of lethal prostate cancer. NPJ
Precis Oncol, 2022. 6: 25.
https://www.ncbi.nlm.nih.gov/pubmed/35396534
54. Plym, A., et al. Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer. J Natl
Cancer Inst, 2022. 114: 771.
https://www.ncbi.nlm.nih.gov/pubmed/33792693
55. Blanc-Lapierre, A., et al. Metabolic syndrome and prostate cancer risk in a population-based case-
control study in Montreal, Canada. BMC Public Health, 2015. 15: 913.
https://www.ncbi.nlm.nih.gov/pubmed/26385727
56. Vidal, A.C., et al. Obesity increases the risk for high-grade prostate cancer: results from the REDUCE
study. Cancer Epidemiol Biomarkers Prev, 2014. 23: 2936.
https://www.ncbi.nlm.nih.gov/pubmed/25261967
57. Davies, N.M., et al. The effects of height and BMI on prostate cancer incidence and mortality:
a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL
consortium. Cancer Causes Control, 2015. 26: 1603.
https://www.ncbi.nlm.nih.gov/pubmed/26387087

162 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

58. Rivera-Izquierdo, M., et al. Obesity as a Risk Factor for Prostate Cancer Mortality: A Systematic
Review and Dose-Response Meta-Analysis of 280,199 Patients. Cancers (Basel), 2021. 13.
https://www.ncbi.nlm.nih.gov/pubmed/34439328
59. Ling, S., et al. Risk of cancer incidence and mortality associated with diabetes: A systematic review
with trend analysis of 203 cohorts. Nutr Metab Cardiovasc Dis, 2021. 31: 14.
https://www.ncbi.nlm.nih.gov/pubmed/33223399
60. Preston, M.A., et al. Metformin use and prostate cancer risk. Eur Urol, 2014. 66: 1012.
https://www.ncbi.nlm.nih.gov/pubmed/24857538
61. Cao, Z., et al. Association Between Statin Exposure and Incidence and Prognosis of Prostate Cancer:
A Meta-analysis Based on Observational Studies. Am J Clin Oncol, 2023. 46: 323.
https://www.ncbi.nlm.nih.gov/pubmed/37143189
62. Li, Y., et al. Effect of Statins on the Risk of Different Stages of Prostate Cancer: A Meta-Analysis. Urol
Int, 2022. 106: 869.
https://www.ncbi.nlm.nih.gov/pubmed/34518476
63. Dickerman, B.A., et al. Alcohol intake, drinking patterns, and prostate cancer risk and mortality: a
30-year prospective cohort study of Finnish twins. Cancer Causes Control, 2016. 27: 1049.
https://www.ncbi.nlm.nih.gov/pubmed/27351919
64. D’Ecclesiis, O., et al. Association between Alcohol Intake and Prostate Cancer Mortality and Survival.
Nutrients, 2023. 15.
https://www.ncbi.nlm.nih.gov/pubmed/36839283
65. Chen, X., et al. Coffee consumption and risk of prostate cancer: a systematic review and meta-
analysis. BMJ Open, 2021. 11: e038902.
https://www.ncbi.nlm.nih.gov/pubmed/33431520
66. Zhao, Z., et al. The association between dairy products consumption and prostate cancer risk: a
systematic review and meta-analysis. Br J Nutr, 2023. 129: 1714.
https://www.ncbi.nlm.nih.gov/pubmed/35945656
67. Alexander, D.D., et al. Meta-Analysis of Long-Chain Omega-3 Polyunsaturated Fatty Acids (LComega-
3PUFA) and Prostate Cancer. Nutr Cancer, 2015. 67: 543.
https://www.ncbi.nlm.nih.gov/pubmed/25826711
68. Lippi, G., et al. Fried food and prostate cancer risk: systematic review and meta-analysis. Int J Food
Sci Nutr, 2015. 66: 587.
https://www.ncbi.nlm.nih.gov/pubmed/26114920
69. Kristal, A.R., et al. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin
E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev, 2014. 23: 1494.
https://www.ncbi.nlm.nih.gov/pubmed/24732629
70. Nyame, Y.A., et al. Associations Between Serum Vitamin D and Adverse Pathology in Men Undergoing
Radical Prostatectomy. J Clin Oncol, 2016. 34: 1345.
https://www.ncbi.nlm.nih.gov/pubmed/26903577
71. Ilic, D., et al. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate
cancer: a systematic review. Maturitas, 2012. 72: 269.
https://www.ncbi.nlm.nih.gov/pubmed/22633187
72. Feiertag, N., et al. Should Men Eat More Plants? A Systematic Review of the Literature on the Effect
of Plant-Forward Diets on Men’s Health. Urology, 2023. 176: 7.
https://www.ncbi.nlm.nih.gov/pubmed/36963667
73. Long, J., et al. Cruciferous Vegetable Intake and Risk of Prostate Cancer: A Systematic Review and
Meta-Analysis. Urol Int, 2023. 107: 723.
https://www.ncbi.nlm.nih.gov/pubmed/37343525
74. Bylsma, L.C., et al. A review and meta-analysis of prospective studies of red and processed meat,
meat cooking methods, heme iron, heterocyclic amines and prostate cancer. Nutr J, 2015. 14: 125.
https://www.ncbi.nlm.nih.gov/pubmed/26689289
75. Nouri-Majd, S., et al. Association Between Red and Processed Meat Consumption and Risk of
Prostate Cancer: A Systematic Review and Meta-Analysis. Front Nutr, 2022. 9: 801722.
https://www.ncbi.nlm.nih.gov/pubmed/35198587
76. Eshaghian, N., et al. Fish consumption and risk of prostate cancer or its mortality: an updated
systematic review and dose-response meta-analysis of prospective cohort studies. Front Nutr, 2023.
10: 1221029.
https://www.ncbi.nlm.nih.gov/pubmed/37593679
77. Applegate, C.C., et al. Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic
Review and Meta-Analysis. Nutrients, 2018. 10.
https://www.ncbi.nlm.nih.gov/pubmed/29300347

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 163

78. Cui, Z., et al. Serum selenium levels and prostate cancer risk: A MOOSE-compliant meta-analysis.
Medicine (Baltimore), 2017. 96: e5944.
https://www.ncbi.nlm.nih.gov/pubmed/28151881
79. Allen, N.E., et al. Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen
Prospective Studies. J Natl Cancer Inst, 2016. 108.
https://www.ncbi.nlm.nih.gov/pubmed/27385803
80. Lippman, S.M., et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers:
the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 2009. 301: 39.
https://www.ncbi.nlm.nih.gov/pubmed/19066370
81. Baboudjian, M., et al. Association Between 5alpha-Reductase Inhibitors and Prostate Cancer
Mortality: A Systematic Review and Meta-analysis. JAMA Oncol, 2023. 9: 847.
https://www.ncbi.nlm.nih.gov/pubmed/37079318
82. Knijnik, P.G., et al. The impact of 5-alpha-reductase inhibitors on mortality in a prostate cancer
chemoprevention setting: a meta-analysis. World J Urol, 2021. 39: 365.
https://www.ncbi.nlm.nih.gov/pubmed/32314009
83. Thompson, I.M., et al. The influence of finasteride on the development of prostate cancer. N Engl J
Med, 2003. 349: 215.
https://www.ncbi.nlm.nih.gov/pubmed/12824459
84. Haider, A., et al. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy:
observations from 5-year median followup of 3 registries. J Urol, 2015. 193: 80.
https://www.ncbi.nlm.nih.gov/pubmed/24980615
85. Watts, E.L., et al. Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20
Prospective Studies. Eur Urol, 2018. 74: 585.
https://www.ncbi.nlm.nih.gov/pubmed/30077399
86. Golla, V., et al. Testosterone Therapy on Active Surveillance and Following Definitive Treatment for
Prostate Cancer. Curr Urol Rep, 2017. 18: 49.
https://www.ncbi.nlm.nih.gov/pubmed/28589395
87. Lophatananon, A., et al. Height, selected genetic markers and prostate cancer risk: results from the
PRACTICAL consortium. Br J Cancer, 2017. 117: 734.
https://www.ncbi.nlm.nih.gov/pubmed/28765617
88. Burns, J.A., et al. Inflammatory Bowel Disease and the Risk of Prostate Cancer. Eur Urol, 2019. 75:
846.
https://www.ncbi.nlm.nih.gov/pubmed/30528221
89. Multigner, L., et al. Chlordecone exposure and risk of prostate cancer. J Clin Oncol, 2010. 28: 3457.
https://www.ncbi.nlm.nih.gov/pubmed/20566993
90. Moon, J., et al. Risk of prostate cancer with increasing years of night shift work: A two-stage dose-
response meta-analysis with duration of night shift work as exposure dose. Heliyon, 2024. 10:
e29080.
https://www.ncbi.nlm.nih.gov/pubmed/38628771
91. Ju-Kun, S., et al. Association Between Cd Exposure and Risk of Prostate Cancer: A PRISMA-
Compliant Systematic Review and Meta-Analysis. Medicine (Baltimore), 2016. 95: e2708.
https://www.ncbi.nlm.nih.gov/pubmed/26871808
92. Islami, F., et al. A systematic review and meta-analysis of tobacco use and prostate cancer mortality
and incidence in prospective cohort studies. Eur Urol, 2014. 66: 1054.
https://www.ncbi.nlm.nih.gov/pubmed/25242554
93. Brookman-May, S.D., et al. Latest Evidence on the Impact of Smoking, Sports, and Sexual Activity
as Modifiable Lifestyle Risk Factors for Prostate Cancer Incidence, Recurrence, and Progression: A
Systematic Review of the Literature by the European Association of Urology Section of Oncological
Urology (ESOU). Eur Urol Focus, 2019. 5: 756.
https://www.ncbi.nlm.nih.gov/pubmed/29576530
94. Russo, G.I., et al. Human papillomavirus and risk of prostate cancer: a systematic review and meta-
analysis. Aging Male, 2020. 23: 132.
https://www.ncbi.nlm.nih.gov/pubmed/29571270
95. Lian, W.Q., et al. Gonorrhea and Prostate Cancer Incidence: An Updated Meta-Analysis of 21
Epidemiologic Studies. Med Sci Monit, 2015. 21: 1902.
https://www.ncbi.nlm.nih.gov/pubmed/26126881
96. Lin, S.W., et al. Prospective study of ultraviolet radiation exposure and risk of cancer in the United
States. Int J Cancer, 2012. 131: E1015.
https://www.ncbi.nlm.nih.gov/pubmed/22539073

164 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

97. Pabalan, N., et al. Association of male circumcision with risk of prostate cancer: a meta-analysis.
Prostate Cancer Prostatic Dis, 2015. 18: 352.
https://www.ncbi.nlm.nih.gov/pubmed/26215783
98. Rider, J.R., et al. Ejaculation Frequency and Risk of Prostate Cancer: Updated Results with an
Additional Decade of Follow-up. Eur Urol, 2016. 70: 974.
https://www.ncbi.nlm.nih.gov/pubmed/27033442
99. Bhindi, B., et al. The Association Between Vasectomy and Prostate Cancer: A Systematic Review and
Meta-analysis. JAMA Intern Med, 2017. 177: 1273.
https://www.ncbi.nlm.nih.gov/pubmed/28715534
100. Cremers, R.G., et al. Self-reported acne is not associated with prostate cancer. Urol Oncol, 2014. 32:
941.
https://www.ncbi.nlm.nih.gov/pubmed/25011577
101. Brierley, J.D., et al., TNM classification of malignant tumors. UICC International Union Against Cancer.
8th edn. 2017.
http://www.uicc.org/tnm/
102. D’Amico, A.V., et al. Biochemical outcome after radical prostatectomy, external beam radiation
therapy, or interstitial radiation therapy for clinically localized prostate cancer. Jama, 1998. 280: 969.
https://www.ncbi.nlm.nih.gov/pubmed/9749478
103. Ploussard, G., et al. Decreased accuracy of the prostate cancer EAU risk group classification in the
era of imaging-guided diagnostic pathway: proposal for a new classification based on MRI-targeted
biopsies and early oncologic outcomes after surgery. World J Urol, 2020. 38: 2493.
https://www.ncbi.nlm.nih.gov/pubmed/31838560
104. Ceci, F., et al. E-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET. Eur J Nucl
Med Mol Imaging, 2021. 48: 1626.
https://www.ncbi.nlm.nih.gov/pubmed/33604691
105. van den Bergh, R.C.N., et al. Re: Andrew Vickers, Sigrid V. Carlsson, Matthew Cooperberg. Routine
Use of Magnetic Resonance Imaging for Early Detection of Prostate Cancer Is Not Justified by the
Clinical Trial Evidence. Eur Urol 2020;78:304-6: Prebiopsy MRI: Through the Looking Glass. Eur Urol,
2020. 78: 310.
https://www.ncbi.nlm.nih.gov/pubmed/32660749
106. Epstein, J.I., et al. The 2005 International Society of Urological Pathology (ISUP) Consensus
Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol, 2005. 29: 1228.
https://www.ncbi.nlm.nih.gov/pubmed/16096414
107. Epstein, J.I., et al. The 2014 International Society of Urological Pathology (ISUP) Consensus
Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal
for a New Grading System. Am J Surg Pathol, 2016. 40: 244.
https://www.ncbi.nlm.nih.gov/pubmed/26492179
108. van Leenders, G., et al. The 2019 International Society of Urological Pathology (ISUP) Consensus
Conference on Grading of Prostatic Carcinoma. Am J Surg Pathol, 2020. 44: e87.
https://www.ncbi.nlm.nih.gov/pubmed/32459716
109. Epstein, J.I., et al. A Contemporary Prostate Cancer Grading System: A Validated Alternative to the
Gleason Score. Eur Urol, 2016. 69: 428.
https://www.ncbi.nlm.nih.gov/pubmed/26166626
110. Moyer, V.A., et al. Screening for prostate cancer: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med, 2012. 157: 120.
https://www.ncbi.nlm.nih.gov/pubmed/22801674
111. Sauter, G., et al. Integrating Tertiary Gleason 5 Patterns into Quantitative Gleason Grading in Prostate
Biopsies and Prostatectomy Specimens. Eur Urol, 2018. 73: 674.
https://www.ncbi.nlm.nih.gov/pubmed/28117112
112. Anderson, B.B., et al. Extraprostatic Extension Is Extremely Rare for Contemporary Gleason Score 6
Prostate Cancer. Eur Urol, 2017. 72: 455.
https://www.ncbi.nlm.nih.gov/pubmed/27986368
113. Ross, H.M., et al. Do adenocarcinomas of the prostate with Gleason score (GS) </=6 have the
potential to metastasize to lymph nodes? Am J Surg Pathol, 2012. 36: 1346.
https://www.ncbi.nlm.nih.gov/pubmed/22531173
114. Alberts, A.R., et al. Biopsy undergrading in men with Gleason score 6 and fatal prostate cancer in the
European Randomized study of Screening for Prostate Cancer Rotterdam. Int J Urol, 2017. 24: 281.
https://www.ncbi.nlm.nih.gov/pubmed/28173626

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 165

115. Tilki, D., et al. Mortality Risk for Patients with Biopsy Gleason Grade Group 1 Prostate Cancer. Eur Urol
Oncol, 2024.
https://www.ncbi.nlm.nih.gov/pubmed/38960834
116. Baboudjian, M., et al. Grade group 1 prostate cancer on biopsy: are we still missing aggressive
disease in the era of image-directed therapy? World J Urol, 2022. 40: 2423.
https://www.ncbi.nlm.nih.gov/pubmed/35980449
117. Stroomberg, H.V., et al. Outcomes of Biopsy Grade Group 1 Prostate Cancer Diagnosis in the Danish
Population. Eur Urol Oncol, 2024. 7: 770.
https://www.ncbi.nlm.nih.gov/pubmed/37884421
118. Zareba, P., et al. The impact of the 2005 International Society of Urological Pathology (ISUP)
consensus on Gleason grading in contemporary practice. Histopathology, 2009. 55: 384.
https://www.ncbi.nlm.nih.gov/pubmed/19817888
119. Goel, S., et al. Concordance Between Biopsy and Radical Prostatectomy Pathology in the Era of
Targeted Biopsy: A Systematic Review and Meta-analysis. Eur Urol Oncol, 2020. 3: 10.
https://www.ncbi.nlm.nih.gov/pubmed/31492650
120. Wang, Y., et al. Predictive Factors for Gleason Score Upgrading in Patients with Prostate Cancer after
Radical Prostatectomy: A Systematic Review and Meta-Analysis. Urol Int, 2023. 107: 460.
https://www.ncbi.nlm.nih.gov/pubmed/36990065
121. Schoots, I.G., et al. Magnetic resonance imaging in active surveillance of prostate cancer: a
systematic review. Eur Urol, 2015. 67: 627.
https://www.ncbi.nlm.nih.gov/pubmed/25511988
122. Inoue, L.Y., et al. Modeling grade progression in an active surveillance study. Stat Med, 2014. 33: 930.
https://www.ncbi.nlm.nih.gov/pubmed/24123208
123. Van der Kwast, T.H., et al. Defining the threshold for significant versus insignificant prostate cancer.
Nat Rev Urol, 2013. 10: 473.
https://www.ncbi.nlm.nih.gov/pubmed/23712205
124. Preisser, F., et al. Intermediate-risk Prostate Cancer: Stratification and Management. Eur Urol Oncol,
2020. 3: 270.
https://www.ncbi.nlm.nih.gov/pubmed/32303478
125. Overland, M.R., et al. Active surveillance for intermediate-risk prostate cancer: yes, but for whom?
Curr Opin Urol, 2019. 29: 605.
https://www.ncbi.nlm.nih.gov/pubmed/31436567
126. Kasivisvanathan, V., et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J
Med, 2018. 378: 1767.
https://www.ncbi.nlm.nih.gov/pubmed/29552975
127. Emmett, L., et al. The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron
Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging
Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study. Eur Urol,
2021. 80: 682.
https://www.ncbi.nlm.nih.gov/pubmed/34465492
128. Ahmed, H.U., et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer
(PROMIS): a paired validating confirmatory study. Lancet, 2017. 389: 815.
https://www.ncbi.nlm.nih.gov/pubmed/28110982
129. Thompson, J.E., et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects
significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective
study. J Urol, 2014. 192: 67.
https://www.ncbi.nlm.nih.gov/pubmed/24518762
130. Kane, C.J., et al. Variability in Outcomes for Patients with Intermediate-risk Prostate Cancer (Gleason
Score 7, International Society of Urological Pathology Gleason Group 2-3) and Implications for Risk
Stratification: A Systematic Review. Eur Urol Focus, 2017. 3: 487.
https://www.ncbi.nlm.nih.gov/pubmed/28753804
131. Zumsteg, Z.S., et al. Unification of favourable intermediate-, unfavourable intermediate-, and very
high-risk stratification criteria for prostate cancer. BJU Int, 2017. 120: E87.
https://www.ncbi.nlm.nih.gov/pubmed/28464446
132. Gnanapragasam, V.J., et al. Improving Clinical Risk Stratification at Diagnosis in Primary Prostate
Cancer: A Prognostic Modelling Study. PLoS Med, 2016. 13: e1002063.
https://www.ncbi.nlm.nih.gov/pubmed/27483464

166 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

133. Gnanapragasam, V.J., et al. The Cambridge Prognostic Groups for improved prediction of disease
mortality at diagnosis in primary non-metastatic prostate cancer: a validation study. BMC Med, 2018.
16: 31.
https://www.ncbi.nlm.nih.gov/pubmed/29490658
134. Parry, M.G., et al. Risk stratification for prostate cancer management: value of the Cambridge
Prognostic Group classification for assessing treatment allocation. BMC Med, 2020. 18: 114.
https://www.ncbi.nlm.nih.gov/pubmed/32460859
135. Zelic, R., et al. Predicting Prostate Cancer Death with Different Pretreatment Risk Stratification Tools:
A Head-to-head Comparison in a Nationwide Cohort Study. Eur Urol, 2020. 77: 180.
https://www.ncbi.nlm.nih.gov/pubmed/31606332
136. Lophatananon, A., et al. Assessing the impact of MRI based diagnostics on pre-treatment disease
classification and prognostic model performance in men diagnosed with new prostate cancer from
an unscreened population. BMC Cancer, 2022. 22: 878.
https://www.ncbi.nlm.nih.gov/pubmed/35953766
137. Kensler, K.H., et al. Prostate Cancer Screening in African American Men: A Review of the Evidence. J
Natl Cancer Inst, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37713266
138. Page, E.C., et al. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen
Screening in BRCA2 Mutation Carriers. Eur Urol, 2019. 76: 831.
https://www.ncbi.nlm.nih.gov/pubmed/31537406
139. Bokhorst, L.P., et al. Prostate-specific antigen-based prostate cancer screening: reduction of prostate
cancer mortality after correction for nonattendance and contamination in the Rotterdam section of
the European Randomized Study of Screening for Prostate Cancer. Eur Urol, 2014. 65: 329.
https://www.ncbi.nlm.nih.gov/pubmed/23954085
140. Arnsrud Godtman, R., et al. Opportunistic testing versus organized prostate-specific antigen
screening: outcome after 18 years in the Goteborg randomized population-based prostate cancer
screening trial. Eur Urol, 2015. 68: 354.
https://www.ncbi.nlm.nih.gov/pubmed/25556937
141. Vickers, A.J., et al. Prostate specific antigen concentration at age 60 and death or metastasis from
prostate cancer: case-control study. BMJ, 2010. 341: c4521.
https://www.ncbi.nlm.nih.gov/pubmed/20843935
142. Bjerner, J., et al. Baseline Serum Prostate-specific Antigen Value Predicts the Risk of Subsequent
Prostate Cancer Death-Results from the Norwegian Prostate Cancer Consortium. Eur Urol, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37169639
143. Vickers, A.J., et al. Strategy for detection of prostate cancer based on relation between prostate
specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ, 2013. 346:
f2023.
https://www.ncbi.nlm.nih.gov/pubmed/23596126
144. Remmers, S., et al. Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and
Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for
Prostate Cancer. Eur Urol, 2023. 84: 503.
https://www.ncbi.nlm.nih.gov/pubmed/37088597
145. Hugosson, J., et al. A 16-yr Follow-up of the European Randomized study of Screening for Prostate
Cancer. Eur Urol, 2019. 76: 43.
https://www.ncbi.nlm.nih.gov/pubmed/30824296
146. Boyle, H.J., et al. Updated recommendations of the International Society of Geriatric Oncology on
prostate cancer management in older patients. Eur J Cancer, 2019. 116: 116.
https://www.ncbi.nlm.nih.gov/pubmed/31195356
147. Loeb, S., et al. Pathological characteristics of prostate cancer detected through prostate specific
antigen based screening. J Urol, 2006. 175: 902.
https://www.ncbi.nlm.nih.gov/pubmed/16469576
148. Etzioni, R., et al. Limitations of basing screening policies on screening trials: The US Preventive
Services Task Force and Prostate Cancer Screening. Med Care, 2013. 51: 295.
https://www.ncbi.nlm.nih.gov/pubmed/23269114
149. Ilic, D., et al. Screening for prostate cancer. Cochrane Database Syst Rev, 2013. 2013: CD004720.
https://www.ncbi.nlm.nih.gov/pubmed/23440794
150. Ilic, D., et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review
and meta-analysis. BMJ, 2018. 362: k3519.
https://www.ncbi.nlm.nih.gov/pubmed/30185521

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 167

151. Hayes, J.H., et al. Screening for prostate cancer with the prostate-specific antigen test: a review of
current evidence. JAMA, 2014. 311: 1143.
https://www.ncbi.nlm.nih.gov/pubmed/24643604
152. Martin, R.M., et al. Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A
Secondary Analysis of the CAP Randomized Clinical Trial. JAMA, 2024. 331: 1460.
https://www.ncbi.nlm.nih.gov/pubmed/38581198
153. Independent, U.K.P.o.B.C.S. The benefits and harms of breast cancer screening: an independent
review. Lancet, 2012. 380: 1778.
https://www.ncbi.nlm.nih.gov/pubmed/23117178
154. de, V., II, et al. A Detailed Evaluation of the Effect of Prostate-specific Antigen-based Screening on
Morbidity and Mortality of Prostate Cancer: 21-year Follow-up Results of the Rotterdam Section of
the European Randomised Study of Screening for Prostate Cancer. Eur Urol, 2023. 84: 426.
https://www.ncbi.nlm.nih.gov/pubmed/37029074
155. Hugosson, J., et al. Eighteen-year follow-up of the Goteborg Randomized Population-based Prostate
Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer
incidence and mortality. Scand J Urol, 2018. 52: 27.
https://www.ncbi.nlm.nih.gov/pubmed/29254399
156. Franlund, M., et al. Results from 22 years of Followup in the Goteborg Randomized Population-Based
Prostate Cancer Screening Trial. J Urol, 2022. 208: 292.
https://www.ncbi.nlm.nih.gov/pubmed/35422134
157. Heijnsdijk, E.A., et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med,
2012. 367: 595.
https://www.ncbi.nlm.nih.gov/pubmed/22894572
158. Vasarainen, H., et al. Effects of prostate cancer screening on health-related quality of life: results of
the Finnish arm of the European randomized screening trial (ERSPC). Acta Oncol, 2013. 52: 1615.
https://www.ncbi.nlm.nih.gov/pubmed/23786174
159. Martin, R.M., et al. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer
Mortality: The CAP Randomized Clinical Trial. JAMA, 2018. 319: 883.
https://www.ncbi.nlm.nih.gov/pubmed/29509864
160. Gelfond, J., et al. Intermediate-Term Risk of Prostate Cancer is Directly Related to Baseline Prostate
Specific Antigen: Implications for Reducing the Burden of Prostate Specific Antigen Screening. J
Urol, 2015. 194: 46.
https://www.ncbi.nlm.nih.gov/pubmed/25686543
161. Roobol, M.J., et al. Improving the Rotterdam European Randomized Study of Screening for Prostate
Cancer Risk Calculator for Initial Prostate Biopsy by Incorporating the 2014 International Society of
Urological Pathology Gleason Grading and Cribriform growth. Eur Urol, 2017. 72: 45.
https://www.ncbi.nlm.nih.gov/pubmed/28162815
162. Bancroft, E.K., et al. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers:
results from the initial screening round of the IMPACT study. Eur Urol, 2014. 66: 489.
https://www.ncbi.nlm.nih.gov/pubmed/24484606
163. Bancroft, E.K., et al. A prospective prostate cancer screening programme for men with pathogenic
variants in mismatch repair genes (IMPACT): initial results from an international prospective study.
Lancet Oncol, 2021. 22: 1618.
https://www.ncbi.nlm.nih.gov/pubmed/34678156
164. Mark, J.R., et al. Genetic Testing Guidelines and Education of Health Care Providers Involved in
Prostate Cancer Care. Urol Clin North Am, 2021. 48: 311.
https://www.ncbi.nlm.nih.gov/pubmed/34210487
165. Giri, V.N., et al. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer
Consensus Conference 2019. J Clin Oncol, 2020. 38: 2798.
https://www.ncbi.nlm.nih.gov/pubmed/32516092
166. John, E.M., et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups.
JAMA, 2007. 298: 2869.
https://www.ncbi.nlm.nih.gov/pubmed/18159056
167. Carvalhal, G.F., et al. Digital rectal examination for detecting prostate cancer at prostate specific
antigen levels of 4 ng./ml. or less. J Urol, 1999. 161: 835.
https://www.ncbi.nlm.nih.gov/pubmed/10022696
168. Gosselaar, C., et al. The role of the digital rectal examination in subsequent screening visits in the
European randomized study of screening for prostate cancer (ERSPC), Rotterdam. Eur Urol, 2008. 54:
581.
https://www.ncbi.nlm.nih.gov/pubmed/18423977

168 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

169. Okotie, O.T., et al. Characteristics of prostate cancer detected by digital rectal examination only.
Urology, 2007. 70: 1117.
https://www.ncbi.nlm.nih.gov/pubmed/18158030
170. Herrera-Caceres, J.O., et al. Utility of digital rectal examination in a population with prostate cancer
treated with active surveillance. Can Urol Assoc J, 2020. 14: E453.
https://www.ncbi.nlm.nih.gov/pubmed/32223879
171. Prebay, Z.J., et al. The prognostic value of digital rectal exam for the existence of advanced
pathologic features after prostatectomy. Prostate, 2021. 81: 1064.
https://www.ncbi.nlm.nih.gov/pubmed/34297858
172. Stamey, T.A., et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate.
N Engl J Med, 1987. 317: 909.
https://www.ncbi.nlm.nih.gov/pubmed/2442609
173. Semjonow, A., et al. Discordance of assay methods creates pitfalls for the interpretation of prostate-
specific antigen values. Prostate Suppl, 1996. 7: 3.
https://www.ncbi.nlm.nih.gov/pubmed/8950358
174. Thompson, I.M., et al. Prevalence of prostate cancer among men with a prostate-specific antigen
level < or =4.0 ng per milliliter. N Engl J Med, 2004. 350: 2239.
https://www.ncbi.nlm.nih.gov/pubmed/15163773
175. Schroder, F.H., et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med, 2012. 366: 981.
https://www.ncbi.nlm.nih.gov/pubmed/22417251
176. Merriel, S.W.D., et al. Systematic review and meta-analysis of the diagnostic accuracy of prostate-
specific antigen (PSA) for the detection of prostate cancer in symptomatic patients. BMC Med, 2022.
20: 54.
https://www.ncbi.nlm.nih.gov/pubmed/35125113
177. Habib, F.K., et al. Differential effect of finasteride on the tissue androgen concentrations in benign
prostatic hyperplasia. Clin Endocrinol (Oxf), 1997. 46: 137.
https://www.ncbi.nlm.nih.gov/pubmed/9135694
178. Roehrborn, C.G., et al. Variability of repeated serum prostate-specific antigen (PSA) measurements
within less than 90 days in a well-defined patient population. Urology, 1996. 47: 59.
https://www.ncbi.nlm.nih.gov/pubmed/8560664
179. Nordstrom, T., et al. Repeat Prostate-Specific Antigen Tests Before Prostate Biopsy Decisions. J Natl
Cancer Inst, 2016. 108.
https://www.ncbi.nlm.nih.gov/pubmed/27418620
180. Rosario, D.J., et al. Contribution of a single repeat PSA test to prostate cancer risk assessment:
experience from the ProtecT study. Eur Urol, 2008. 53: 777.
https://www.ncbi.nlm.nih.gov/pubmed/18079051
181. Eastham, J.A., et al. Variations among individual surgeons in the rate of positive surgical margins in
radical prostatectomy specimens. J Urol, 2003. 170: 2292.
https://www.ncbi.nlm.nih.gov/pubmed/14634399
182. Stephan, C., et al. Interchangeability of measurements of total and free prostate-specific antigen in
serum with 5 frequently used assay combinations: an update. Clin Chem, 2006. 52: 59.
https://www.ncbi.nlm.nih.gov/pubmed/16391327
183. Gill, N., et al. Prostate-Specific Antigen: a Review of Assay Techniques, Variability and Their Clinical
Implications. BioNanoSci, 2017. 8: 707.
https://link.springer.com/article/10.1007/s12668-017-0465-4
184. Yan, Y. Intraindividual variation of prostate specific antigen measurement and implications for early
detection of prostate carcinoma. Cancer, 2001. 92: 776.
https://www.ncbi.nlm.nih.gov/pubmed/11550147
185. el-Shirbiny, A.M. Prostatic specific antigen. Adv Clin Chem, 1994. 31: 99.
https://www.ncbi.nlm.nih.gov/pubmed/7533474
186. Zackrisson, B., et al. Evolution of free, complexed, and total serum prostate-specific antigen and their
ratios during 1 year of follow-up of men with febrile urinary tract infection. Urology, 2003. 62: 278.
https://www.ncbi.nlm.nih.gov/pubmed/12893335
187. Aliasgari, M., et al. The effect of acute urinary retention on serum prostate-specific antigen level. Urol
J, 2005. 2: 89.
https://www.ncbi.nlm.nih.gov/pubmed/17629877
188. Oesterling, J.E., et al. Effect of cystoscopy, prostate biopsy, and transurethral resection of prostate on
serum prostate-specific antigen concentration. Urology, 1993. 42: 276.
https://www.ncbi.nlm.nih.gov/pubmed/7691013

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 169

189. Kim, D.K., et al. Association between prostate-specific antigen and serum testosterone: A systematic
review and meta-analysis. Andrology, 2020. 8: 1194.
https://www.ncbi.nlm.nih.gov/pubmed/32329181
190. Massengill, J.C., et al. Pretreatment total testosterone level predicts pathological stage in patients
with localized prostate cancer treated with radical prostatectomy. J Urol, 2003. 169: 1670.
https://www.ncbi.nlm.nih.gov/pubmed/12686805
191. Yuan, J.J., et al. Effects of rectal examination, prostatic massage, ultrasonography and needle biopsy
on serum prostate specific antigen levels. J Urol, 1992. 147: 810.
https://www.ncbi.nlm.nih.gov/pubmed/1371553
192. Maggi, M., et al. Prostate Imaging Reporting and Data System 3 Category Cases at Multiparametric
Magnetic Resonance for Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus,
2020. 6: 463.
https://www.ncbi.nlm.nih.gov/pubmed/31279677
193. Nordstrom, T., et al. Prostate-specific antigen (PSA) density in the diagnostic algorithm of prostate
cancer. Prostate Cancer Prostatic Dis, 2018. 21: 57.
https://www.ncbi.nlm.nih.gov/pubmed/29259293
194. Yusim, I., et al. The use of prostate specific antigen density to predict clinically significant prostate
cancer. Sci Rep, 2020. 10: 20015.
https://www.ncbi.nlm.nih.gov/pubmed/33203873
195. Denijs, F.B., et al. Risk calculators for the detection of prostate cancer: a systematic review. Prostate
Cancer Prostatic Dis, 2024. 27: 544.
https://www.ncbi.nlm.nih.gov/pubmed/38830997
196. Roehrborn, C.G., et al. Correlation between prostate size estimated by digital rectal examination and
measured by transrectal ultrasound. Urology, 1997. 49: 548.
https://www.ncbi.nlm.nih.gov/pubmed/9111624
197. Hamzaoui, D., et al. Prostate volume prediction on MRI: tools, accuracy and variability. Eur Radiol,
2022. 32: 4931.
https://www.ncbi.nlm.nih.gov/pubmed/35169895
198. Choe, S., et al. MRI vs Transrectal Ultrasound to Estimate Prostate Volume and PSAD: Impact on
Prostate Cancer Detection. Urology, 2023. 171: 172.
https://www.ncbi.nlm.nih.gov/pubmed/36152871
199. de, V., II, et al. Prostate cancer risk assessment by the primary care physician and urologist:
transabdominal- versus transrectal ultrasound prostate volume-based use of the Rotterdam Prostate
Cancer Risk Calculator. Transl Androl Urol, 2023. 12: 241.
https://www.ncbi.nlm.nih.gov/pubmed/36915892
200. Wang, S., et al. Diagnostic Performance of Prostate-specific Antigen Density for Detecting Clinically
Significant Prostate Cancer in the Era of Magnetic Resonance Imaging: A Systematic Review and
Meta-analysis. Eur Urol Oncol, 2024. 7: 189.
https://www.ncbi.nlm.nih.gov/pubmed/37640584
201. Haj-Mirzaian, A., et al. Magnetic Resonance Imaging, Clinical, and Biopsy Findings in Suspected
Prostate Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open, 2024. 7: e244258.
https://www.ncbi.nlm.nih.gov/pubmed/38551559
202. Turkbey, B., et al. Prostate Imaging Reporting and Data System Version 2.1: 2019 Update of Prostate
Imaging Reporting and Data System Version 2. Eur Urol, 2019. 76: 340.
https://www.ncbi.nlm.nih.gov/pubmed/30898406
203. Weinreb, J.C., et al. PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. Eur Urol,
2016. 69: 16.
https://www.ncbi.nlm.nih.gov/pubmed/26427566
204. Bratan, F., et al. Influence of imaging and histological factors on prostate cancer detection and
localisation on multiparametric MRI: a prospective study. Eur Radiol, 2013. 23: 2019.
https://www.ncbi.nlm.nih.gov/pubmed/23494494
205. Borofsky, S., et al. What Are We Missing? False-Negative Cancers at Multiparametric MR Imaging of
the Prostate. Radiology, 2018. 286: 186.
https://www.ncbi.nlm.nih.gov/pubmed/29053402
206. Johnson, D.C., et al. Detection of Individual Prostate Cancer Foci via Multiparametric Magnetic
Resonance Imaging. Eur Urol, 2019. 75: 712.
https://www.ncbi.nlm.nih.gov/pubmed/30509763

170 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

207. Yaxley, W.J., et al. Histological findings of totally embedded robot assisted laparoscopic
radical prostatectomy (RALP) specimens in 1197 men with a negative (low risk) preoperative
multiparametric magnetic resonance imaging (mpMRI) prostate lobe and clinical implications.
Prostate Cancer Prostatic Dis, 2021. 24: 398.
https://www.ncbi.nlm.nih.gov/pubmed/32999464
208. Drost, F.H., et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for
detecting prostate cancer. Cochrane Database Syst Rev, 2019. 4: CD012663.
https://www.ncbi.nlm.nih.gov/pubmed/31022301
209. Smeenge, M., et al. Role of transrectal ultrasonography (TRUS) in focal therapy of prostate cancer:
report from a Consensus Panel. BJU Int, 2012. 110: 942.
https://www.ncbi.nlm.nih.gov/pubmed/22462566
210. Rouviere, O., et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric
MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet
Oncol, 2019. 20: 100.
https://www.ncbi.nlm.nih.gov/pubmed/30470502
211. Correas, J.M., et al. Advanced ultrasound in the diagnosis of prostate cancer. World J Urol, 2021. 39:
661.
https://www.ncbi.nlm.nih.gov/pubmed/32306060
212. Mannaerts, C.K., et al. Detection of clinically significant prostate cancer in biopsy-naive men: direct
comparison of systematic biopsy, multiparametric MRI- and contrast-ultrasound-dispersion imaging-
targeted biopsy. BJU Int, 2020. 126: 481.
https://www.ncbi.nlm.nih.gov/pubmed/32315112
213. Grey, A.D.R., et al. Multiparametric ultrasound versus multiparametric MRI to diagnose prostate
cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study. Lancet Oncol, 2022.
23: 428.
https://www.ncbi.nlm.nih.gov/pubmed/35240084
214. Hofbauer, S.L., et al. A non-inferiority comparative analysis of micro-ultrasonography and MRI-
targeted biopsy in men at risk of prostate cancer. BJU Int, 2022. 129: 648.
https://www.ncbi.nlm.nih.gov/pubmed/34773679
215. Ghai, S., et al. Comparison of Micro-US and Multiparametric MRI for Prostate Cancer Detection in
Biopsy-Naive Men. Radiology, 2022. 305: 390.
https://www.ncbi.nlm.nih.gov/pubmed/35852425
216. Dias, A.B., et al. Multiparametric ultrasound and micro-ultrasound in prostate cancer: a
comprehensive review. Br J Radiol, 2022. 95: 20210633.
https://www.ncbi.nlm.nih.gov/pubmed/34752132
217. Kawada, T., et al. Diagnostic Performance of Prostate-specific Membrane Antigen Positron Emission
Tomography-targeted biopsy for Detection of Clinically Significant Prostate Cancer: A Systematic
Review and Meta-analysis. Eur Urol Oncol, 2022. 5: 390.
https://www.ncbi.nlm.nih.gov/pubmed/35715320
218. Kretschmer, A., et al. Biomarkers in prostate cancer - Current clinical utility and future perspectives.
Crit Rev Oncol Hematol, 2017. 120: 180.
https://www.ncbi.nlm.nih.gov/pubmed/29198331
219. Strom, P., et al. The Stockholm-3 Model for Prostate Cancer Detection: Algorithm Update, Biomarker
Contribution, and Reflex Test Potential. Eur Urol, 2018. 74: 204.
https://www.ncbi.nlm.nih.gov/pubmed/29331214
220. Wagaskar, V.G., et al. A 4K score/MRI-based nomogram for predicting prostate cancer, clinically
significant prostate cancer, and unfavorable prostate cancer. Cancer Rep (Hoboken), 2021. 4: e1357.
https://www.ncbi.nlm.nih.gov/pubmed/33661541
221. Hendriks, R.J., et al. Clinical use of the SelectMDx urinary-biomarker test with or without mpMRI in
prostate cancer diagnosis: a prospective, multicenter study in biopsy-naive men. Prostate Cancer
Prostatic Dis, 2021. 24: 1110.
https://www.ncbi.nlm.nih.gov/pubmed/33941866
222. Bryant, R.J., et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein
markers measured in blood in the ProtecT study. J Natl Cancer Inst, 2015. 107.
https://www.ncbi.nlm.nih.gov/pubmed/25863334
223. Catalona, W.J., et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate
specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/
ml prostate specific antigen range. J Urol, 2011. 185: 1650.
https://www.ncbi.nlm.nih.gov/pubmed/21419439

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 171

224. Nordstrom, T., et al. Comparison Between the Four-kallikrein Panel and Prostate Health Index for
Predicting Prostate Cancer. Eur Urol, 2015. 68: 139.
https://www.ncbi.nlm.nih.gov/pubmed/25151013
225. Wagaskar, V.G., et al. Clinical Utility of Negative Multiparametric Magnetic Resonance Imaging in the
Diagnosis of Prostate Cancer and Clinically Significant Prostate Cancer. Eur Urol Open Sci, 2021. 28:
9.
https://www.ncbi.nlm.nih.gov/pubmed/34337520
226. Gronberg, H., et al. Prostate Cancer Diagnostics Using a Combination of the Stockholm3 Blood Test
and Multiparametric Magnetic Resonance Imaging. Eur Urol, 2018. 74: 722.
https://www.ncbi.nlm.nih.gov/pubmed/30001824
227. Nordstrom, T., et al. Prostate cancer screening using a combination of risk-prediction, MRI, and
targeted prostate biopsies (STHLM3-MRI): a prospective, population-based, randomised, open-label,
non-inferiority trial. Lancet Oncol, 2021. 22: 1240.
https://www.ncbi.nlm.nih.gov/pubmed/34391509
228. Morote, J., et al. Improving the Early Detection of Clinically Significant Prostate Cancer in Men in the
Challenging Prostate Imaging-Reporting and Data System 3 Category. Eur Urol Open Sci, 2022. 37:
38.
https://www.ncbi.nlm.nih.gov/pubmed/35243388
229. Ploussard, G., et al. The role of prostate cancer antigen 3 (PCA3) in prostate cancer detection. Expert
Rev Anticancer Ther, 2018. 18: 1013.
https://www.ncbi.nlm.nih.gov/pubmed/30016891
230. Van Neste, L., et al. Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-
Based Risk Score. Eur Urol, 2016. 70: 740.
https://www.ncbi.nlm.nih.gov/pubmed/27108162
231. Maggi, M., et al. SelectMDx and Multiparametric Magnetic Resonance Imaging of the Prostate for
Men Undergoing Primary Prostate Biopsy: A Prospective Assessment in a Multi-Institutional Study.
Cancers (Basel), 2021. 13.
https://www.ncbi.nlm.nih.gov/pubmed/33922626
232. Lendinez-Cano, G., et al. Prospective study of diagnostic accuracy in the detection of high-grade
prostate cancer in biopsy-naive patients with clinical suspicion of prostate cancer who underwent the
Select MDx test. Prostate, 2021. 81: 857.
https://www.ncbi.nlm.nih.gov/pubmed/34184761
233. Roumiguie, M., et al. Independent Evaluation of the Respective Predictive Values for High-Grade
Prostate Cancer of Clinical Information and RNA Biomarkers after Upfront MRI and Image-Guided
Biopsies. Cancers (Basel), 2020. 12.
https://www.ncbi.nlm.nih.gov/pubmed/31991591
234. Tomlins, S.A., et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate
cancer. Science, 2005. 310: 644.
https://www.ncbi.nlm.nih.gov/pubmed/16254181
235. Tomlins, S.A., et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk
Assessment. Eur Urol, 2016. 70: 45.
https://www.ncbi.nlm.nih.gov/pubmed/25985884
236. Tosoian, J.J., et al. Development and Validation of an 18-Gene Urine Test for High-Grade Prostate
Cancer. JAMA Oncol, 2024. 10: 726.
https://www.ncbi.nlm.nih.gov/pubmed/38635241
237. Donovan, M.J., et al. A molecular signature of PCA3 and ERG exosomal RNA from non-DRE urine is
predictive of initial prostate biopsy result. Prostate Cancer Prostatic Dis, 2015. 18: 370.
https://www.ncbi.nlm.nih.gov/pubmed/26345389
238. McKiernan, J., et al. A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate
Cancer at Initial Biopsy. JAMA Oncol, 2016. 2: 882.
https://www.ncbi.nlm.nih.gov/pubmed/27032035
239. Vedder, M.M., et al. The added value of percentage of free to total prostate-specific antigen, PCA3,
and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men. Eur Urol,
2014. 66: 1109.
https://www.ncbi.nlm.nih.gov/pubmed/25168616
240. Lamy, P.J., et al. Prognostic Biomarkers Used for Localised Prostate Cancer Management: A
Systematic Review. Eur Urol Focus, 2018. 4: 790.
https://www.ncbi.nlm.nih.gov/pubmed/28753865

172 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

241. Iczkowski, K.A., et al. Needle core length in sextant biopsy influences prostate cancer detection rate.
Urology, 2002. 59: 698.
https://www.ncbi.nlm.nih.gov/pubmed/11992843
242. Egevad, L., et al. Dataset for the reporting of prostate carcinoma in core needle biopsy and
transurethral resection and enucleation specimens: recommendations from the International
Collaboration on Cancer Reporting (ICCR). Pathology, 2019. 51: 11.
https://www.ncbi.nlm.nih.gov/pubmed/30477882
243. Van der Kwast, T., et al. Guidelines on processing and reporting of prostate biopsies: the 2013 update
of the pathology committee of the European Randomized Study of Screening for Prostate Cancer
(ERSPC). Virchows Arch, 2013. 463: 367.
https://www.ncbi.nlm.nih.gov/pubmed/23918245
244. Epstein, J.I., et al. Best practices recommendations in the application of immunohistochemistry in
the prostate: report from the International Society of Urologic Pathology consensus conference. Am
J Surg Pathol, 2014. 38: e6.
https://www.ncbi.nlm.nih.gov/pubmed/25029122
245. Chen, R.C., et al. Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care
Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J
Clin Oncol, 2016. 34: 2182.
https://www.ncbi.nlm.nih.gov/pubmed/26884580
246. Deng, F.M., et al. Size-adjusted Quantitative Gleason Score as a Predictor of Biochemical Recurrence
after Radical Prostatectomy. Eur Urol, 2016. 70: 248.
https://www.ncbi.nlm.nih.gov/pubmed/26525839
247. Kweldam, C.F., et al. Disease-specific survival of patients with invasive cribriform and intraductal
prostate cancer at diagnostic biopsy. Mod Pathol, 2016. 29: 630.
https://www.ncbi.nlm.nih.gov/pubmed/26939875
248. Kweldam, C.F., et al. On cribriform prostate cancer. Transl Androl Urol, 2018. 7: 145.
https://www.ncbi.nlm.nih.gov/pubmed/29594028
249. Russo, G.I., et al. Oncological outcomes of cribriform histology pattern in prostate cancer patients: a
systematic review and meta-analysis. Prostate Cancer Prostatic Dis, 2023. 26: 646.
https://www.ncbi.nlm.nih.gov/pubmed/36216967
250. Marra, G., et al. Impact of Epithelial Histological Types, Subtypes, and Growth Patterns on
Oncological Outcomes for Patients with Nonmetastatic Prostate Cancer Treated with Curative Intent:
A Systematic Review. Eur Urol, 2023. 84: 65.
https://www.ncbi.nlm.nih.gov/pubmed/37117107
251. van der Kwast, T.H., et al. ISUP Consensus Definition of Cribriform Pattern Prostate Cancer. Am J
Surg Pathol, 2021. 45: 1118.
https://www.ncbi.nlm.nih.gov/pubmed/33999555
252. Zhou, M. High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and
intraductal carcinoma of the prostate. Mod Pathol, 2018. 31: S71.
https://www.ncbi.nlm.nih.gov/pubmed/29297491
253. Saeter, T., et al. Intraductal Carcinoma of the Prostate on Diagnostic Needle Biopsy Predicts Prostate
Cancer Mortality: A Population-Based Study. Prostate, 2017. 77: 859.
https://www.ncbi.nlm.nih.gov/pubmed/28240424
254. Miura, N., et al. The Prognostic Impact of Intraductal Carcinoma of the Prostate: A Systematic Review
and Meta-Analysis. J Urol, 2020. 204: 909.
https://www.ncbi.nlm.nih.gov/pubmed/32698712
255. Shah, R.B., et al. Atypical intraductal proliferation detected in prostate needle biopsy is a marker
of unsampled intraductal carcinoma and other adverse pathological features: a prospective
clinicopathological study of 62 cases with emphasis on pathological outcomes. Histopathology,
2019. 75: 346.
https://www.ncbi.nlm.nih.gov/pubmed/31012493
256. Hickman, R.A., et al. Atypical Intraductal Cribriform Proliferations of the Prostate Exhibit Similar
Molecular and Clinicopathologic Characteristics as Intraductal Carcinoma of the Prostate. Am J Surg
Pathol, 2017. 41: 550.
https://www.ncbi.nlm.nih.gov/pubmed/28009609
257. Pepdjonovic, L., et al. Zero hospital admissions for infection after 577 transperineal prostate biopsies
using single-dose cephazolin prophylaxis. World J Urol, 2017. 35: 1199.
https://www.ncbi.nlm.nih.gov/pubmed/27987032

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 173

258. Epstein, J.I., et al. The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary
Grading of Prostate Cancer. Arch Pathol Lab Med, 2021. 145: 461.
https://www.ncbi.nlm.nih.gov/pubmed/32589068
259. Tumours, E.B.W.C.o., WHO Classification of Tumours. Urinary and male genital tumours. 8th ed, ed.
I.A.f.R.o. Cancer. Vol. 5th Edn.; vol 8. 2022, Lyon (France).
https://publications.iarc.fr/610
260. Gordetsky, J.B., et al. Histologic findings associated with false-positive multiparametric magnetic
resonance imaging performed for prostate cancer detection. Hum Pathol, 2019. 83: 159.
https://www.ncbi.nlm.nih.gov/pubmed/30179687
261. Srigley, J.R., et al. Controversial issues in Gleason and International Society of Urological Pathology
(ISUP) prostate cancer grading: proposed recommendations for international implementation.
Pathology, 2019. 51: 463.
https://www.ncbi.nlm.nih.gov/pubmed/31279442
262. Strom, P., et al. Prognostic value of perineural invasion in prostate needle biopsies: a population-
based study of patients treated by radical prostatectomy. J Clin Pathol, 2020. 73: 630.
https://www.ncbi.nlm.nih.gov/pubmed/32034057
263. Fleshner, K., et al. Clinical Findings and Treatment Outcomes in Patients with Extraprostatic
Extension Identified on Prostate Biopsy. J Urol, 2016. 196: 703.
https://www.ncbi.nlm.nih.gov/pubmed/27049874
264. Karwacki, J., et al. Association of Lymphovascular Invasion with Biochemical Recurrence and
Adverse Pathological Characteristics of Prostate Cancer: A Systematic Review and Meta-analysis.
Eur Urol Open Sci, 2024. 69: 112.
https://www.ncbi.nlm.nih.gov/pubmed/39430411
265. Li, H., et al. Perineural invasion detected in prostate biopsy is a predictor of positive surgical margin
of radical prostatectomy specimen: A meta-analysis. Andrologia, 2022. 54: e14395.
https://www.ncbi.nlm.nih.gov/pubmed/35233813
266. Wu, S., et al. Impact of biopsy perineural invasion on the outcomes of patients who underwent radical
prostatectomy: a systematic review and meta-analysis. Scand J Urol, 2019. 53: 287.
https://www.ncbi.nlm.nih.gov/pubmed/31401922
267. Morozov, A., et al. A systematic review and meta-analysis of artificial intelligence diagnostic accuracy
in prostate cancer histology identification and grading. Prostate Cancer Prostatic Dis, 2023. 26: 681.
https://www.ncbi.nlm.nih.gov/pubmed/37185992
268. Freedland, S.J., et al. Preoperative model for predicting prostate specific antigen recurrence after
radical prostatectomy using percent of biopsy tissue with cancer, biopsy Gleason grade and serum
prostate specific antigen. J Urol, 2004. 171: 2215.
https://www.ncbi.nlm.nih.gov/pubmed/15126788
269. Grossklaus, D.J., et al. Percent of cancer in the biopsy set predicts pathological findings after
prostatectomy. J Urol, 2002. 167: 2032.
https://www.ncbi.nlm.nih.gov/pubmed/11956432
270. Brimo, F., et al. Prognostic value of various morphometric measurements of tumour extent in
prostate needle core tissue. Histopathology, 2008. 53: 177.
https://www.ncbi.nlm.nih.gov/pubmed/18752501
271. Nguyen, P.L., et al. Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-
Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3
Randomized Trials. Int J Radiat Oncol Biol Phys, 2023. 116: 521.
https://www.ncbi.nlm.nih.gov/pubmed/36596347
272. Spratt, D.E., et al. Genomic Classifier Performance in Intermediate-Risk Prostate Cancer: Results
From NRG Oncology/RTOG 0126 Randomized Phase 3 Trial. Int J Radiat Oncol Biol Phys, 2023. 117:
370.
https://www.ncbi.nlm.nih.gov/pubmed/37137444
273. de Bono, J., et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med, 2020.
382: 2091.
https://www.ncbi.nlm.nih.gov/pubmed/32343890
274. Mateo, J., et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin
Invest, 2020. 130: 1743.
https://www.ncbi.nlm.nih.gov/pubmed/31874108
275. Schweizer, M.T., et al. Concordance of DNA Repair Gene Mutations in Paired Primary Prostate Cancer
Samples and Metastatic Tissue or Cell-Free DNA. JAMA Oncol, 2021. 7: 1.
https://www.ncbi.nlm.nih.gov/pubmed/34086042

174 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

276. Robinson, D., et al. Integrative clinical genomics of advanced prostate cancer. Cell, 2015. 161: 1215.
https://www.ncbi.nlm.nih.gov/pubmed/26000489
277. Matsubara, N., et al. Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate
Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA. Clin
Cancer Res, 2023. 29: 92.
https://www.ncbi.nlm.nih.gov/pubmed/36318705
278. Chi, K.N., et al. Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and
Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound. Clin Cancer Res,
2023. 29: 81.
https://www.ncbi.nlm.nih.gov/pubmed/36043882
279. Iremashvili, V., et al. Partial sampling of radical prostatectomy specimens: detection of positive
margins and extraprostatic extension. Am J Surg Pathol, 2013. 37: 219.
https://www.ncbi.nlm.nih.gov/pubmed/23095506
280. Kench, J.G., et al. Dataset for the reporting of prostate carcinoma in radical prostatectomy
specimens: updated recommendations from the International Collaboration on Cancer Reporting.
Virchows Arch, 2019. 475: 263.
https://www.ncbi.nlm.nih.gov/pubmed/31098802
281. Gandaglia, G., et al. A Novel Nomogram to Identify Candidates for Extended Pelvic Lymph Node
Dissection Among Patients with Clinically Localized Prostate Cancer Diagnosed with Magnetic
Resonance Imaging-targeted and Systematic Biopsies. Eur Urol, 2019. 75: 506.
https://www.ncbi.nlm.nih.gov/pubmed/30342844
282. Partin, A.W., et al. Contemporary update of prostate cancer staging nomograms (Partin Tables) for
the new millennium. Urology, 2001. 58: 843.
https://www.ncbi.nlm.nih.gov/pubmed/11744442
283. Magi-Galluzzi, C., et al. International Society of Urological Pathology (ISUP) Consensus Conference
on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic
extension, lymphovascular invasion and locally advanced disease. Mod Pathol, 2011. 24: 26.
https://www.ncbi.nlm.nih.gov/pubmed/20802467
284. Lazzereschi, L., et al. Does the extent of extraprostatic extension at radical prostatectomy predict
outcome?-a systematic review and meta-analysis. Histopathology, 2024. 85: 727.
https://www.ncbi.nlm.nih.gov/pubmed/39108209
285. van Veggel, B.A., et al. Quantification of extraprostatic extension in prostate cancer: different
parameters correlated to biochemical recurrence after radical prostatectomy. Histopathology, 2011.
59: 692.
https://www.ncbi.nlm.nih.gov/pubmed/22014050
286. Aydin, H., et al. Positive proximal (bladder neck) margin at radical prostatectomy confers greater risk
of biochemical progression. Urology, 2004. 64: 551.
https://www.ncbi.nlm.nih.gov/pubmed/15351591
287. Ploussard, G., et al. The prognostic significance of bladder neck invasion in prostate cancer: is
microscopic involvement truly a T4 disease? BJU Int, 2010. 105: 776.
https://www.ncbi.nlm.nih.gov/pubmed/19863529
288. Stamey, T.A., et al. Prostate cancer is highly predictable: a prognostic equation based on all
morphological variables in radical prostatectomy specimens. J Urol, 2000. 163: 1155.
https://www.ncbi.nlm.nih.gov/pubmed/10737486
289. van Oort, I.M., et al. Maximum tumor diameter is not an independent prognostic factor in high-risk
localized prostate cancer. World J Urol, 2008. 26: 237.
https://www.ncbi.nlm.nih.gov/pubmed/18265988
290. van der Kwast, T.H., et al. International Society of Urological Pathology (ISUP) Consensus Conference
on Handling and Staging of Radical Prostatectomy Specimens. Working group 2: T2 substaging and
prostate cancer volume. Mod Pathol, 2011. 24: 16.
https://www.ncbi.nlm.nih.gov/pubmed/20818340
291. Epstein, J.I., et al. Prognostic factors and reporting of prostate carcinoma in radical prostatectomy
and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl, 2005: 34.
https://www.ncbi.nlm.nih.gov/pubmed/16019758
292. Evans, A.J., et al. Interobserver variability between expert urologic pathologists for extraprostatic
extension and surgical margin status in radical prostatectomy specimens. Am J Surg Pathol, 2008.
32: 1503.
https://www.ncbi.nlm.nih.gov/pubmed/18708939

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 175

293. Chuang, A.Y., et al. Positive surgical margins in areas of capsular incision in otherwise organ-
confined disease at radical prostatectomy: histologic features and pitfalls. Am J Surg Pathol, 2008.
32: 1201.
https://www.ncbi.nlm.nih.gov/pubmed/18580493
294. Hollemans, E., et al. Prostate Carcinoma Grade and Length But Not Cribriform Architecture at Positive
Surgical Margins Are Predictive for Biochemical Recurrence After Radical Prostatectomy. Am J Surg
Pathol, 2020. 44: 191.
https://www.ncbi.nlm.nih.gov/pubmed/31592799
295. Cao, D., et al. Ability of linear length of positive margin in radical prostatectomy specimens to predict
biochemical recurrence. Urology, 2011. 77: 1409.
https://www.ncbi.nlm.nih.gov/pubmed/21256540
296. John, A., et al. Length of positive surgical margins after radical prostatectomy: Does size matter? - A
systematic review and meta-analysis. Prostate Cancer Prostatic Dis, 2023. 26: 673.
https://www.ncbi.nlm.nih.gov/pubmed/36859711
297. Sammon, J.D., et al. Risk factors for biochemical recurrence following radical perineal prostatectomy
in a large contemporary series: a detailed assessment of margin extent and location. Urol Oncol,
2013. 31: 1470.
https://www.ncbi.nlm.nih.gov/pubmed/22534086
298. Chapin, B.F., et al. Positive margin length and highest Gleason grade of tumor at the margin predict
for biochemical recurrence after radical prostatectomy in patients with organ-confined prostate
cancer. Prostate Cancer Prostatic Dis, 2018. 21: 221.
https://www.ncbi.nlm.nih.gov/pubmed/29230008
299. Dinneen, E.P., et al. Intraoperative Frozen Section for Margin Evaluation During Radical
Prostatectomy: A Systematic Review. Eur Urol Focus, 2020. 6: 664.
https://www.ncbi.nlm.nih.gov/pubmed/31787570
300. Schlomm, T., et al. Neurovascular structure-adjacent frozen-section examination (NeuroSAFE)
increases nerve-sparing frequency and reduces positive surgical margins in open and robot-assisted
laparoscopic radical prostatectomy: experience after 11,069 consecutive patients. Eur Urol, 2012. 62:
333.
https://www.ncbi.nlm.nih.gov/pubmed/22591631
301. Mirmilstein, G., et al. The neurovascular structure-adjacent frozen-section examination (NeuroSAFE)
approach to nerve sparing in robot-assisted laparoscopic radical prostatectomy in a British setting - a
prospective observational comparative study. BJU Int, 2018. 121: 854.
https://www.ncbi.nlm.nih.gov/pubmed/29124889
302. van der Slot, M.A., et al. NeuroSAFE in radical prostatectomy increases the rate of nerve-sparing
surgery without affecting oncological outcome. BJU Int, 2022. 130: 628.
https://www.ncbi.nlm.nih.gov/pubmed/35536200
303. Koseoglu, E., et al. Intraoperative Frozen Section via Neurosafe During Robotic Radical Prostatectomy
in the Era of Preoperative Risk Stratifications and Primary Staging With mpMRI and PSMA-PET CT: Is
There a Perfect Candidate? Clin Genitourin Cancer, 2023. 21: 602.
https://www.ncbi.nlm.nih.gov/pubmed/37451883
304. Dinneen, E., et al. NeuroSAFE PROOF: study protocol for a single-blinded, IDEAL stage 3, multi-centre,
randomised controlled trial of NeuroSAFE robotic-assisted radical prostatectomy versus standard
robotic-assisted radical prostatectomy in men with localized prostate cancer. Trials, 2022. 23: 584.
https://www.ncbi.nlm.nih.gov/pubmed/35869497
305. Farrell, C., et al. Prostate Multiparametric Magnetic Resonance Imaging Program Implementation and
Impact: Initial Clinical Experience in a Community Based Health System. Urol Pract, 2018. 5: 165.
https://www.ncbi.nlm.nih.gov/pubmed/37300235
306. Reesink, D.J., et al. Comparison of risk-calculator and MRI and consecutive pathways as upfront
stratification for prostate biopsy. World J Urol, 2021. 39: 2453.
https://www.ncbi.nlm.nih.gov/pubmed/33090259
307. Louie, K.S., et al. Do prostate cancer risk models improve the predictive accuracy of PSA screening?
A meta-analysis. Ann Oncol, 2015. 26: 848.
https://www.ncbi.nlm.nih.gov/pubmed/25403590
308. Mannaerts, C.K., et al. Prostate Cancer Risk Assessment in Biopsy-naïve Patients: The Rotterdam
Prostate Cancer Risk Calculator in Multiparametric Magnetic Resonance Imaging-Transrectal
Ultrasound (TRUS) Fusion Biopsy and Systematic TRUS Biopsy. Eur Urol Oncol, 2018. 1: 109.
https://www.ncbi.nlm.nih.gov/pubmed/31100233

176 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

309. Kim, L., et al. Clinical utility and cost modelling of the phi test to triage referrals into image-based
diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study. BMC Med,
2020. 18: 95.
https://www.ncbi.nlm.nih.gov/pubmed/32299423
310. Morote, J., et al. A Clinically Significant Prostate Cancer Predictive Model Using Digital Rectal
Examination Prostate Volume Category to Stratify Initial Prostate Cancer Suspicion and Reduce
Magnetic Resonance Imaging Demand. Cancers (Basel), 2022. 14.
https://www.ncbi.nlm.nih.gov/pubmed/36291883
311. Moldovan, P.C., et al. What Is the Negative Predictive Value of Multiparametric Magnetic Resonance
Imaging in Excluding Prostate Cancer at Biopsy? A Systematic Review and Meta-analysis from the
European Association of Urology Prostate Cancer Guidelines Panel. Eur Urol, 2017. 72: 250.
https://www.ncbi.nlm.nih.gov/pubmed/28336078
312. Kamal, O., et al. Intermediate-term oncological outcomes after a negative endorectal coil
multiparametric MRI of the prostate in patients without biopsy proven prostate cancer. Clin Imaging,
2022. 92: 112.
https://www.ncbi.nlm.nih.gov/pubmed/36306588
313. Oerther, B., et al. Update on PI-RADS Version 2.1 Diagnostic Performance Benchmarks for Prostate
MRI: Systematic Review and Meta-Analysis. Radiology, 2024. 312: e233337.
https://www.ncbi.nlm.nih.gov/pubmed/39136561
314. van der Leest, M., et al. Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy
Versus Multiparametric Prostate Resonance Imaging with Subsequent Magnetic Resonance-guided
Biopsy in Biopsy-naive Men with Elevated Prostate-specific Antigen: A Large Prospective Multicenter
Clinical Study. Eur Urol, 2019. 75: 570.
https://www.ncbi.nlm.nih.gov/pubmed/30477981
315. Wagensveld, I.M., et al. A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-
directed and Magnetic Resonance Imaging-directed Diagnostic Pathways for Suspected Prostate
Cancer in Biopsy-naive Men. Eur Urol, 2022. 82: 318.
https://www.ncbi.nlm.nih.gov/pubmed/35341658
316. Distler, F.A., et al. The Value of PSA Density in Combination with PI-RADS for the Accuracy of Prostate
Cancer Prediction. J Urol, 2017. 198: 575.
https://www.ncbi.nlm.nih.gov/pubmed/28373135
317. Washino, S., et al. Combination of prostate imaging reporting and data system (PI-RADS) score and
prostate-specific antigen (PSA) density predicts biopsy outcome in prostate biopsy naive patients.
BJU Int, 2017. 119: 225.
https://www.ncbi.nlm.nih.gov/pubmed/26935594
318. Schoots, I.G., et al. Risk-adapted biopsy decision based on prostate magnetic resonance imaging and
prostate-specific antigen density for enhanced biopsy avoidance in first prostate cancer diagnostic
evaluation. BJU Int, 2021. 127: 175.
https://www.ncbi.nlm.nih.gov/pubmed/33089586
319. Hansen, N.L., et al. Multicentre evaluation of targeted and systematic biopsies using magnetic
resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a
previous negative biopsy. BJU Int, 2017. 120: 631.
https://www.ncbi.nlm.nih.gov/pubmed/27862869
320. Pagniez, M.A., et al. Predictive Factors of Missed Clinically Significant Prostate Cancers in Men with
Negative Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis. J Urol, 2020. 204:
24.
https://www.ncbi.nlm.nih.gov/pubmed/31967522
321. Boesen, L., et al. Prebiopsy Biparametric Magnetic Resonance Imaging Combined with Prostate-
specific Antigen Density in Detecting and Ruling out Gleason 7-10 Prostate Cancer in Biopsy-naive
Men. Eur Urol Oncol, 2019. 2: 311.
https://www.ncbi.nlm.nih.gov/pubmed/31200846
322. Hansen, N.L., et al. The influence of prostate-specific antigen density on positive and negative
predictive values of multiparametric magnetic resonance imaging to detect Gleason score 7-10
prostate cancer in a repeat biopsy setting. BJU Int, 2017. 119: 724.
https://www.ncbi.nlm.nih.gov/pubmed/27488931
323. Oishi, M., et al. Which Patients with Negative Magnetic Resonance Imaging Can Safely Avoid Biopsy
for Prostate Cancer? J Urol, 2019. 201: 268.
https://www.ncbi.nlm.nih.gov/pubmed/30189186

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 177

324. Sigle, A., et al. Prediction of Significant Prostate Cancer in Equivocal Magnetic Resonance Imaging
Lesions: A High-volume International Multicenter Study. Eur Urol Focus, 2023. 9: 606.
https://www.ncbi.nlm.nih.gov/pubmed/36804191
325. Kortenbach, K.C., et al. Early experience in avoiding biopsies for biopsy-naive men with clinical
suspicion of prostate cancer but non-suspicious biparametric magnetic resonance imaging results
and prostate-specific antigen density < 0.15 ng/mL(2): A 2-year follow-up study. Acta Radiol Open,
2022. 11: 20584601221094825.
https://www.ncbi.nlm.nih.gov/pubmed/35464293
326. Konishi, T., et al. Combination of biparametric magnetic resonance imaging with prostate-specific
antigen density to stratify the risk of significant prostate cancer: Initial biopsy and long-term follow-
up results. Int J Urol, 2022. 29: 1031.
https://www.ncbi.nlm.nih.gov/pubmed/35697503
327. Schoots, I.G., et al. Multivariate risk prediction tools including MRI for individualized biopsy decision
in prostate cancer diagnosis: current status and future directions. World J Urol, 2020. 38: 517.
https://www.ncbi.nlm.nih.gov/pubmed/30868240
328. Saba, K., et al. External Validation and Comparison of Prostate Cancer Risk Calculators Incorporating
Multiparametric Magnetic Resonance Imaging for Prediction of Clinically Significant Prostate Cancer.
J Urol, 2020. 203: 719.
https://www.ncbi.nlm.nih.gov/pubmed/31651228
329. Radtke, J.P., et al. Prediction of significant prostate cancer in biopsy-naive men: Validation of a novel
risk model combining MRI and clinical parameters and comparison to an ERSPC risk calculator and
PI-RADS. PLoS One, 2019. 14: e0221350.
https://www.ncbi.nlm.nih.gov/pubmed/31450235
330. Pallauf, M., et al. External validation of two mpMRI-risk calculators predicting risk of prostate cancer
before biopsy. World J Urol, 2022. 40: 2451.
https://www.ncbi.nlm.nih.gov/pubmed/35941246
331. Peters, M., et al. Predicting the Need for Biopsy to Detect Clinically Significant Prostate Cancer
in Patients with a Magnetic Resonance Imaging-detected Prostate Imaging Reporting and Data
System/Likert >/=3 Lesion: Development and Multinational External Validation of the Imperial Rapid
Access to Prostate Imaging and Diagnosis Risk Score. Eur Urol, 2022. 82: 559.
https://www.ncbi.nlm.nih.gov/pubmed/35963650
332. Fazekas, T., et al. Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review
and Meta-Analysis. JAMA Oncol, 2024. 10: 745.
https://www.ncbi.nlm.nih.gov/pubmed/38576242
333. Eldred-Evans, D., et al. An Evaluation of Screening Pathways Using a Combination of Magnetic
Resonance Imaging and Prostate-specific Antigen: Results from the IP1-PROSTAGRAM Study. Eur
Urol Oncol, 2023. 6: 295.
https://www.ncbi.nlm.nih.gov/pubmed/37080821
334. Nam, R.K., et al. A Pilot Study to Evaluate the Role of Magnetic Resonance Imaging for Prostate
Cancer Screening in the General Population. J Urol, 2016. 196: 361.
https://www.ncbi.nlm.nih.gov/pubmed/26880413
335. Nam, R., et al. Prostate MRI versus PSA screening for prostate cancer detection (the MVP Study): a
randomised clinical trial. BMJ Open, 2022. 12: e059482.
https://www.ncbi.nlm.nih.gov/pubmed/36351725
336. Eichler, K., et al. Diagnostic value of systematic biopsy methods in the investigation of prostate
cancer: a systematic review. J Urol, 2006. 175: 1605.
https://www.ncbi.nlm.nih.gov/pubmed/16600713
337. Watts, K.L., et al. Systematic review and meta-analysis comparing cognitive vs. image-guided fusion
prostate biopsy for the detection of prostate cancer. Urol Oncol, 2020. 38: 734 e19.
https://www.ncbi.nlm.nih.gov/pubmed/32321689
338. Wegelin, O., et al. The FUTURE Trial: A Multicenter Randomised Controlled Trial on Target Biopsy
Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients
with Prior Negative Biopsies. Eur Urol, 2019. 75: 582.
https://www.ncbi.nlm.nih.gov/pubmed/30522912
339. Wegelin, O., et al. Comparing Three Different Techniques for Magnetic Resonance Imaging-targeted
Prostate Biopsies: A Systematic Review of In-bore versus Magnetic Resonance Imaging-transrectal
Ultrasound fusion versus Cognitive Registration. Is There a Preferred Technique? Eur Urol, 2017. 71:
517.
https://www.ncbi.nlm.nih.gov/pubmed/27568655

178 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

340. Klotz, L., et al. Comparison of Multiparametric Magnetic Resonance Imaging-Targeted Biopsy With
Systematic Transrectal Ultrasonography Biopsy for Biopsy-Naive Men at Risk for Prostate Cancer: A
Phase 3 Randomized Clinical Trial. JAMA Oncol, 2021. 7: 534.
https://www.ncbi.nlm.nih.gov/pubmed/33538782
341. Goldberg, H., et al. Comparison of Magnetic Resonance Imaging and Transrectal Ultrasound
Informed Prostate Biopsy for Prostate Cancer Diagnosis in Biopsy Naive Men: A Systematic Review
and Meta-Analysis. J Urol, 2020. 203: 1085.
https://www.ncbi.nlm.nih.gov/pubmed/31609177
342. Wei, C., et al. Multicenter Randomized Trial Assessing MRI and Image-guided Biopsy for Suspected
Prostate Cancer: The MULTIPROS Study. Radiology, 2023. 308: e221428.
https://www.ncbi.nlm.nih.gov/pubmed/37489992
343. Exterkate, L., et al. Is There Still a Need for Repeated Systematic Biopsies in Patients with Previous
Negative Biopsies in the Era of Magnetic Resonance Imaging-targeted Biopsies of the Prostate? Eur
Urol Oncol, 2020. 3: 216.
https://www.ncbi.nlm.nih.gov/pubmed/31239236
344. Leow, J.J., et al. Can we omit systematic biopsies in patients undergoing MRI fusion-targeted
prostate biopsies? Asian J Androl, 2023. 25: 43.
https://www.ncbi.nlm.nih.gov/pubmed/35488666
345. Deniffel, D., et al. Prostate biopsy in the era of MRI-targeting: towards a judicious use of additional
systematic biopsy. Eur Radiol, 2022. 32: 7544.
https://www.ncbi.nlm.nih.gov/pubmed/35507051
346. Barrett, T., et al. Quality checkpoints in the MRI-directed prostate cancer diagnostic pathway. Nat Rev
Urol, 2023. 20: 9.
https://www.ncbi.nlm.nih.gov/pubmed/36168056
347. Zattoni, F., et al. Enhancing Prostate Cancer Detection Accuracy in Magnetic Resonance Imaging-
targeted Prostate Biopsy: Optimizing the Number of Cores Taken. Eur Urol Open Sci, 2024. 66: 16.
https://www.ncbi.nlm.nih.gov/pubmed/39027654
348. Bryk, D.J., et al. The Role of Ipsilateral and Contralateral Transrectal Ultrasound-guided Systematic
Prostate Biopsy in Men With Unilateral Magnetic Resonance Imaging Lesion Undergoing Magnetic
Resonance Imaging-ultrasound Fusion-targeted Prostate Biopsy. Urology, 2017. 102: 178.
https://www.ncbi.nlm.nih.gov/pubmed/27871829
349. Freifeld, Y., et al. Optimal sampling scheme in men with abnormal multiparametric MRI undergoing
MRI-TRUS fusion prostate biopsy. Urol Oncol, 2019. 37: 57.
https://www.ncbi.nlm.nih.gov/pubmed/30446460
350. Jager, A., et al. An optimized prostate biopsy strategy in patients with a unilateral lesion on
prostate magnetic resonance imaging avoids unnecessary biopsies. Ther Adv Urol, 2022. 14:
17562872221111410.
https://www.ncbi.nlm.nih.gov/pubmed/35924207
351. Ruan, M., et al. Novel sampling scheme with reduced cores in men with multiparametric MRI-visible
lesions undergoing prostate biopsy. Abdom Radiol (NY), 2023. 48: 2139.
https://www.ncbi.nlm.nih.gov/pubmed/37036488
352. Zambon, A., et al. Which protocol for prostate biopsies in patients with a positive MRI? Interest of
systematic biopsies by sectors. Prostate Cancer Prostatic Dis, 2024. 27: 500.
https://www.ncbi.nlm.nih.gov/pubmed/38114598
353. Brisbane, W.G., et al. Targeted Prostate Biopsy: Umbra, Penumbra, and Value of Perilesional
Sampling. Eur Urol, 2022. 82: 303.
https://www.ncbi.nlm.nih.gov/pubmed/35115177
354. Noujeim, J.P., et al. Optimizing multiparametric magnetic resonance imaging-targeted biopsy and
detection of clinically significant prostate cancer: the role of perilesional sampling. Prostate Cancer
Prostatic Dis, 2023. 26: 575.
https://www.ncbi.nlm.nih.gov/pubmed/36509930
355. Hagens, M.J., et al. An Magnetic Resonance Imaging-directed Targeted-plus-perilesional Biopsy
Approach for Prostate Cancer Diagnosis: “Less Is More”. Eur Urol Open Sci, 2022. 43: 68.
https://www.ncbi.nlm.nih.gov/pubmed/36353069
356. Hagens, M.J., et al. Diagnostic Performance of a Magnetic Resonance Imaging-directed Targeted
plus Regional Biopsy Approach in Prostate Cancer Diagnosis: A Systematic Review and Meta-
analysis. Eur Urol Open Sci, 2022. 40: 95.
https://www.ncbi.nlm.nih.gov/pubmed/35540708

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 179

357. Hsieh, P.-F., et al. Saturation target biopsy can overcome the learning curve of magnetic resonance
imaging/ultrasound fusion biopsy of the prostate. J Men’s Health, 2022. 18: 1.
https://www.jomh.org/articles/10.31083/j.jomh1806127
358. Diamand, R., et al. The role of perilesional and multiparametric resonance imaging-targeted biopsies
to reduce the risk of upgrading at radical prostatectomy pathology: A retrospective monocentric
study. Urol Oncol, 2022. 40: 192 e11.
https://www.ncbi.nlm.nih.gov/pubmed/35236622
359. Ahdoot, M., et al. Using Prostate Imaging-Reporting and Data System (PI-RADS) Scores to Select an
Optimal Prostate Biopsy Method: A Secondary Analysis of the Trio Study. Eur Urol Oncol, 2022. 5:
176.
https://www.ncbi.nlm.nih.gov/pubmed/33846112
360. Barletta, F., et al. Assessing the need for systematic biopsies in addition to targeted biopsies
according to the characteristics of the index lesion at mpMRI. Results from a large, multi-institutional
database. World J Urol, 2022. 40: 2683.
https://www.ncbi.nlm.nih.gov/pubmed/36149448
361. Hou, Y., et al. A clinical available decision support scheme for optimizing prostate biopsy based on
mpMRI. Prostate Cancer Prostatic Dis, 2022. 25: 727.
https://www.ncbi.nlm.nih.gov/pubmed/35067674
362. Di Franco, F., et al. Characterization of high-grade prostate cancer at multiparametric MRI:
assessment of PI-RADS version 2.1 and version 2 descriptors across 21 readers with varying
experience (MULTI study). Insights Imaging, 2023. 14: 49.
https://www.ncbi.nlm.nih.gov/pubmed/36939970
363. de Rooij, M., et al. ESUR/ESUI consensus statements on multi-parametric MRI for the detection of
clinically significant prostate cancer: quality requirements for image acquisition, interpretation and
radiologists’ training. Eur Radiol, 2020. 30: 5404.
https://www.ncbi.nlm.nih.gov/pubmed/32424596
364. Meng, X., et al. The Institutional Learning Curve of Magnetic Resonance Imaging-Ultrasound Fusion
Targeted Prostate Biopsy: Temporal Improvements in Cancer Detection in 4 Years. J Urol, 2018. 200:
1022.
https://www.ncbi.nlm.nih.gov/pubmed/29886090
365. Saha, A., et al. Artificial intelligence and radiologists in prostate cancer detection on MRI (PI-CAI): an
international, paired, non-inferiority, confirmatory study. Lancet Oncol, 2024. 25: 879.
https://www.ncbi.nlm.nih.gov/pubmed/38876123
366. Rouviere, O., et al. Artificial intelligence algorithms aimed at characterizing or detecting prostate
cancer on MRI: How accurate are they when tested on independent cohorts? - A systematic review.
Diagn Interv Imaging, 2023. 104: 221.
https://www.ncbi.nlm.nih.gov/pubmed/36517398
367. Dell’Oglio, P., et al. Impact of multiparametric MRI and MRI-targeted biopsy on pre-therapeutic risk
assessment in prostate cancer patients candidate for radical prostatectomy. World J Urol, 2019. 37:
221.
https://www.ncbi.nlm.nih.gov/pubmed/29948044
368. Faiena, I., et al. PI-RADS Version 2 Category on 3 Tesla Multiparametric Prostate Magnetic
Resonance Imaging Predicts Oncologic Outcomes in Gleason 3 + 4 Prostate Cancer on Biopsy. J
Urol, 2019. 201: 91.
https://www.ncbi.nlm.nih.gov/pubmed/30142318
369. Houlahan, K.E., et al. Molecular Hallmarks of Multiparametric Magnetic Resonance Imaging Visibility
in Prostate Cancer. Eur Urol, 2019. 76: 18.
https://www.ncbi.nlm.nih.gov/pubmed/30685078
370. Gaffney, C.D., et al. The oncologic risk of magnetic resonance imaging-targeted and systematic cores
in patients treated with radical prostatectomy. Cancer, 2023. 129: 3790.
https://www.ncbi.nlm.nih.gov/pubmed/37584213
371. Scuderi, S., et al. The Highest Grade Group Does Not Drive the Risk of Recurrence when Systematic
and Multiparametric Magnetic Resonance Imaging (MRI)-targeted Biopsies are Discordant:
Preliminary Findings Using Radical Prostatectomy Pathology as a Surrogate for MRI-targeted Biopsy
Grade. Eur Urol Focus, 2024. 10: 486.
https://www.ncbi.nlm.nih.gov/pubmed/37739916
372. Lam, T.B.L., et al. EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guideline Panel Consensus
Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer from an
International Collaborative Study (DETECTIVE Study). Eur Urol, 2019. 76: 790.
https://www.ncbi.nlm.nih.gov/pubmed/31587989

180 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

373. Kanagarajah, A., et al. A systematic review on the outcomes of local anaesthetic transperineal
prostate biopsy. BJU Int, 2023. 131: 408.
https://www.ncbi.nlm.nih.gov/pubmed/36177521
374. Pradere, B., et al. Nonantibiotic Strategies for the Prevention of Infectious Complications following
Prostate Biopsy: A Systematic Review and Meta-Analysis. J Urol, 2021. 205: 653.
https://www.ncbi.nlm.nih.gov/pubmed/33026903
375. Tu, X., et al. Transperineal Magnetic Resonance Imaging-Targeted Biopsy May Perform Better Than
Transrectal Route in the Detection of Clinically Significant Prostate Cancer: Systematic Review and
Meta-analysis. Clin Genitourin Cancer, 2019. 17: e860.
https://www.ncbi.nlm.nih.gov/pubmed/31281065
376. Hu, J.C., et al. Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted and
Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial.
Eur Urol, 2024. 86: 61.
https://www.ncbi.nlm.nih.gov/pubmed/38212178
377. Mian, B.M., et al. Complications Following Transrectal and Transperineal Prostate Biopsy: Results of
the ProBE-PC Randomized Clinical Trial. J Urol, 2024. 211: 205.
https://www.ncbi.nlm.nih.gov/pubmed/37976319
378. Ploussard, G., et al. Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted Biopsies
for Prostate Cancer Diagnosis: Final Results of the Randomized PERFECT trial (CCAFU-PR1). Eur Urol
Oncol, 2024. 7: 1080.
https://www.ncbi.nlm.nih.gov/pubmed/38403523
379. von Knobloch, R., et al. Bilateral fine-needle administered local anaesthetic nerve block for pain
control during TRUS-guided multi-core prostate biopsy: a prospective randomised trial. Eur Urol,
2002. 41: 508.
https://www.ncbi.nlm.nih.gov/pubmed/12074792
380. Adamakis, I., et al. Pain during transrectal ultrasonography guided prostate biopsy: a randomized
prospective trial comparing periprostatic infiltration with lidocaine with the intrarectal instillation of
lidocaine-prilocain cream. World J Urol, 2004. 22: 281.
https://www.ncbi.nlm.nih.gov/pubmed/14689224
381. Bass, E.J., et al. Magnetic resonance imaging targeted transperineal prostate biopsy: a local
anaesthetic approach. Prostate Cancer Prostatic Dis, 2017. 20: 311.
https://www.ncbi.nlm.nih.gov/pubmed/28485391
382. Xiang, J., et al. Transperineal versus transrectal prostate biopsy in the diagnosis of prostate cancer: a
systematic review and meta-analysis. World J Surg Oncol, 2019. 17: 31.
https://www.ncbi.nlm.nih.gov/pubmed/30760274
383. Iremashvili, V.V., et al. Periprostatic local anesthesia with pudendal block for transperineal ultrasound-
guided prostate biopsy: a randomized trial. Urology, 2010. 75: 1023.
https://www.ncbi.nlm.nih.gov/pubmed/20080288
384. He, B.M., et al. Perineal nerve block versus periprostatic block for patients undergoing transperineal
prostate biopsy (APROPOS): a prospective, multicentre, randomised controlled study. EClinMed,
2023. 58: 101919.
https://www.ncbi.nlm.nih.gov/pubmed/37007736
385. Meyer, A.R., et al. Initial Experience Performing In-office Ultrasound-guided Transperineal Prostate
Biopsy Under Local Anesthesia Using the PrecisionPoint Transperineal Access System. Urology,
2018. 115: 8.
https://www.ncbi.nlm.nih.gov/pubmed/29409845
386. Lam, W., et al. Prostate cancer detection, tolerability and safety of transperineal prostate biopsy
under local-anaesthesia vs standard transrectal biopsy in biopsy-naive men: a pragmatic, parallel
group, randomized controlled study. BJU Int, 2022. 129: 9.
https://bjui-journals.onlinelibrary.wiley.com/F/epdf/10.1111/bju.15675
387. Farooq, K., et al. Role of Povidone-Iodine-Soaked Gauze in Preventing Infectious Complications
Following Trans Rectal Digital Guided Prostate Biopsy. J Postgrad Med Inst, 2021. 35: 225.
https://jpmi.org.pk/index.php/jpmi/article/view/2849
388. Bennett, H.Y., et al. The global burden of major infectious complications following prostate biopsy.
Epidemiol Infect, 2016. 144: 1784.
https://www.ncbi.nlm.nih.gov/pubmed/26645476
389. Berry, B., et al. Comparison of complications after transrectal and transperineal prostate biopsy: a
national population-based study. BJU Int, 2020. 126: 97.
https://www.ncbi.nlm.nih.gov/pubmed/32124525

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 181

390. Castellani, D., et al. Infection Rate after Transperineal Prostate Biopsy with and without Prophylactic
Antibiotics: Results from a Systematic Review and Meta-Analysis of Comparative Studies. J Urol,
2022. 207: 25.
https://www.ncbi.nlm.nih.gov/pubmed/34555932
391. Basourakos, S.P., et al. Role of Prophylactic Antibiotics in Transperineal Prostate Biopsy: A
Systematic Review and Meta-analysis. Eur Urol Open Sci, 2022. 37: 53.
https://www.ncbi.nlm.nih.gov/pubmed/35243391
392. Chernysheva, D.Y., et al. The first experience of transperineal prostate biopsy without antibiotic
prophylaxis. Cancer Urol, 2021. 17: 46.
https://oncourology.abvpress.ru/oncur/article/view/1392
393. Jacewicz, M., et al. Antibiotic prophylaxis versus no antibiotic prophylaxis in transperineal prostate
biopsies (NORAPP): a randomised, open-label, non-inferiority trial. Lancet Infect Dis, 2022. 22: 1465.
https://www.ncbi.nlm.nih.gov/pubmed/35839791
394. Shaker, H.S., et al. Does The Use Of Povidone Iodine Suppository Decrease The Infective
Complications Of TRUS Guided Prostate Biopsies? A Randomized Prospective Study. QJM: Int J Med,
2020. 113.
https://academic.oup.com/qjmed/article/113/Supplement_1/hcaa070.024/5829649
395. Yu, L., et al. [Impact of insertion timing of iodophor cotton ball on the control of infection
complications after transrectal ultrasound guided prostate biopsy]. Zhonghua Yi Xue Za Zhi, 2014.
94: 609.
https://www.ncbi.nlm.nih.gov/pubmed/24762693
396. Pilatz, A., et al. Antibiotic Prophylaxis for the Prevention of Infectious Complications following
Prostate Biopsy: A Systematic Review and Meta-Analysis. J Urol, 2020. 204: 224.
https://www.ncbi.nlm.nih.gov/pubmed/32105195
397. EMA. Disabling and potentially permanent side effects lead to suspension or restrictions of
quinolone and fluoroquinolone antibiotics. 2019. EMA/175398/2019.
https://www.ema.europa.eu/en/news/disabling-potentially-permanent-side-effects-lead-suspension-
or-restrictions-quinolone-fluoroquinolone-antibiotics
398. Carignan, A., et al. Effectiveness of fosfomycin tromethamine prophylaxis in preventing infection
following transrectal ultrasound-guided prostate needle biopsy: Results from a large Canadian
cohort. J Glob Antimicrob Resist, 2019. 17: 112.
https://www.ncbi.nlm.nih.gov/pubmed/30553114
399. Wegelin, O., et al. Complications and Adverse Events of Three Magnetic Resonance Imaging-based
Target Biopsy Techniques in the Diagnosis of Prostate Cancer Among Men with Prior Negative
Biopsies: Results from the FUTURE Trial, a Multicentre Randomised Controlled Trial. Eur Urol Oncol,
2019. 2: 617.
https://www.ncbi.nlm.nih.gov/pubmed/31519516
400. Borghesi, M., et al. Complications After Systematic, Random, and Image-guided Prostate Biopsy. Eur
Urol, 2017. 71: 353.
https://www.ncbi.nlm.nih.gov/pubmed/27543165
401. Giannarini, G., et al. Continuing or discontinuing low-dose aspirin before transrectal prostate biopsy:
results of a prospective randomized trial. Urology, 2007. 70: 501.
https://www.ncbi.nlm.nih.gov/pubmed/17688919
402. Garcia, C., et al. Does transperineal prostate biopsy reduce complications compared with transrectal
biopsy? a systematic review and meta-analysis of randomised controlled trials. 2016. 195:4 SUPPL. 1
p. e328.
http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=cctr&NEWS=N&AN=CN-01142664
403. Xue, J., et al. Comparison between transrectal and transperineal prostate biopsy for detection of
prostate cancer: a meta-analysis and trial sequential analysis. Oncotarget, 2017. 8: 23322.
https://www.ncbi.nlm.nih.gov/pubmed/28177897
404. Padhani, A.R., et al. PI-RADS Steering Committee: The PI-RADS Multiparametric MRI and MRI-directed
Biopsy Pathway. Radiology, 2019. 292: 464.
https://www.ncbi.nlm.nih.gov/pubmed/31184561
405. Stranne, J., et al. Systematic Biopsies as a Complement to Magnetic Resonance Imaging-targeted
Biopsies: “To Be or Not To Be”? Eur Urol, 2023. 83: 381.
https://www.ncbi.nlm.nih.gov/pubmed/36737297
406. Schoots, I.G., et al. Analysis of Magnetic Resonance Imaging-directed Biopsy Strategies for Changing
the Paradigm of Prostate Cancer Diagnosis. Eur Urol Oncol, 2020. 3: 32.
https://www.ncbi.nlm.nih.gov/pubmed/31706946

182 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

407. Bittencourt, L.K., et al. Risk-based MRI-directed diagnostic pathway outperforms non-risk-based
pathways in suspected prostate cancer biopsy-naive men: a large cohort validation study. Eur Radiol,
2022. 32: 2330.
https://www.ncbi.nlm.nih.gov/pubmed/35028750
408. Stroomberg, H.V., et al. Standardized prostate cancer incidence and mortality rates following initial
non-malignant biopsy result. BJU Int, 2023. 132: 181.
https://www.ncbi.nlm.nih.gov/pubmed/36847603
409. Grivas, N., et al. Prostate Cancer Detection Percentages of Repeat Biopsy in Patients with Positive
Multiparametric Magnetic Resonance Imaging (Prostate Imaging Reporting and Data System/Likert
3-5) and Negative Initial Biopsy. A Mini Systematic Review. Eur Urol, 2022. 82: 452.
https://www.ncbi.nlm.nih.gov/pubmed/35985901
410. Ericson, K.J., et al. Prostate cancer detection following diagnosis of atypical small acinar
proliferation. Can J Urol, 2017. 24: 8714.
https://www.ncbi.nlm.nih.gov/pubmed/28436357
411. Wiener, S., et al. Incidence of Clinically Significant Prostate Cancer After a Diagnosis of Atypical
Small Acinar Proliferation, High-grade Prostatic Intraepithelial Neoplasia, or Benign Tissue. Urology,
2017. 110: 161.
https://www.ncbi.nlm.nih.gov/pubmed/28888752
412. Walz, J., et al. High incidence of prostate cancer detected by saturation biopsy after previous
negative biopsy series. Eur Urol, 2006. 50: 498.
https://www.ncbi.nlm.nih.gov/pubmed/16631303
413. Moran, B.J., et al. Re-biopsy of the prostate using a stereotactic transperineal technique. J Urol, 2006.
176: 1376.
https://www.ncbi.nlm.nih.gov/pubmed/16952636
414. Panebianco, V., et al. Negative Multiparametric Magnetic Resonance Imaging for Prostate Cancer:
What’s Next? Eur Urol, 2018. 74: 48.
https://www.ncbi.nlm.nih.gov/pubmed/29566957
415. Linzer, D.G., et al. Seminal vesicle biopsy: accuracy and implications for staging of prostate cancer.
Urology, 1996. 48: 757.
https://www.ncbi.nlm.nih.gov/pubmed/8911521
416. Pelzer, A.E., et al. Are transition zone biopsies still necessary to improve prostate cancer detection?
Results from the tyrol screening project. Eur Urol, 2005. 48: 916.
https://www.ncbi.nlm.nih.gov/pubmed/16126324
417. Paner, G.P., et al. Updates in the Eighth Edition of the Tumor-Node-Metastasis Staging Classification
for Urologic Cancers. Eur Urol, 2018. 73: 560.
https://www.ncbi.nlm.nih.gov/pubmed/29325693
418. Expert Panel on Urologic, I., et al. ACR Appropriateness Criteria((R)) Prostate Cancer-Pretreatment
Detection, Surveillance, and Staging. J Am Coll Radiol, 2017. 14: S245.
https://www.ncbi.nlm.nih.gov/pubmed/28473080
419. de Rooij, M., et al. Accuracy of Magnetic Resonance Imaging for Local Staging of Prostate Cancer: A
Diagnostic Meta-analysis. Eur Urol, 2016. 70: 233.
https://www.ncbi.nlm.nih.gov/pubmed/26215604
420. Chandrasekar, T., et al. Multiparametric MRI is not sufficient for prostate cancer staging: A single
institutional experience validated by a multi-institutional regional collaborative. Urol Oncol, 2023. 41:
355 e1.
https://www.ncbi.nlm.nih.gov/pubmed/37357123
421. Merriman, K.M., et al. Comparison of MRI-Based Staging and Pathologic Staging for Predicting
Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy. AJR Am J Roentgenol,
2023. 221: 773.
https://www.ncbi.nlm.nih.gov/pubmed/37404084
422. Soeterik, T.F.W., et al. Multiparametric Magnetic Resonance Imaging Should Be Preferred Over Digital
Rectal Examination for Prostate Cancer Local Staging and Disease Risk Classification. Urology, 2021.
147: 205.
https://www.ncbi.nlm.nih.gov/pubmed/33129868
423. Futterer, J.J., et al. Staging prostate cancer with dynamic contrast-enhanced endorectal MR imaging
prior to radical prostatectomy: experienced versus less experienced readers. Radiology, 2005. 237:
541.
https://www.ncbi.nlm.nih.gov/pubmed/16244263

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 183

424. Kim, T.H., et al. The Diagnostic Performance of the Length of Tumor Capsular Contact on MRI for
Detecting Prostate Cancer Extraprostatic Extension: A Systematic Review and Meta-Analysis. Korean
J Radiol, 2020. 21: 684.
https://www.ncbi.nlm.nih.gov/pubmed/32410407
425. Valentin, B., et al. Magnetic resonance imaging improves the prediction of tumor staging in localized
prostate cancer. Abdom Radiol (NY), 2021. 46: 2751.
https://www.ncbi.nlm.nih.gov/pubmed/33452898
426. Gatti, M., et al. mEPE-score: a comprehensive grading system for predicting pathologic extraprostatic
extension of prostate cancer at multiparametric magnetic resonance imaging. Eur Radiol, 2022. 32:
4942.
https://www.ncbi.nlm.nih.gov/pubmed/35290508
427. Park, K.J., et al. Extraprostatic Tumor Extension: Comparison of Preoperative Multiparametric MRI
Criteria and Histopathologic Correlation after Radical Prostatectomy. Radiology, 2020. 296: 87.
https://www.ncbi.nlm.nih.gov/pubmed/32368959
428. Morlacco, A., et al. Nomograms in Urologic Oncology: Lights and Shadows. J Clin Med, 2021. 10.
https://www.ncbi.nlm.nih.gov/pubmed/33801184
429. Leyh-Bannurah, S.R., et al. Combined systematic versus stand-alone multiparametric MRI-guided
targeted fusion biopsy: nomogram prediction of non-organ-confined prostate cancer. World J Urol,
2021. 39: 81.
https://www.ncbi.nlm.nih.gov/pubmed/32248363
430. Diamand, R., et al. External Validation of a Multiparametric Magnetic Resonance Imaging-based
Nomogram for the Prediction of Extracapsular Extension and Seminal Vesicle Invasion in Prostate
Cancer Patients Undergoing Radical Prostatectomy. Eur Urol, 2021. 79: 180.
https://www.ncbi.nlm.nih.gov/pubmed/33023770
431. Alves, J.R., et al. Independent external validation of nomogram to predict extracapsular extension in
patients with prostate cancer. Eur Radiol, 2020. 30: 5004.
https://www.ncbi.nlm.nih.gov/pubmed/32307562
432. Abuzallouf, S., et al. Baseline staging of newly diagnosed prostate cancer: a summary of the
literature. J Urol, 2004. 171: 2122.
https://www.ncbi.nlm.nih.gov/pubmed/15126770
433. Kiss, B., et al. Current Status of Lymph Node Imaging in Bladder and Prostate Cancer. Urology, 2016.
96: 1.
https://www.ncbi.nlm.nih.gov/pubmed/26966038
434. Harisinghani, M.G., et al. Noninvasive detection of clinically occult lymph-node metastases in
prostate cancer. N Engl J Med, 2003. 348: 2491.
https://www.ncbi.nlm.nih.gov/pubmed/12815134
435. Hovels, A.M., et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in
patients with prostate cancer: a meta-analysis. Clin Radiol, 2008. 63: 387.
https://www.ncbi.nlm.nih.gov/pubmed/18325358
436. Valentin, B., et al. Comparison of 3 T mpMRI and pelvic CT examinations for detection of lymph node
metastases in patients with prostate cancer. Eur J Radiol, 2022. 147: 110110.
https://www.ncbi.nlm.nih.gov/pubmed/34952329
437. Lebastchi, A.H., et al. Comparison of cross-sectional imaging techniques for the detection of prostate
cancer lymph node metastasis: a critical review. Transl Androl Urol, 2020. 9: 1415.
https://www.ncbi.nlm.nih.gov/pubmed/32676426
438. Draulans, C., et al. Development and External Validation of a Multiparametric Magnetic Resonance
Imaging and International Society of Urological Pathology Based Add-On Prediction Tool to Identify
Prostate Cancer Candidates for Pelvic Lymph Node Dissection. J Urol, 2020. 203: 713.
https://www.ncbi.nlm.nih.gov/pubmed/31718396
439. Gandaglia, G., et al. External Validation of the 2019 Briganti Nomogram for the Identification of
Prostate Cancer Patients Who Should Be Considered for an Extended Pelvic Lymph Node Dissection.
Eur Urol, 2020. 78: 138.
https://www.ncbi.nlm.nih.gov/pubmed/32268944
440. Di Pierro, G.B., et al. Comparison of Four Validated Nomograms (Memorial Sloan Kettering Cancer
Center, Briganti 2012, 2017, and 2019) Predicting Lymph Node Invasion in Patients with High-Risk
Prostate Cancer Candidates for Radical Prostatectomy and Extended Pelvic Lymph Node Dissection:
Clinical Experience and Review of the Literature. Cancers (Basel), 2023. 15.
https://www.ncbi.nlm.nih.gov/pubmed/36980571

184 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

441. Lodeta, B., et al. Benefit and harm of lymphadenectomy in intermediate risk prostate cancer:
comparison of five nomograms. BMC Urol, 2023. 23: 190.
https://www.ncbi.nlm.nih.gov/pubmed/37980520
442. Gandaglia, G., et al. Identification of the Optimal Candidates for Nodal Staging with Extended Pelvic
Lymph Node Dissection Among Prostate Cancer Patients Who Underwent Preoperative Prostate-
specific Membrane Antigen Positron Emission Tomography. External Validation of the Memorial
Sloan Kettering Cancer Center and Briganti Nomograms and Development of a Novel Tool. Eur Urol
Oncol, 2023. 6: 543.
https://www.ncbi.nlm.nih.gov/pubmed/37270378
443. von Eyben, F.E., et al. Meta-analysis of (11)C-choline and (18)F-choline PET/CT for management of
patients with prostate cancer. Nucl Med Commun, 2014. 35: 221.
https://www.ncbi.nlm.nih.gov/pubmed/24240194
444. Van den Bergh, L., et al. Final analysis of a prospective trial on functional imaging for nodal staging in
patients with prostate cancer at high risk for lymph node involvement. Urol Oncol, 2015. 33: 109 e23.
https://www.ncbi.nlm.nih.gov/pubmed/25655681
445. Schiavina, R., et al. Preoperative Staging With (11)C-Choline PET/CT Is Adequately Accurate in
Patients With Very High-Risk Prostate Cancer. Clin Genitourin Cancer, 2018. 16: 305.
https://www.ncbi.nlm.nih.gov/pubmed/29859737
446. Evangelista, L., et al. A Prospective Randomized Multicenter Study on the Impact of [(18)F]F-Choline
PET/CT Versus Conventional Imaging for Staging Intermediate- to High-Risk Prostate Cancer. J Nucl
Med, 2024. 65: 1013.
https://www.ncbi.nlm.nih.gov/pubmed/38844361
447. Maurer, T., et al. Current use of PSMA-PET in prostate cancer management. Nat Rev Urol, 2016. 13:
226.
https://www.ncbi.nlm.nih.gov/pubmed/26902337
448. Werner, R.A., et al. (18)F-Labeled, PSMA-Targeted Radiotracers: Leveraging the Advantages of
Radiofluorination for Prostate Cancer Molecular Imaging. Theranostics, 2020. 10: 1.
https://www.ncbi.nlm.nih.gov/pubmed/31903102
449. Hope, T.A., et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection
Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection: A Multicenter Prospective Phase
3 Imaging Trial. JAMA Oncol, 2021. 7: 1635.
https://www.ncbi.nlm.nih.gov/pubmed/34529005
450. van Kalmthout, L.W.M., et al. Prospective Validation of Gallium-68 Prostate Specific Membrane
Antigen-Positron Emission Tomography/Computerized Tomography for Primary Staging of Prostate
Cancer. J Urol, 2020. 203: 537.
https://www.ncbi.nlm.nih.gov/pubmed/31487220
451. Jansen, B.H.E., et al. Pelvic lymph-node staging with (18)F-DCFPyL PET/CT prior to extended pelvic
lymph-node dissection in primary prostate cancer - the SALT trial. Eur J Nucl Med Mol Imaging, 2021.
48: 509.
https://www.ncbi.nlm.nih.gov/pubmed/32789599
452. Pienta, K.J., et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate
Specific Membrane Antigen PET/CT with (18)F-DCFPyL in Prostate Cancer Patients (OSPREY). J Urol,
2021. 206: 52.
https://www.ncbi.nlm.nih.gov/pubmed/33634707
453. Perera, M., et al. Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography
in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of
Prostate-specific Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis. Eur Urol,
2020. 77: 403.
https://www.ncbi.nlm.nih.gov/pubmed/30773328
454. Wu, H., et al. Diagnostic Performance of (68)Gallium Labelled Prostate-Specific Membrane Antigen
Positron Emission Tomography/Computed Tomography and Magnetic Resonance Imaging for
Staging the Prostate Cancer with Intermediate or High Risk Prior to Radical Prostatectomy: A
Systematic Review and Meta-analysis. World J Mens Health, 2020. 38: 208.
https://www.ncbi.nlm.nih.gov/pubmed/31081294
455. Van Damme, J., et al. Comparison of (68)Ga-Prostate Specific Membrane Antigen (PSMA) Positron
Emission Tomography Computed Tomography (PET-CT) and Whole-Body Magnetic Resonance
Imaging (WB-MRI) with Diffusion Sequences (DWI) in the Staging of Advanced Prostate Cancer.
Cancers (Basel), 2021. 13.
https://www.ncbi.nlm.nih.gov/pubmed/34771449

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 185

456. Meijer, D., et al. External Validation and Addition of Prostate-specific Membrane Antigen Positron
Emission Tomography to the Most Frequently Used Nomograms for the Prediction of Pelvic Lymph-
node Metastases: an International Multicenter Study. Eur Urol, 2021. 80: 234.
https://www.ncbi.nlm.nih.gov/pubmed/34024652
457. Vis, A.N., et al. Development and External Validation of a Novel Nomogram to Predict the Probability
of Pelvic Lymph-node Metastases in Prostate Cancer Patients Using Magnetic Resonance Imaging
and Molecular Imaging with Prostate-specific Membrane Antigen Positron Emission Tomography.
Eur Urol Oncol, 2023. 6: 553.
https://www.ncbi.nlm.nih.gov/pubmed/37045707
458. Fossati, N., et al. The Benefits and Harms of Different Extents of Lymph Node Dissection During
Radical Prostatectomy for Prostate Cancer: A Systematic Review. Eur Urol, 2017. 72: 84.
https://www.ncbi.nlm.nih.gov/pubmed/28126351
459. Lestingi, J.F.P., et al. Extended Versus Limited Pelvic Lymph Node Dissection During Radical
Prostatectomy for Intermediate- and High-risk Prostate Cancer: Early Oncological Outcomes from a
Randomized Phase 3 Trial. Eur Urol, 2021. 79: 595.
https://www.ncbi.nlm.nih.gov/pubmed/33293077
460. Touijer, K.A., et al. Limited versus Extended Pelvic Lymph Node Dissection for Prostate Cancer: A
Randomized Clinical Trial. Eur Urol Oncol, 2021. 4: 532.
https://www.ncbi.nlm.nih.gov/pubmed/33865797
461. Touijer, K.A., et al. Pelvic Lymph Node Dissection in Prostate Cancer: Update from a Randomized
Clinical Trial of Limited Versus Extended Dissection. Eur Urol, 2024.
https://www.ncbi.nlm.nih.gov/pubmed/39472200
462. Engel, J., et al. Survival benefit of radical prostatectomy in lymph node-positive patients with prostate
cancer. Eur Urol, 2010. 57: 754.
https://www.ncbi.nlm.nih.gov/pubmed/20106588
463. van der Poel, H.G., et al. Sentinel node biopsy for prostate cancer: report from a consensus panel
meeting. BJU Int, 2017. 120: 204.
https://www.ncbi.nlm.nih.gov/pubmed/28188689
464. Harke, N.N., et al. Fluorescence-supported lymphography and extended pelvic lymph node dissection
in robot-assisted radical prostatectomy: a prospective, randomized trial. World J Urol, 2018. 36: 1817.
https://www.ncbi.nlm.nih.gov/pubmed/29767326
465. Wit, E.M.K., et al. Sentinel Node Procedure in Prostate Cancer: A Systematic Review to Assess
Diagnostic Accuracy. Eur Urol, 2017. 71: 596.
https://www.ncbi.nlm.nih.gov/pubmed/27639533
466. de Pablos-Rodriguez, P., et al. Personalised indocyanine-guided lymphadenectomy for prostate
cancer: a randomised clinical trial. BJU Int, 2023. 132: 591.
https://www.ncbi.nlm.nih.gov/pubmed/37410659
467. Berrens, A.C., et al. State of the Art in Prostate-specific Membrane Antigen-targeted Surgery-A
Systematic Review. Eur Urol Open Sci, 2023. 54: 43.
https://www.ncbi.nlm.nih.gov/pubmed/37361200
468. Burkhard, F.C., et al. The role of lymphadenectomy in prostate cancer. Nat Clin Pract Urol, 2005. 2:
336.
https://www.ncbi.nlm.nih.gov/pubmed/16474786
469. Briganti, A., et al. Complications and other surgical outcomes associated with extended pelvic
lymphadenectomy in men with localized prostate cancer. Eur Urol, 2006. 50: 1006.
https://www.ncbi.nlm.nih.gov/pubmed/16959399
470. Tyritzis, S.I., et al. Thromboembolic complications in 3,544 patients undergoing radical
prostatectomy with or without lymph node dissection. J Urol, 2015. 193: 117.
https://www.ncbi.nlm.nih.gov/pubmed/25158271
471. May, M., et al. Impact of Peritoneal Interposition Flap on Patients Undergoing Robot-assisted Radical
Prostatectomy and Pelvic Lymph Node Dissection: A Systematic Review and Meta-analysis of
Randomized Controlled Trials. Eur Urol Focus, 2024. 10: 80.
https://www.ncbi.nlm.nih.gov/pubmed/37541915
472. Neuberger, M., et al. Peritoneal Flap for Lymphocele Prophylaxis Following Robotic-assisted Radical
Prostatectomy with Lymph Node Dissection: The Randomised Controlled Phase 3 PELYCAN Trial. Eur
Urol Oncol, 2024. 7: 53.
https://www.ncbi.nlm.nih.gov/pubmed/37543465
473. Shen, G., et al. Comparison of choline-PET/CT, MRI, SPECT, and bone scintigraphy in the diagnosis of
bone metastases in patients with prostate cancer: a meta-analysis. Skeletal Radiol, 2014. 43: 1503.
https://www.ncbi.nlm.nih.gov/pubmed/24841276

186 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

474. Briganti, A., et al. When to perform bone scan in patients with newly diagnosed prostate cancer:
external validation of the currently available guidelines and proposal of a novel risk stratification tool.
Eur Urol, 2010. 57: 551.
https://www.ncbi.nlm.nih.gov/pubmed/20034730
475. Lin, Y., et al. When to perform bone scintigraphy in patients with newly diagnosed prostate cancer? a
retrospective study. BMC Urol, 2017. 17: 41.
https://www.ncbi.nlm.nih.gov/pubmed/28606069
476. O’Sullivan, J.M., et al. Broadening the criteria for avoiding staging bone scans in prostate cancer: a
retrospective study of patients at the Royal Marsden Hospital. BJU Int, 2003. 92: 685.
https://www.ncbi.nlm.nih.gov/pubmed/14616446
477. Ayyathurai, R., et al. A study on staging bone scans in newly diagnosed prostate cancer. Urol Int,
2006. 76: 209.
https://www.ncbi.nlm.nih.gov/pubmed/16601380
478. Mohseninia, N., et al. Bone Metastasis in Prostate Cancer: Bone Scan Versus PET Imaging. Semin
Nucl Med, 2024. 54: 97.
https://www.ncbi.nlm.nih.gov/pubmed/37596138
479. Benard, F., et al. Intra-individual comparison of (18)F-sodium fluoride PET-CT and (99m)Tc bone
scintigraphy with SPECT in patients with prostate cancer or breast cancer at high risk for skeletal
metastases (MITNEC-A1): a multicentre, phase 3 trial. Lancet Oncol, 2022. 23: 1499.
https://www.ncbi.nlm.nih.gov/pubmed/36343655
480. Tateishi, U., et al. A meta-analysis of (18)F-Fluoride positron emission tomography for assessment of
metastatic bone tumor. Ann Nucl Med, 2010. 24: 523.
https://www.ncbi.nlm.nih.gov/pubmed/20559896
481. Evangelista, L., et al. Diagnostic imaging to detect and evaluate response to therapy in bone
metastases from prostate cancer: current modalities and new horizons. Eur J Nucl Med Mol Imaging,
2016. 43: 1546.
https://www.ncbi.nlm.nih.gov/pubmed/26956538
482. Zacho, H.D., et al. No Added Value of (18)F-Sodium Fluoride PET/CT for the Detection of Bone
Metastases in Patients with Newly Diagnosed Prostate Cancer with Normal Bone Scintigraphy. J
Nucl Med, 2019. 60: 1713.
https://www.ncbi.nlm.nih.gov/pubmed/31147402
483. Brogsitter, C., et al. 18F-Choline, 11C-choline and 11C-acetate PET/CT: comparative analysis for
imaging prostate cancer patients. Eur J Nucl Med Mol Imaging, 2013. 40 Suppl 1: S18.
https://www.ncbi.nlm.nih.gov/pubmed/23579863
484. Picchio, M., et al. [11C]Choline PET/CT detection of bone metastases in patients with PSA
progression after primary treatment for prostate cancer: comparison with bone scintigraphy. Eur J
Nucl Med Mol Imaging, 2012. 39: 13.
https://www.ncbi.nlm.nih.gov/pubmed/21932120
485. Uprimny, C., et al. (68)Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason
score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging,
2017. 44: 941.
https://www.ncbi.nlm.nih.gov/pubmed/28138747
486. Van Nieuwenhove, S., et al. Whole-body magnetic resonance imaging for prostate cancer
assessment: Current status and future directions. J Magn Reson Imaging, 2022. 55: 653.
https://www.ncbi.nlm.nih.gov/pubmed/33382151
487. Corfield, J., et al. (68)Ga-prostate specific membrane antigen (PSMA) positron emission tomography
(PET) for primary staging of high-risk prostate cancer: a systematic review. World J Urol, 2018. 36:
519.
https://www.ncbi.nlm.nih.gov/pubmed/29344682
488. Hofman, M.S., et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate
cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised,
multicentre study. Lancet, 2020. 395: 1208.
https://www.ncbi.nlm.nih.gov/pubmed/32209449
489. Anttinen, M., et al. A Prospective Comparison of (18)F-prostate-specific Membrane Antigen-1007
Positron Emission Tomography Computed Tomography, Whole-body 1.5 T Magnetic Resonance
Imaging with Diffusion-weighted Imaging, and Single-photon Emission Computed Tomography/
Computed Tomography with Traditional Imaging in Primary Distant Metastasis Staging of Prostate
Cancer (PROSTAGE). Eur Urol Oncol, 2021. 4: 635.
https://www.ncbi.nlm.nih.gov/pubmed/32675047

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 187

490. Djaileb, L., et al. Presurgical (68)Ga-PSMA-11 Positron Emission Tomography for Biochemical
Recurrence Risk Assessment: A Follow-up Analysis of a Multicenter Prospective Phase 3 Imaging
Trial. Eur Urol, 2023. 84: 588.
https://www.ncbi.nlm.nih.gov/pubmed/37482512
491. Cornford, P., et al. Prostate-specific Membrane Antigen Positron Emission Tomography Scans Before
Curative Treatment: Ready for Prime Time? Eur Urol, 2020. 78: e125.
https://www.ncbi.nlm.nih.gov/pubmed/32624287
492. Hicks, R.J., et al. Seduction by Sensitivity: Reality, Illusion, or Delusion? The Challenge of Assessing
Outcomes after PSMA Imaging Selection of Patients for Treatment. J Nucl Med, 2017. 58: 1969.
https://www.ncbi.nlm.nih.gov/pubmed/28935839
493. Smith, B.D., et al. Future of cancer incidence in the United States: burdens upon an aging, changing
nation. J Clin Oncol, 2009. 27: 2758.
https://www.ncbi.nlm.nih.gov/pubmed/19403886
494. Arnold, M., et al. Recent trends in incidence of five common cancers in 26 European countries since
1988: Analysis of the European Cancer Observatory. Eur J Cancer, 2015. 51: 1164.
https://www.ncbi.nlm.nih.gov/pubmed/24120180
495. Liu, D., et al. Active surveillance versus surgery for low risk prostate cancer: a clinical decision
analysis. J Urol, 2012. 187: 1241.
https://www.ncbi.nlm.nih.gov/pubmed/22335873
496. Bill-Axelson, A., et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J
Med, 2014. 370: 932.
https://www.ncbi.nlm.nih.gov/pubmed/24597866
497. Kupelian, P.A., et al. Comparison of the efficacy of local therapies for localized prostate cancer in the
prostate-specific antigen era: a large single-institution experience with radical prostatectomy and
external-beam radiotherapy. J Clin Oncol, 2002. 20: 3376.
https://www.ncbi.nlm.nih.gov/pubmed/12177097
498. Bubolz, T., et al. Treatments for prostate cancer in older men: 1984-1997. Urology, 2001. 58: 977.
https://www.ncbi.nlm.nih.gov/pubmed/11744472
499. Houterman, S., et al. Impact of comorbidity on treatment and prognosis of prostate cancer patients: a
population-based study. Crit Rev Oncol Hematol, 2006. 58: 60.
https://www.ncbi.nlm.nih.gov/pubmed/16213153
500. Ries L.A.G., et al. eds. SEER cancer Statistics Review, 1975-2005. 2008. 2022.
http://seer.cancer.gov/csr/1975_2011/
501. Scosyrev, E., et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and
disease-specific mortality. Cancer, 2012. 118: 3062.
https://www.ncbi.nlm.nih.gov/pubmed/22006014
502. Richstone, L., et al. Radical prostatectomy in men aged >or=70 years: effect of age on upgrading,
upstaging, and the accuracy of a preoperative nomogram. BJU Int, 2008. 101: 541.
https://www.ncbi.nlm.nih.gov/pubmed/18257855
503. Sun, L., et al. Men older than 70 years have higher risk prostate cancer and poorer survival in the early
and late prostate specific antigen eras. J Urol, 2009. 182: 2242.
https://www.ncbi.nlm.nih.gov/pubmed/19758616
504. Hamilton, A.S., et al. Trends in the treatment of localized prostate cancer using supplemented cancer
registry data. BJU Int, 2011. 107: 576.
https://www.ncbi.nlm.nih.gov/pubmed/20735387
505. Studenski, S., et al. Gait speed and survival in older adults. JAMA, 2011. 305: 50.
https://www.ncbi.nlm.nih.gov/pubmed/21205966
506. Ethun, C.G., et al. Frailty and cancer: Implications for oncology surgery, medical oncology, and
radiation oncology. CA Cancer J Clin, 2017. 67: 362.
https://www.ncbi.nlm.nih.gov/pubmed/28731537
507. Bellera, C.A., et al. Screening older cancer patients: first evaluation of the G-8 geriatric screening tool.
Ann Oncol, 2012. 23: 2166.
https://www.ncbi.nlm.nih.gov/pubmed/22250183
508. Hamaker, M.E., et al. The effect of a geriatric evaluation on treatment decisions and outcome for
older cancer patients - A systematic review. J Geriatr Oncol, 2018. 9: 430.
https://www.ncbi.nlm.nih.gov/pubmed/29631898
509. Rockwood, K., et al. Using the Clinical Frailty Scale in Allocating Scarce Health Care Resources. Can
Geriatr J, 2020. 23: 210.
https://www.ncbi.nlm.nih.gov/pubmed/32904824

188 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

510. McIsaac, D.I., et al. Frailty as a Predictor of Death or New Disability After Surgery: A Prospective
Cohort Study. Ann Surg, 2020. 271: 283.
https://www.ncbi.nlm.nih.gov/pubmed/30048320
511. van Walree, I.C., et al. Clinical judgment versus geriatric assessment for frailty in older patients with
cancer. J Geriatr Oncol, 2020. 11: 1138.
https://www.ncbi.nlm.nih.gov/pubmed/32576520
512. Albertsen, P.C., et al. Impact of comorbidity on survival among men with localized prostate cancer. J
Clin Oncol, 2011. 29: 1335.
https://www.ncbi.nlm.nih.gov/pubmed/21357791
513. Tewari, A., et al. Long-term survival probability in men with clinically localized prostate cancer: a
case-control, propensity modeling study stratified by race, age, treatment and comorbidities. J Urol,
2004. 171: 1513.
https://www.ncbi.nlm.nih.gov/pubmed/15017210
514. Parmelee, P.A., et al. Validation of the Cumulative Illness Rating Scale in a geriatric residential
population. J Am Geriatr Soc, 1995. 43: 130.
https://www.ncbi.nlm.nih.gov/pubmed/7836636
515. Groome, P.A., et al. Assessing the impact of comorbid illnesses on death within 10 years in prostate
cancer treatment candidates. Cancer, 2011. 117: 3943.
https://www.ncbi.nlm.nih.gov/pubmed/21858801
516. Charlson, M.E., et al. A new method of classifying prognostic comorbidity in longitudinal studies:
development and validation. J Chronic Dis, 1987. 40: 373.
https://www.ncbi.nlm.nih.gov/pubmed/3558716
517. Blanc-Bisson, C., et al. Undernutrition in elderly patients with cancer: target for diagnosis and
intervention. Crit Rev Oncol Hematol, 2008. 67: 243.
https://www.ncbi.nlm.nih.gov/pubmed/18554922
518. Sachs, G.A., et al. Cognitive impairment: an independent predictor of excess mortality: a cohort
study. Ann Intern Med, 2011. 155: 300.
https://www.ncbi.nlm.nih.gov/pubmed/21893623
519. Robinson, T.N., et al. Preoperative cognitive dysfunction is related to adverse postoperative outcomes
in the elderly. J Am Coll Surg, 2012. 215: 12.
https://www.ncbi.nlm.nih.gov/pubmed/22626912
520. Borson, S., et al. The Mini-Cog as a screen for dementia: validation in a population-based sample. J
Am Geriatr Soc, 2003. 51: 1451.
https://www.ncbi.nlm.nih.gov/pubmed/14511167
521. Korc-Grodzicki, B., et al. Prevention of post-operative delirium in older patients with cancer
undergoing surgery. J Geriatr Oncol, 2015. 6: 60.
https://www.ncbi.nlm.nih.gov/pubmed/25454768
522. Oken, M.M., et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J
Clin Oncol, 1982. 5: 649.
https://www.ncbi.nlm.nih.gov/pubmed/7165009
523. Katz, S., et al. Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of Biological
and Psychosocial Function. JAMA, 1963. 185: 914.
https://www.ncbi.nlm.nih.gov/pubmed/14044222
524. Lawton, M.P., et al. Assessment of older people: self-maintaining and instrumental activities of daily
living. Gerontologist, 1969. 9: 179.
https://www.ncbi.nlm.nih.gov/pubmed/5349366
525. Stineman, M.G., et al. All-cause 1-, 5-, and 10-year mortality in elderly people according to activities of
daily living stage. J Am Geriatr Soc, 2012. 60: 485.
https://www.ncbi.nlm.nih.gov/pubmed/22352414
526. Paladino, J., et al. Communication Strategies for Sharing Prognostic Information With Patients:
Beyond Survival Statistics. JAMA, 2019. 322: 1345.
https://www.ncbi.nlm.nih.gov/pubmed/31415085
527. Rostoft, S., et al. Shared decision-making in older patients with cancer - What does the patient want?
J Geriatr Oncol, 2021. 12: 339.
https://www.ncbi.nlm.nih.gov/pubmed/32839118
528. Soubeyran, P., et al. Screening for vulnerability in older cancer patients: the ONCODAGE Prospective
Multicenter Cohort Study. PLoS One, 2014. 9: e115060.
https://www.ncbi.nlm.nih.gov/pubmed/25503576

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 189

529. IARC France All Cancers (excluding non-melanoma skin cancer) Estimated Incidence, Mortality and
Prevalence Worldwide in 2012. 2014.
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
530. Klotz, L. Overdiagnosis in urologic cancer : For World Journal of Urology Symposium on active
surveillance in prostate and renal cancer. World J Urol, 2022. 40: 1.
https://www.ncbi.nlm.nih.gov/pubmed/33492425
531. Johansson, J.E., et al. Natural history of localised prostatic cancer. A population-based study in 223
untreated patients. Lancet, 1989. 1: 799.
https://www.ncbi.nlm.nih.gov/pubmed/2564901
532. Jonsson, E., et al. Adenocarcinoma of the prostate in Iceland: a population-based study of stage,
Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987. Scand
J Urol Nephrol, 2006. 40: 265.
https://www.ncbi.nlm.nih.gov/pubmed/16916765
533. Lu-Yao, G.L., et al. Outcomes of localized prostate cancer following conservative management.
JAMA, 2009. 302: 1202.
https://www.ncbi.nlm.nih.gov/pubmed/19755699
534. Adolfsson, J., et al. The 20-Yr outcome in patients with well- or moderately differentiated clinically
localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumour ploidy and
comorbidity. Eur Urol, 2007. 52: 1028.
https://www.ncbi.nlm.nih.gov/pubmed/17467883
535. Hamdy, F.C., et al. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate
Cancer. N Engl J Med, 2023. 388: 1547.
https://www.ncbi.nlm.nih.gov/pubmed/36912538
536. Timilshina, N., et al. Long-term Outcomes Following Active Surveillance of Low-grade Prostate
Cancer: A Population-based Study Using a Landmark Approach. J Urol, 2023. 209: 540.
https://www.ncbi.nlm.nih.gov/pubmed/36475730
537. Ventimiglia, E., et al. Long-term Outcomes Among Men Undergoing Active Surveillance for Prostate
Cancer in Sweden. JAMA Netw Open, 2022. 5: e2231015.
https://www.ncbi.nlm.nih.gov/pubmed/36103180
538. Parker, C.C., et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised,
controlled phase 3 trial. Lancet, 2020. 396: 1413.
https://www.ncbi.nlm.nih.gov/pubmed/33002429
539. Thurtle, D.R., et al. Individual prognosis at diagnosis in nonmetastatic prostate cancer: Development
and external validation of the PREDICT Prostate multivariable model. PLoS Med, 2019. 16: e1002758.
https://www.ncbi.nlm.nih.gov/pubmed/30860997
540. Heidenreich, A. Identification of high-risk prostate cancer: role of prostate-specific antigen, PSA
doubling time, and PSA velocity. Eur Urol, 2008. 54: 976.
https://www.ncbi.nlm.nih.gov/pubmed/18640768
541. Thomsen, F.B., et al. Survival benefit of early androgen receptor inhibitor therapy in locally advanced
prostate cancer: long-term follow-up of the SPCG-6 study. Eur J Cancer, 2015. 51: 1283.
https://www.ncbi.nlm.nih.gov/pubmed/25892647
542. Ventimiglia, E., et al. Natural History of Nonmetastatic Prostate Cancer Managed With Watchful
Waiting. JAMA Netw Open, 2024. 7: e2414599.
https://www.ncbi.nlm.nih.gov/pubmed/38833251
543. Bill-Axelson, A., et al. Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-
up. N Engl J Med, 2018. 379: 2319.
https://www.ncbi.nlm.nih.gov/pubmed/30575473
544. Wilt, T.J., et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer:
Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol,
2020. 77: 713.
https://www.ncbi.nlm.nih.gov/pubmed/32089359
545. Steineck, G., et al. Quality of life after radical prostatectomy or watchful waiting. N Engl J Med, 2002.
347: 790.
https://www.ncbi.nlm.nih.gov/pubmed/12226149
546. Vernooij, R.W., et al. Radical prostatectomy versus deferred treatment for localised prostate cancer.
Cochrane Database Syst Rev, 2020. 6: CD006590.
https://www.ncbi.nlm.nih.gov/pubmed/32495338

190 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

547. Graversen, P.H., et al. Radical prostatectomy versus expectant primary treatment in stages I and II
prostatic cancer. A fifteen-year follow-up. Urology, 1990. 36: 493.
https://www.ncbi.nlm.nih.gov/pubmed/2247914
548. Bruinsma, S.M., et al. Expert consensus document: Semantics in active surveillance for men with
localized prostate cancer - results of a modified Delphi consensus procedure. Nat Rev Urol, 2017. 14:
312.
https://www.ncbi.nlm.nih.gov/pubmed/28290462
549. Thomsen, F.B., et al. Active surveillance for clinically localized prostate cancer--a systematic review. J
Surg Oncol, 2014. 109: 830.
https://www.ncbi.nlm.nih.gov/pubmed/24610744
550. Tosoian, J.J., et al. Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance
Program for Favorable-Risk Prostate Cancer. J Clin Oncol, 2015. 33: 3379.
https://www.ncbi.nlm.nih.gov/pubmed/26324359
551. Hamdy, F.C., et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized
Prostate Cancer. N Engl J Med, 2016. 375: 1415.
https://www.ncbi.nlm.nih.gov/pubmed/27626136
552. Bryant, R.J., et al. The ProtecT trial: analysis of the patient cohort, baseline risk stratification and
disease progression. BJU Int, 2020. 125: 506.
https://www.ncbi.nlm.nih.gov/pubmed/31900963
553. Willemse, P.M., et al. Systematic Review of Active Surveillance for Clinically Localised Prostate
Cancer to Develop Recommendations Regarding Inclusion of Intermediate-risk Disease, Biopsy
Characteristics at Inclusion and Monitoring, and Surveillance Repeat Biopsy Strategy. Eur Urol, 2022.
81: 337.
https://www.ncbi.nlm.nih.gov/pubmed/34980492
554. Loeb, S., et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic
variables and biomarkers for risk stratification. Eur Urol, 2015. 67: 619.
https://www.ncbi.nlm.nih.gov/pubmed/25457014
555. Ha, Y.S., et al. Prostate-specific antigen density toward a better cutoff to identify better candidates for
active surveillance. Urology, 2014. 84: 365.
https://www.ncbi.nlm.nih.gov/pubmed/24925834
556. Mazzone, P.J., et al. Evaluating the Patient With a Pulmonary Nodule: A Review. JAMA, 2022. 327:
264.
https://www.ncbi.nlm.nih.gov/pubmed/35040882
557. Moore, C.M., et al. Best Current Practice and Research Priorities in Active Surveillance for Prostate
Cancer-A Report of a Movember International Consensus Meeting. Eur Urol Oncol, 2023. 6: 160.
https://www.ncbi.nlm.nih.gov/pubmed/36710133
558. Petrelli, F., et al. Predictive Factors for Reclassification and Relapse in Prostate Cancer Eligible for
Active Surveillance: A Systematic Review and Meta-analysis. Urology, 2016. 91: 136.
https://www.ncbi.nlm.nih.gov/pubmed/26896733
559. Vigneswaran, H.T., et al. Progression on active surveillance for prostate cancer in Black men: a
systematic review and meta-analysis. Prostate Cancer Prostatic Dis, 2022. 25: 165.
https://www.ncbi.nlm.nih.gov/pubmed/34239046
560. Marks, R.A., et al. The relationship between the extent of surgical margin positivity and prostate
specific antigen recurrence in radical prostatectomy specimens. Hum Pathol, 2007. 38: 1207.
https://www.ncbi.nlm.nih.gov/pubmed/17490720
561. Moreira, D.M., et al. Baseline Perineural Invasion is Associated with Shorter Time to Progression in
Men with Prostate Cancer Undergoing Active Surveillance: Results from the REDEEM Study. J Urol,
2015. 194: 1258.
https://www.ncbi.nlm.nih.gov/pubmed/25988518
562. Baboudjian, M., et al. Active Surveillance for Intermediate-risk Prostate Cancer: A Systematic Review,
Meta-analysis, and Metaregression. Eur Urol Oncol, 2022. 5: 617.
https://www.ncbi.nlm.nih.gov/pubmed/35934625
563. Mukherjee, S., et al. Comparison of Outcomes of Active Surveillance in Intermediate-Risk Versus
Low-Risk Localised Prostate Cancer Patients: A Systematic Review and Meta-Analysis. J Clin Med,
2023. 12.
https://www.ncbi.nlm.nih.gov/pubmed/37048815
564. Enikeev, D., et al. Active Surveillance for Intermediate-Risk Prostate Cancer: Systematic Review and
Meta-analysis of Current Protocols and Outcomes. Clin Genitourin Cancer, 2020. 18: e739.
https://www.ncbi.nlm.nih.gov/pubmed/32768356

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 191

565. Shee, K., et al. The Impact of Delayed Radical Prostatectomy on Recurrence Outcomes After Initial
Active Surveillance: Results from a Large Institutional Cohort. Eur Urol Oncol, 2024. 7: 838.
https://www.ncbi.nlm.nih.gov/pubmed/38057193
566. Morash, C., et al. Active surveillance for the management of localized prostate cancer: Guideline
recommendations. Can Urol Assoc J, 2015. 9: 171.
https://www.ncbi.nlm.nih.gov/pubmed/26225165
567. Musunuru, H.B., et al. Active Surveillance for Intermediate Risk Prostate Cancer: Survival Outcomes in
the Sunnybrook Experience. J Urol, 2016. 196: 1651.
https://www.ncbi.nlm.nih.gov/pubmed/27569437
568. Raldow, A.C., et al. Risk Group and Death From Prostate Cancer: Implications for Active Surveillance
in Men With Favorable Intermediate-Risk Prostate Cancer. JAMA Oncol, 2015. 1: 334.
https://www.ncbi.nlm.nih.gov/pubmed/26181182
569. Chiam, K., et al. Use of multiparametric magnetic resonance imaging (mpMRI) in active surveillance
for low-risk prostate cancer: a scoping review on the benefits and harm of mpMRI in different biopsy
scenarios. Prostate Cancer Prostatic Dis, 2021. 24: 662.
https://www.ncbi.nlm.nih.gov/pubmed/33654249
570. Dieffenbacher, S., et al. Standardized Magnetic Resonance Imaging Reporting Using the Prostate
Cancer Radiological Estimation of Change in Sequential Evaluation Criteria and Magnetic Resonance
Imaging/Transrectal Ultrasound Fusion with Transperineal Saturation Biopsy to Select Men on Active
Surveillance. Eur Urol Focus, 2021. 7: 102.
https://www.ncbi.nlm.nih.gov/pubmed/30878348
571. Dominique, G., et al. The utility of prostate MRI within active surveillance: description of the evidence.
World J Urol, 2022. 40: 71.
https://www.ncbi.nlm.nih.gov/pubmed/34860274
572. Klotz, L., et al. Randomized Study of Systematic Biopsy Versus Magnetic Resonance Imaging and
Targeted and Systematic Biopsy in Men on Active Surveillance (ASIST): 2-year Postbiopsy Follow-up.
Eur Urol, 2020. 77: 311.
https://www.ncbi.nlm.nih.gov/pubmed/31708295
573. Schiavina, R., et al. The role of multiparametric MRI in active surveillance for low-risk prostate cancer:
The ROMAS randomized controlled trial. Urol Oncol, 2021. 39: 433 e1.
https://www.ncbi.nlm.nih.gov/pubmed/33191117
574. Schoots, I.G., et al. Is magnetic resonance imaging-targeted biopsy a useful addition to systematic
confirmatory biopsy in men on active surveillance for low-risk prostate cancer? A systematic review
and meta-analysis. BJU Int, 2018. 122: 946.
https://www.ncbi.nlm.nih.gov/pubmed/29679430
575. Amin, A., et al. The Magnetic Resonance Imaging in Active Surveillance (MRIAS) Trial: Use of Baseline
Multiparametric Magnetic Resonance Imaging and Saturation Biopsy to Reduce the Frequency of
Surveillance Prostate Biopsies. J Urol, 2020. 203: 910.
https://www.ncbi.nlm.nih.gov/pubmed/31825297
576. Heetman, J.G., et al. Gallium-68 Prostate-specific Membrane Antigen Positron Emission
Tomography/Computed Tomography in Active Surveillance for Prostate Cancer Trial (PASPoRT). Eur
Urol Oncol, 2023.
https://www.ncbi.nlm.nih.gov/pubmed/37296065
577. Ross, A.E., et al. Prostate-specific antigen kinetics during follow-up are an unreliable trigger for
intervention in a prostate cancer surveillance program. J Clin Oncol, 2010. 28: 2810.
https://www.ncbi.nlm.nih.gov/pubmed/20439642
578. Thomsen, F.B., et al. Association between PSA kinetics and cancer-specific mortality in patients with
localised prostate cancer: analysis of the placebo arm of the SPCG-6 study. Ann Oncol, 2016. 27:
460.
https://www.ncbi.nlm.nih.gov/pubmed/26681677
579. Moore, C.M., et al. Reporting Magnetic Resonance Imaging in Men on Active Surveillance for Prostate
Cancer: The PRECISE Recommendations-A Report of a European School of Oncology Task Force. Eur
Urol, 2017. 71: 648.
https://www.ncbi.nlm.nih.gov/pubmed/27349615
580. Chu, C.E., et al. Diagnostic Accuracy and Prognostic Value of Serial Prostate Multiparametric
Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer. Eur Urol Oncol,
2022. 5: 537.
https://www.ncbi.nlm.nih.gov/pubmed/33483265

192 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

581. Schoots, I.G., et al. Role of MRI in low-risk prostate cancer: finding the wolf in sheep’s clothing or the
sheep in wolf’s clothing? Curr Opin Urol, 2017. 27: 238.
https://www.ncbi.nlm.nih.gov/pubmed/28306604
582. Hettiarachchi, D., et al. Can the Use of Serial Multiparametric Magnetic Resonance Imaging During
Active Surveillance of Prostate Cancer Avoid the Need for Prostate Biopsies?-A Systematic
Diagnostic Test Accuracy Review. Eur Urol Oncol, 2021. 4: 426.
https://www.ncbi.nlm.nih.gov/pubmed/32972894
583. Rajwa, P., et al. Reliability of Serial Prostate Magnetic Resonance Imaging to Detect Prostate Cancer
Progression During Active Surveillance: A Systematic Review and Meta-analysis. Eur Urol, 2021. 80:
549.
https://www.ncbi.nlm.nih.gov/pubmed/34020828
584. Yerram, N.K., et al. Magnetic Resonance Imaging-Targeted and Systematic Biopsy for Detection of
Grade Progression in Patients on Active Surveillance for Prostate Cancer. J Urol, 2021. 205: 1352.
https://www.ncbi.nlm.nih.gov/pubmed/33356479
585. Chu, C.E., et al. Multiparametric Magnetic Resonance Imaging Alone is Insufficient to Detect Grade
Reclassification in Active Surveillance for Prostate Cancer. Eur Urol, 2020. 78: 515.
https://www.ncbi.nlm.nih.gov/pubmed/32631744
586. Fujihara, A., et al. Multiparametric magnetic resonance imaging facilitates reclassification during
active surveillance for prostate cancer. BJU Int, 2021. 127: 712.
https://www.ncbi.nlm.nih.gov/pubmed/33043575
587. Stavrinides, V., et al. Mapping PSA density to outcome of MRI-based active surveillance for prostate
cancer through joint longitudinal-survival models. Prostate Cancer Prostatic Dis, 2021. 24: 1028.
https://www.ncbi.nlm.nih.gov/pubmed/33958731
588. Gallagher, K.M., et al. Four-year outcomes from a multiparametric magnetic resonance imaging
(MRI)-based active surveillance programme: PSA dynamics and serial MRI scans allow omission of
protocol biopsies. BJU Int, 2019. 123: 429.
https://www.ncbi.nlm.nih.gov/pubmed/30113755
589. Olivier, J., et al. Low-risk prostate cancer selected for active surveillance with negative MRI at entry:
can repeat biopsies at 1 year be avoided? A pilot study. World J Urol, 2019. 37: 253.
https://www.ncbi.nlm.nih.gov/pubmed/30039385
590. Caglic, I., et al. MRI-derived PRECISE scores for predicting pathologically-confirmed radiological
progression in prostate cancer patients on active surveillance. Eur Radiol, 2021. 31: 2696.
https://www.ncbi.nlm.nih.gov/pubmed/33196886
591. Deniffel, D., et al. Does the Visibility of Grade Group 1 Prostate Cancer on Baseline Multiparametric
Magnetic Resonance Imaging Impact Clinical Outcomes? J Urol, 2020. 204: 1187.
https://www.ncbi.nlm.nih.gov/pubmed/32496160
592. Mamawala, M.K., et al. Utility of multiparametric magnetic resonance imaging in the risk stratification
of men with Grade Group 1 prostate cancer on active surveillance. BJU Int, 2020. 125: 861.
https://www.ncbi.nlm.nih.gov/pubmed/32039537
593. Olivier, J., et al. Prostate Cancer Patients Under Active Surveillance with a Suspicious Magnetic
Resonance Imaging Finding Are at Increased Risk of Needing Treatment: Results of the Movember
Foundation’s Global Action Plan Prostate Cancer Active Surveillance (GAP3) Consortium. Eur Urol
Open Sci, 2022. 35: 59.
https://www.ncbi.nlm.nih.gov/pubmed/35024633
594. Rajwa, P., et al. Association of Negative Followup Biopsy and Reclassification during Active
Surveillance of Prostate Cancer: A Systematic Review and Meta-Analysis. J Urol, 2021. 205: 1559.
https://www.ncbi.nlm.nih.gov/pubmed/33683937
595. Chu, C.E., et al. The Clinical Significance of Multiple Negative Surveillance Prostate Biopsies for Men
on Active Surveillance-Does Cancer Vanish or Simply Hide? J Urol, 2021. 205: 109.
https://www.ncbi.nlm.nih.gov/pubmed/33198555
596. O’Connor, L.P., et al. Changes in Magnetic Resonance Imaging Using the Prostate Cancer Radiologic
Estimation of Change in Sequential Evaluation Criteria to Detect Prostate Cancer Progression for
Men on Active Surveillance. Eur Urol Oncol, 2021. 4: 227.
https://www.ncbi.nlm.nih.gov/pubmed/33867045
597. Van Hemelrijck, M., et al. Reasons for Discontinuing Active Surveillance: Assessment of 21 Centres in
12 Countries in the Movember GAP3 Consortium. Eur Urol, 2019. 75: 523.
https://www.ncbi.nlm.nih.gov/pubmed/30385049
598. Perera, M., et al. Outcomes of Grade Group 2 and 3 Prostate Cancer on Initial Versus Confirmatory
Biopsy: Implications for Active Surveillance. Eur Urol Focus, 2023. 9: 662.
https://www.ncbi.nlm.nih.gov/pubmed/36566100

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 193

599. Liu, J.L., et al. Advances in the selection of patients with prostate cancer for active surveillance. Nat
Rev Urol, 2021. 18: 197.
https://www.ncbi.nlm.nih.gov/pubmed/33623103
600. Paudel, R., et al. The Use and Short-term Outcomes of Active Surveillance in Men With National
Comprehensive Cancer Network Favorable Intermediate-risk Prostate Cancer: The Initial Michigan
Urological Surgery Improvement Collaborative Experience. J Urol, 2023. 209: 170.
https://www.ncbi.nlm.nih.gov/pubmed/36265120
601. Klotz, L., et al. Clinical results of long-term follow-up of a large, active surveillance cohort with
localized prostate cancer. J Clin Oncol, 2010. 28: 126.
https://www.ncbi.nlm.nih.gov/pubmed/19917860
602. Cunningham, M., et al. Patient reported factors influencing the decision-making process of men with
localised prostate cancer when considering Active Surveillance-A systematic review and thematic
synthesis. Psychooncology, 2022. 31: 388.
https://www.ncbi.nlm.nih.gov/pubmed/34605104
603. Ahlberg, M.S., et al. Variations in the Uptake of Active Surveillance for Prostate Cancer and Its Impact
on Outcomes. Eur Urol Open Sci, 2023. 52: 166.
https://www.ncbi.nlm.nih.gov/pubmed/37284040
604. Matsukawa, A., et al. Nonsurgical Interventions to Prevent Disease Progression in Prostate Cancer
Patients on Active Surveillance: A Systematic Review and Meta-analysis. Eur Urol Oncol, 2024. 7: 376.
https://www.ncbi.nlm.nih.gov/pubmed/38277189
605. Shore, N.D., et al. Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or
Intermediate-risk Localized Prostate Cancer: The ENACT Randomized Clinical Trial. JAMA Oncol,
2022. 8: 1128.
https://www.ncbi.nlm.nih.gov/pubmed/35708696
606. Newcomb, L.F., et al. Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance
for Prostate Cancer. JAMA, 2024. 331: 2084.
https://www.ncbi.nlm.nih.gov/pubmed/38814624
607. Adolfsson, J. Watchful waiting and active surveillance: the current position. BJU Int, 2008. 102: 10.
https://www.ncbi.nlm.nih.gov/pubmed/18422774
608. Hatzinger, M., et al. [The history of prostate cancer from the beginning to DaVinci]. Aktuelle Urol,
2012. 43: 228.
https://www.ncbi.nlm.nih.gov/pubmed/23035261
609. Kretschmer, A., et al. Perioperative patient education improves long-term satisfaction rates of low-
risk prostate cancer patients after radical prostatectomy. World J Urol, 2017. 35: 1205.
https://www.ncbi.nlm.nih.gov/pubmed/28093628
610. Gyomber, D., et al. Improving informed consent for patients undergoing radical prostatectomy using
multimedia techniques: a prospective randomized crossover study. BJU Int, 2010. 106: 1152.
https://www.ncbi.nlm.nih.gov/pubmed/20346048
611. Huber, J., et al. Multimedia support for improving preoperative patient education: a randomized
controlled trial using the example of radical prostatectomy. Ann Surg Oncol, 2013. 20: 15.
https://www.ncbi.nlm.nih.gov/pubmed/22851045
612. Wake, N., et al. Patient-specific 3D printed and augmented reality kidney and prostate cancer models:
impact on patient education. 3D Print Med, 2019. 5: 4.
https://www.ncbi.nlm.nih.gov/pubmed/30783869
613. Leyh-Bannurah, S.R., et al. Perioperative and Postoperative Outcomes of Robot-Assisted Radical
Prostatectomy in Prostate Cancer Patients with Prior Transurethral Subvesical Deobstruction:
Results of a High-Volume Center. J Urol, 2021. 206: 308.
https://www.ncbi.nlm.nih.gov/pubmed/33904761
614. Weng, W.C., et al. Impact of prostatic anterior fat pads with lymph node staging in prostate cancer. J
Cancer, 2018. 9: 3361.
https://www.ncbi.nlm.nih.gov/pubmed/30271497
615. Hosny, M., et al. Can Anterior Prostatic Fat Harbor Prostate Cancer Metastasis? A Prospective Cohort
Study. Curr Urol, 2017. 10: 182.
https://www.ncbi.nlm.nih.gov/pubmed/29234260
616. Ball, M.W., et al. Pathological analysis of the prostatic anterior fat pad at radical prostatectomy:
insights from a prospective series. BJU Int, 2017. 119: 444.
https://www.ncbi.nlm.nih.gov/pubmed/27611825
617. Kwon, Y.S., et al. Oncologic outcomes in men with metastasis to the prostatic anterior fat pad lymph
nodes: a multi-institution international study. BMC Urol, 2015. 15: 79.
https://www.ncbi.nlm.nih.gov/pubmed/26231860

194 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

618. Ozkan, B., et al. Role of anterior prostatic fat pad dissection for extended lymphadenectomy in
prostate cancer: a non-randomized study of 100 patients. Int Urol Nephrol, 2015. 47: 959.
https://www.ncbi.nlm.nih.gov/pubmed/25899767
619. Kim, I.Y., et al. Detailed analysis of patients with metastasis to the prostatic anterior fat pad lymph
nodes: a multi-institutional study. J Urol, 2013. 190: 527.
https://www.ncbi.nlm.nih.gov/pubmed/23485503
620. Hansen, J., et al. Assessment of rates of lymph nodes and lymph node metastases in periprostatic
fat pads in a consecutive cohort treated with retropubic radical prostatectomy. Urology, 2012. 80:
877.
https://www.ncbi.nlm.nih.gov/pubmed/22950996
621. Walsh, P.C., et al. Impotence following radical prostatectomy: insight into etiology and prevention. J
Urol, 1982. 128: 492.
https://www.ncbi.nlm.nih.gov/pubmed/7120554
622. Rainwater, L.M., et al. Technical consideration in radical retropubic prostatectomy: blood loss after
ligation of dorsal venous complex. J Urol, 1990. 143: 1163.
https://www.ncbi.nlm.nih.gov/pubmed/2342176
623. Woldu, S.L., et al. Outcomes with delayed dorsal vein complex ligation during robotic assisted
laparoscopic prostatectomy. Can J Urol, 2013. 20: 7079.
https://www.ncbi.nlm.nih.gov/pubmed/24331354
624. Lei, Y., et al. Athermal division and selective suture ligation of the dorsal vein complex during robot-
assisted laparoscopic radical prostatectomy: description of technique and outcomes. Eur Urol, 2011.
59: 235.
https://www.ncbi.nlm.nih.gov/pubmed/20863611
625. Wu, S.D., et al. Suture versus staple ligation of the dorsal venous complex during robot-assisted
laparoscopic radical prostatectomy. BJU Int, 2010. 106: 385.
https://www.ncbi.nlm.nih.gov/pubmed/20067457
626. Walsh, P.C., et al. Radical prostatectomy and cystoprostatectomy with preservation of potency.
Results using a new nerve-sparing technique. Br J Urol, 1984. 56: 694.
https://www.ncbi.nlm.nih.gov/pubmed/6534493
627. Walz, J., et al. A Critical Analysis of the Current Knowledge of Surgical Anatomy of the Prostate
Related to Optimisation of Cancer Control and Preservation of Continence and Erection in
Candidates for Radical Prostatectomy: An Update. Eur Urol, 2016. 70: 301.
https://www.ncbi.nlm.nih.gov/pubmed/26850969
628. Michl, U., et al. Nerve-sparing Surgery Technique, Not the Preservation of the Neurovascular Bundles,
Leads to Improved Long-term Continence Rates After Radical Prostatectomy. Eur Urol, 2016. 69: 584.
https://www.ncbi.nlm.nih.gov/pubmed/26277303
629. Avulova, S., et al. The Effect of Nerve Sparing Status on Sexual and Urinary Function: 3-Year Results
from the CEASAR Study. J Urol, 2018. 199: 1202.
https://www.ncbi.nlm.nih.gov/pubmed/29253578
630. Xiang, P., et al. Is there any difference in urinary continence between bilateral and unilateral nerve
sparing during radical prostatectomy? A systematic review and meta-analysis. World J Surg Oncol,
2024. 22: 66.
https://www.ncbi.nlm.nih.gov/pubmed/38395861
631. Stolzenburg, J.U., et al. A comparison of outcomes for interfascial and intrafascial nerve-sparing
radical prostatectomy. Urology, 2010. 76: 743.
https://www.ncbi.nlm.nih.gov/pubmed/20573384
632. Steineck, G., et al. Degree of preservation of the neurovascular bundles during radical prostatectomy
and urinary continence 1 year after surgery. Eur Urol, 2015. 67: 559.
https://www.ncbi.nlm.nih.gov/pubmed/25457018
633. Shikanov, S., et al. Extrafascial versus interfascial nerve-sparing technique for robotic-assisted
laparoscopic prostatectomy: comparison of functional outcomes and positive surgical margins
characteristics. Urology, 2009. 74: 611.
https://www.ncbi.nlm.nih.gov/pubmed/19616830
634. Tewari, A.K., et al. Anatomical grades of nerve sparing: a risk-stratified approach to neural-hammock
sparing during robot-assisted radical prostatectomy (RARP). BJU Int, 2011. 108: 984.
https://www.ncbi.nlm.nih.gov/pubmed/21917101
635. Nielsen, M.E., et al. High anterior release of the levator fascia improves sexual function following
open radical retropubic prostatectomy. J Urol, 2008. 180: 2557.
https://www.ncbi.nlm.nih.gov/pubmed/18930504

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 195

636. Ko, Y.H., et al. Retrograde versus antegrade nerve sparing during robot-assisted radical
prostatectomy: which is better for achieving early functional recovery? Eur Urol, 2013. 63: 169.
https://www.ncbi.nlm.nih.gov/pubmed/23092543
637. Tewari, A.K., et al. Functional outcomes following robotic prostatectomy using athermal, traction free
risk-stratified grades of nerve sparing. World J Urol, 2013. 31: 471.
https://www.ncbi.nlm.nih.gov/pubmed/23354288
638. Basourakos, S.P., et al. Clipless Robotic-assisted Radical Prostatectomy and Impact on Outcomes.
Eur Urol Focus, 2022. 8: 1176.
https://www.ncbi.nlm.nih.gov/pubmed/34246618
639. Vis, A.N., et al. Selection of patients for nerve sparing surgery in robot-assisted radical
prostatectomy. BJUI Compass, 2022. 3: 6.
https://www.ncbi.nlm.nih.gov/pubmed/35475150
640. Preisser, F., et al. Association of neurovascular bundle preservation with oncological outcomes in
patients with high-risk prostate cancer. Prostate Cancer Prostatic Dis, 2021. 24: 193.
https://www.ncbi.nlm.nih.gov/pubmed/32814844
641. Moris, L., et al. Evaluation of Oncological Outcomes and Data Quality in Studies Assessing Nerve-
sparing Versus Non-Nerve-sparing Radical Prostatectomy in Nonmetastatic Prostate Cancer: A
Systematic Review. Eur Urol Focus, 2022. 8: 690.
https://www.ncbi.nlm.nih.gov/pubmed/34147405
642. Kozikowski, M., et al. Clinical utility of MRI in the decision-making process before radical
prostatectomy: Systematic review and meta-analysis. PLoS One, 2019. 14: e0210194.
https://www.ncbi.nlm.nih.gov/pubmed/30615661
643. Beulens, A.J.W., et al. Linking surgical skills to postoperative outcomes: a Delphi study on the robot-
assisted radical prostatectomy. J Robot Surg, 2019. 13: 675.
https://www.ncbi.nlm.nih.gov/pubmed/30610535
644. Gilbert, S.M., et al. Functional Outcomes Following Nerve Sparing Prostatectomy Augmented with
Seminal Vesicle Sparing Compared to Standard Nerve Sparing Prostatectomy: Results from a
Randomized Controlled Trial. J Urol, 2017. 198: 600.
https://www.ncbi.nlm.nih.gov/pubmed/28392393
645. Schoeppler, G.M., et al. The impact of bladder neck mucosal eversion during open radical
prostatectomy on bladder neck stricture and urinary extravasation. Int Urol Nephrol, 2012. 44: 1403.
https://www.ncbi.nlm.nih.gov/pubmed/22585294
646. Borboroglu, P.G., et al. Risk factors for vesicourethral anastomotic stricture after radical
prostatectomy. Urology, 2000. 56: 96.
https://www.ncbi.nlm.nih.gov/pubmed/10869633
647. Roemeling, S., et al. Active surveillance for prostate cancers detected in three subsequent rounds of
a screening trial: characteristics, PSA doubling times, and outcome. Eur Urol, 2007. 51: 1244.
https://www.ncbi.nlm.nih.gov/pubmed/17161520
648. Bellangino, M., et al. Systematic Review of Studies Reporting Positive Surgical Margins After Bladder
Neck Sparing Radical Prostatectomy. Curr Urol Rep, 2017. 18: 99.
https://www.ncbi.nlm.nih.gov/pubmed/29116405
649. Nyarangi-Dix, J.N., et al. Complete bladder neck preservation promotes long-term post-prostatectomy
continence without compromising midterm oncological outcome: analysis of a randomised
controlled cohort. World J Urol, 2018. 36: 349.
https://www.ncbi.nlm.nih.gov/pubmed/29214353
650. Ma, X., et al. Bladder neck preservation improves time to continence after radical prostatectomy: a
systematic review and meta-analysis. Oncotarget, 2016. 7: 67463.
https://www.ncbi.nlm.nih.gov/pubmed/27634899
651. Veerman, H., et al. The detection rate of apical tumour involvement on preoperative MRI and its
impact on clinical outcomes in patients with localized prostate cancer. J Robot Surg, 2022. 16: 1047.
https://www.ncbi.nlm.nih.gov/pubmed/34783953
652. Lardas, M., et al. Patient- and Tumour-related Prognostic Factors for Urinary Incontinence After
Radical Prostatectomy for Nonmetastatic Prostate Cancer: A Systematic Review and Meta-analysis.
Eur Urol Focus, 2022. 8: 674.
https://www.ncbi.nlm.nih.gov/pubmed/33967010
653. Mungovan, S.F., et al. Preoperative Membranous Urethral Length Measurement and Continence
Recovery Following Radical Prostatectomy: A Systematic Review and Meta-analysis. Eur Urol, 2017.
71: 368.
https://www.ncbi.nlm.nih.gov/pubmed/27394644

196 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

654. van Dijk-de Haan, M.C., et al. Value of Different Magnetic Resonance Imaging-based Measurements
of Anatomical Structures on Preoperative Prostate Imaging in Predicting Urinary Continence After
Radical Prostatectomy in Men with Prostate Cancer: A Systematic Review and Meta-analysis. Eur
Urol Focus, 2022. 8: 1211.
https://www.ncbi.nlm.nih.gov/pubmed/35181284
655. Veerman, H., et al. A standardized method to measure the membranous urethral length (MUL) on MRI
of the prostate with high inter- and intra-observer agreement. Eur Radiol, 2023. 33: 3295.
https://www.ncbi.nlm.nih.gov/pubmed/36512044
656. Steiner, M.S., et al. Impact of anatomical radical prostatectomy on urinary continence. J Urol, 1991.
145: 512.
https://www.ncbi.nlm.nih.gov/pubmed/1997701
657. Li, H., et al. The Use of Unidirectional Barbed Suture for Urethrovesical Anastomosis during Robot-
Assisted Radical Prostatectomy: A Systematic Review and Meta-Analysis of Efficacy and Safety.
PLoS One, 2015. 10: e0131167.
https://www.ncbi.nlm.nih.gov/pubmed/26135310
658. Kowalewski, K.F., et al. Interrupted versus Continuous Suturing for Vesicourethral Anastomosis
During Radical Prostatectomy: A Systematic Review and Meta-analysis. Eur Urol Focus, 2019. 5: 980.
https://www.ncbi.nlm.nih.gov/pubmed/29907547
659. Matsuyama, H., et al. Running suture versus interrupted suture for vesicourethral anastomosis in
retropubic radical prostatectomy: a randomized study. Int J Urol, 2015. 22: 271.
https://www.ncbi.nlm.nih.gov/pubmed/25400263
660. Wiatr, T., et al. Single Running Suture versus Single-Knot Running Suture for Vesicourethral
Anastomosis in Laparoscopic Radical Prostatectomy: A Prospective Randomised Comparative
Study. Urol Int, 2015. 95: 445.
https://www.ncbi.nlm.nih.gov/pubmed/26655169
661. Van Velthoven, R.F., et al. Technique for laparoscopic running urethrovesical anastomosis:the single
knot method. Urology, 2003. 61: 699.
https://www.ncbi.nlm.nih.gov/pubmed/12670546
662. Gratzke, C., et al. Early Catheter Removal after Robot-assisted Radical Prostatectomy: Surgical
Technique and Outcomes for the Aalst Technique (ECaRemA Study). Eur Urol, 2016. 69: 917.
https://www.ncbi.nlm.nih.gov/pubmed/26578444
663. James, P., et al. Safe removal of the urethral catheter 2 days following laparoscopic radical
prostatectomy. ISRN Oncol, 2012. 2012: 912642.
https://www.ncbi.nlm.nih.gov/pubmed/22957273
664. Lista, G., et al. Early Catheter Removal After Robot-assisted Radical Prostatectomy: Results from a
Prospective Single-institutional Randomized Trial (Ripreca Study). Eur Urol Focus, 2020. 6: 259.
https://www.ncbi.nlm.nih.gov/pubmed/30413390
665. Brassetti, A., et al. Removing the urinary catheter on post-operative day 2 after robot-assisted
laparoscopic radical prostatectomy: a feasibility study from a single high-volume referral centre. J
Robot Surg, 2018. 12: 467.
https://www.ncbi.nlm.nih.gov/pubmed/29177945
666. Tilki, D., et al. The impact of time to catheter removal on short-, intermediate- and long-term urinary
continence after radical prostatectomy. World J Urol, 2018. 36: 1247.
https://www.ncbi.nlm.nih.gov/pubmed/29582100
667. Berrondo, C., et al. Antibiotic prophylaxis at the time of catheter removal after radical prostatectomy:
A prospective randomized clinical trial. Urol Oncol, 2019. 37: 181 e7.
https://www.ncbi.nlm.nih.gov/pubmed/30558984
668. Martinschek, A., et al. Transurethral versus suprapubic catheter at robot-assisted radical
prostatectomy: a prospective randomized trial with 1-year follow-up. World J Urol, 2016. 34: 407.
https://www.ncbi.nlm.nih.gov/pubmed/26337521
669. Harke, N., et al. Postoperative patient comfort in suprapubic drainage versus transurethral
catheterization following robot-assisted radical prostatectomy: a prospective randomized clinical
trial. World J Urol, 2017. 35: 389.
https://www.ncbi.nlm.nih.gov/pubmed/27334135
670. Krane, L.S., et al. Impact of percutaneous suprapubic tube drainage on patient discomfort after
radical prostatectomy. Eur Urol, 2009. 56: 325.
https://www.ncbi.nlm.nih.gov/pubmed/19394131
671. Morgan, M.S., et al. An Assessment of Patient Comfort and Morbidity After Robot-Assisted Radical
Prostatectomy with Suprapubic Tube Versus Urethral Catheter Drainage. J Endourol, 2016. 30: 300.
https://www.ncbi.nlm.nih.gov/pubmed/26472083

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 197

672. Galfano, A., et al. Pain and discomfort after Retzius-sparing robot-assisted radical prostatectomy:
a comparative study between suprapubic cystostomy and urethral catheter as urinary drainage.
Minerva Urol Nefrol, 2019. 71: 381.
https://www.ncbi.nlm.nih.gov/pubmed/31144484
673. Prasad, S.M., et al. Early removal of urethral catheter with suprapubic tube drainage versus urethral
catheter drainage alone after robot-assisted laparoscopic radical prostatectomy. J Urol, 2014. 192:
89.
https://www.ncbi.nlm.nih.gov/pubmed/24440236
674. Afzal, M.Z., et al. Modification of Technique for Suprapubic Catheter Placement After Robot-assisted
Radical Prostatectomy Reduces Catheter-associated Complications. Urology, 2015. 86: 401.
https://www.ncbi.nlm.nih.gov/pubmed/26189333
675. Guru, K.A., et al. Is a cystogram necessary after robot-assisted radical prostatectomy? Urol Oncol,
2007. 25: 465.
https://www.ncbi.nlm.nih.gov/pubmed/18047953
676. Tillier, C., et al. Vesico-urethral anastomosis (VUA) evaluation of short- and long-term outcome after
robot-assisted laparoscopic radical prostatectomy (RARP): selective cystogram to improve outcome.
J Robot Surg, 2017. 11: 441.
https://www.ncbi.nlm.nih.gov/pubmed/28078524
677. Yadav, R., et al. Selective indication for check cystogram before catheter removal following robot
assisted radical prostatectomy. Indian J Urol, 2016. 32: 120.
https://www.ncbi.nlm.nih.gov/pubmed/27127354
678. Schoeppler, G.M., et al. Detection of urinary leakage after radical retropubic prostatectomy by
contrast enhanced ultrasound - do we still need conventional retrograde cystography? BJU Int, 2010.
106: 1632.
https://www.ncbi.nlm.nih.gov/pubmed/20590540
679. Porcaro, A.B., et al. Is a Drain Needed After Robotic Radical Prostatectomy With or Without Pelvic
Lymph Node Dissection? Results of a Single-Center Randomized Clinical Trial. J Endourol, 2021. 35:
922.
https://www.ncbi.nlm.nih.gov/pubmed/30398382
680. Chenam, A., et al. Prospective randomised non-inferiority trial of pelvic drain placement vs no pelvic
drain placement after robot-assisted radical prostatectomy. BJU Int, 2018. 121: 357.
https://www.ncbi.nlm.nih.gov/pubmed/28872774
681. Ramsay, C., et al. Systematic review and economic modelling of the relative clinical benefit and cost-
effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with
localised prostate cancer. Health Technol Assess, 2012. 16: 1.
https://www.ncbi.nlm.nih.gov/pubmed/23127367
682. Alhusseinawi, H., et al. Low- versus standard- pneumoperitoneum in patients undergoing robot-
assisted radical prostatectomy: a randomised, triple-blinded study. BJU Int, 2023. 132: 560.
https://www.ncbi.nlm.nih.gov/pubmed/37358048
683. Novara, G., et al. Systematic review and meta-analysis of studies reporting oncologic outcome after
robot-assisted radical prostatectomy. Eur Urol, 2012. 62: 382.
https://www.ncbi.nlm.nih.gov/pubmed/22749851
684. Novara, G., et al. Systematic review and meta-analysis of perioperative outcomes and complications
after robot-assisted radical prostatectomy. Eur Urol, 2012. 62: 431.
https://www.ncbi.nlm.nih.gov/pubmed/22749853
685. Ficarra, V., et al. Systematic review and meta-analysis of studies reporting potency rates after robot-
assisted radical prostatectomy. Eur Urol, 2012. 62: 418.
https://www.ncbi.nlm.nih.gov/pubmed/22749850
686. Ficarra, V., et al. Systematic review and meta-analysis of studies reporting urinary continence
recovery after robot-assisted radical prostatectomy. Eur Urol, 2012. 62: 405.
https://www.ncbi.nlm.nih.gov/pubmed/22749852
687. Maffezzini, M., et al. Evaluation of complications and results in a contemporary series of 300
consecutive radical retropubic prostatectomies with the anatomic approach at a single institution.
Urology, 2003. 61: 982.
https://www.ncbi.nlm.nih.gov/pubmed/12736020
688. Haglind, E., et al. Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical
Prostatectomy: A Prospective, Controlled, Nonrandomised Trial. Eur Urol, 2015. 68: 216.
https://www.ncbi.nlm.nih.gov/pubmed/25770484

198 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

689. Mukkala, A.N., et al. A systematic review and meta-analysis of unplanned hospital visits and
re-admissions following radical prostatectomy for prostate cancer. Can Urol Assoc J, 2021. 15: E531.
https://www.ncbi.nlm.nih.gov/pubmed/33750517
690. Yaxley, J.W., et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic
prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet, 2016. 388:
1057.
https://www.ncbi.nlm.nih.gov/pubmed/27474375
691. Haney, C.M., et al. Robot-assisted Versus Conventional Laparoscopic Radical Prostatectomy: A
Systematic Review and Meta-analysis of Randomised Controlled Trials. Eur Urol Focus, 2023. 9: 930.
https://www.ncbi.nlm.nih.gov/pubmed/37353415
692. Dindo, D., et al. Classification of surgical complications: a new proposal with evaluation in a cohort of
6336 patients and results of a survey. Ann Surg, 2004. 240: 205.
https://www.ncbi.nlm.nih.gov/pubmed/15273542
693. Joshi, N., et al. Impact of posterior musculofascial reconstruction on early continence after robot-
assisted laparoscopic radical prostatectomy: results of a prospective parallel group trial. Eur Urol,
2010. 58: 84.
https://www.ncbi.nlm.nih.gov/pubmed/20362386
694. Sutherland, D.E., et al. Posterior rhabdosphincter reconstruction during robotic assisted radical
prostatectomy: results from a phase II randomized clinical trial. J Urol, 2011. 185: 1262.
https://www.ncbi.nlm.nih.gov/pubmed/21334025
695. Jeong, C.W., et al. Effects of new 1-step posterior reconstruction method on recovery of continence
after robot-assisted laparoscopic prostatectomy: results of a prospective, single-blind, parallel group,
randomized, controlled trial. J Urol, 2015. 193: 935.
https://www.ncbi.nlm.nih.gov/pubmed/25315960
696. Menon, M., et al. Assessment of early continence after reconstruction of the periprostatic tissues
in patients undergoing computer assisted (robotic) prostatectomy: results of a 2 group parallel
randomized controlled trial. J Urol, 2008. 180: 1018.
https://www.ncbi.nlm.nih.gov/pubmed/18639300
697. Stolzenburg, J.U., et al. Influence of bladder neck suspension stitches on early continence after
radical prostatectomy: a prospective randomized study of 180 patients. Asian J Androl, 2011. 13:
806.
https://www.ncbi.nlm.nih.gov/pubmed/21909121
698. Hurtes, X., et al. Anterior suspension combined with posterior reconstruction during robot-assisted
laparoscopic prostatectomy improves early return of urinary continence: a prospective randomized
multicentre trial. BJU Int, 2012. 110: 875.
https://www.ncbi.nlm.nih.gov/pubmed/22260307
699. Student, V., Jr., et al. Advanced Reconstruction of Vesicourethral Support (ARVUS) during Robot-
assisted Radical Prostatectomy: One-year Functional Outcomes in a Two-group Randomised
Controlled Trial. Eur Urol, 2017. 71: 822.
https://www.ncbi.nlm.nih.gov/pubmed/27283216
700. Noguchi, M., et al. A randomized clinical trial of suspension technique for improving early recovery of
urinary continence after radical retropubic prostatectomy. BJU Int, 2008. 102: 958.
https://www.ncbi.nlm.nih.gov/pubmed/18485031
701. Jia, Z., et al. Sustainable functional urethral reconstruction improves early urinary continence after
robot-assisted radical prostatectomy: a randomised controlled trial. BJU Int, 2023. 131: 720.
https://www.ncbi.nlm.nih.gov/pubmed/36545839
702. Viani, G.A., et al. Intensity-modulated radiotherapy reduces toxicity with similar biochemical control
compared with 3-dimensional conformal radiotherapy for prostate cancer: A randomized clinical trial.
Cancer, 2016. 122: 2004.
https://www.ncbi.nlm.nih.gov/pubmed/27028170
703. Yu, T., et al. The Effectiveness of Intensity Modulated Radiation Therapy versus Three-Dimensional
Radiation Therapy in Prostate Cancer: A Meta-Analysis of the Literatures. PLoS One, 2016. 11:
e0154499.
https://www.ncbi.nlm.nih.gov/pubmed/27171271
704. de Crevoisier, R., et al. Daily Versus Weekly Prostate Cancer Image Guided Radiation Therapy: Phase
3 Multicenter Randomized Trial. Int J Radiat Oncol Biol Phys, 2018. 102: 1420.
https://www.ncbi.nlm.nih.gov/pubmed/30071296

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 199

705. Murray, J., et al. A randomised assessment of image guided radiotherapy within a phase 3 trial of
conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer.
Radiother Oncol, 2020. 142: 62.
https://www.ncbi.nlm.nih.gov/pubmed/31767473
706. Tocco, B.R., et al. MR-Guided Radiotherapy for Prostate Cancer. Front Oncol, 2020. 10: 616291.
https://www.ncbi.nlm.nih.gov/pubmed/33363041
707. Christiansen, R.L., et al. Online adaptive radiotherapy potentially reduces toxicity for high-risk prostate
cancer treatment. Radiother Oncol, 2022. 167: 165.
https://www.ncbi.nlm.nih.gov/pubmed/34923034
708. Tetar, S.U., et al. Magnetic Resonance-guided Stereotactic Radiotherapy for Localized Prostate
Cancer: Final Results on Patient-reported Outcomes of a Prospective Phase 2 Study. Eur Urol Oncol,
2021. 4: 628.
https://www.ncbi.nlm.nih.gov/pubmed/32536573
709. Kishan, A.U., et al. Magnetic Resonance Imaging-Guided vs Computed Tomography-Guided
Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE Randomized Clinical Trial. JAMA
Oncol, 2023. 9: 365.
https://www.ncbi.nlm.nih.gov/pubmed/36633877
710. Kishan, A.U., et al. Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate
Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials. Eur Urol, 2020. 77: 201.
https://www.ncbi.nlm.nih.gov/pubmed/31718822
711. Michalski, J.M., et al. Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With
Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial. JAMA
Oncol, 2018. 4: e180039.
https://www.ncbi.nlm.nih.gov/pubmed/29543933
712. Zietman, A.L., et al. Randomized trial comparing conventional-dose with high-dose conformal
radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton
radiation oncology group/american college of radiology 95-09. J Clin Oncol, 2010. 28: 1106.
https://www.ncbi.nlm.nih.gov/pubmed/20124169
713. Viani, G.A., et al. Higher-than-conventional radiation doses in localized prostate cancer treatment: a
meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys, 2009. 74: 1405.
https://www.ncbi.nlm.nih.gov/pubmed/19616743
714. Peeters, S.T., et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch
multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol,
2006. 24: 1990.
https://www.ncbi.nlm.nih.gov/pubmed/16648499
715. Beckendorf, V., et al. 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06
randomized trial. Int J Radiat Oncol Biol Phys, 2011. 80: 1056.
https://www.ncbi.nlm.nih.gov/pubmed/21147514
716. Heemsbergen, W.D., et al. Long-term results of the Dutch randomized prostate cancer trial: impact of
dose-escalation on local, biochemical, clinical failure, and survival. Radiother Oncol, 2014. 110: 104.
https://www.ncbi.nlm.nih.gov/pubmed/24246414
717. Dearnaley, D.P., et al. Escalated-dose versus control-dose conformal radiotherapy for prostate cancer:
long-term results from the MRC RT01 randomised controlled trial. Lancet Oncol, 2014. 15: 464.
https://www.ncbi.nlm.nih.gov/pubmed/24581940
718. Pasalic, D., et al. Dose Escalation for Prostate Adenocarcinoma: A Long-Term Update on the
Outcomes of a Phase 3, Single Institution Randomized Clinical Trial. Int J Radiat Oncol Biol Phys,
2019. 104: 790.
https://www.ncbi.nlm.nih.gov/pubmed/30836166
719. Kalbasi, A., et al. Dose-Escalated Irradiation and Overall Survival in Men With Nonmetastatic Prostate
Cancer. JAMA Oncol, 2015. 1: 897.
https://www.ncbi.nlm.nih.gov/pubmed/26181727
720. Kerkmeijer, L.G.W., et al. Focal Boost to the Intraprostatic Tumor in External Beam Radiotherapy for
Patients With Localized Prostate Cancer: Results From the FLAME Randomized Phase III Trial. J Clin
Oncol, 2021. 39: 787.
https://www.ncbi.nlm.nih.gov/pubmed/33471548
721. Groen, V.H., et al. Patterns of Failure Following External Beam Radiotherapy With or Without an
Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer. Eur
Urol, 2022. 82: 252.
https://www.ncbi.nlm.nih.gov/pubmed/34953603

200 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

722. Poon, D.M.C., et al. Magnetic Resonance Imaging–guided Focal Boost to Intraprostatic Lesions Using
External Beam Radiotherapy for Localized Prostate Cancer: A Systematic Review and Meta-analysis.
Eur Urol Oncol, 2023. 6: 116.
https://www.sciencedirect.com/science/article/pii/S2588931122001687
723. Fowler, J.F. The radiobiology of prostate cancer including new aspects of fractionated radiotherapy.
Acta Oncol, 2005. 44: 265.
https://www.ncbi.nlm.nih.gov/pubmed/16076699
724. Dasu, A., et al. Prostate alpha/beta revisited -- an analysis of clinical results from 14 168 patients.
Acta Oncol, 2012. 51: 963.
https://www.ncbi.nlm.nih.gov/pubmed/22966812
725. Kuban, D.A., et al. Preliminary Report of a Randomized Dose Escalation Trial for Prostate Cancer
using Hypofractionation. Int J Radiat Oncol Biol Phys, 2010. 78: S58.
https://www.redjournal.org/article/S0360-3016(10)01144-2/fulltext
726. Pollack, A., et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate
cancer. J Clin Oncol, 2013. 31: 3860.
https://www.ncbi.nlm.nih.gov/pubmed/24101042
727. Lee, W.R., et al. Randomized Phase III Noninferiority Study Comparing Two Radiotherapy
Fractionation Schedules in Patients With Low-Risk Prostate Cancer. J Clin Oncol, 2016. 34: 2325.
https://www.ncbi.nlm.nih.gov/pubmed/27044935
728. Dearnaley, D., et al. Conventional versus hypofractionated high-dose intensity-modulated
radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP
trial. Lancet Oncol, 2016. 17: 1047.
https://www.ncbi.nlm.nih.gov/pubmed/27339115
729. Incrocci, L., et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with
localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label,
phase 3 trial. Lancet Oncol, 2016. 17: 1061.
https://www.ncbi.nlm.nih.gov/pubmed/27339116
730. Catton, C.N., et al. Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of
Localized Prostate Cancer. J Clin Oncol, 2017. 35: 1884.
https://www.ncbi.nlm.nih.gov/pubmed/28296582
731. Koontz, B.F., et al. A systematic review of hypofractionation for primary management of prostate
cancer. Eur Urol, 2015. 68: 683.
https://www.ncbi.nlm.nih.gov/pubmed/25171903
732. Hocht, S., et al. Hypofractionated radiotherapy for localized prostate cancer. Strahlenther Onkol,
2017. 193: 1.
https://www.ncbi.nlm.nih.gov/pubmed/27628966
733. Hickey, B.E., et al. Hypofractionation for clinically localized prostate cancer. Cochrane Database Syst
Rev, 2019. 9: CD011462.
https://www.ncbi.nlm.nih.gov/pubmed/31476800
734. Niazi, T., et al. Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer:
The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de
Quebec Led Phase 3 Trial. Int J Radiat Oncol Biol Phys, 2023. 118: 52.
https://www.ncbi.nlm.nih.gov/pubmed/37224928
735. Niazi, T., et al. Hypofractionated Dose Escalation Radiotherapy for High-risk Prostate Cancer: The
Survival Analysis of the Prostate Cancer Study 5, a Groupe de Radio-oncologie Genito-urinaire du
Quebec-led Phase 3 Trial. Eur Urol, 2024.
https://www.ncbi.nlm.nih.gov/pubmed/39271420
736. Glicksman, R.M., et al. Randomized Trial of Concomitant Hypofractionated Intensity Modulated
Radiation Therapy Boost Versus Conventionally Fractionated Intensity Modulated Radiation Therapy
Boost for Localized High-Risk Prostate Cancer (pHART2-RCT). Int J Radiat Oncol Biol Phys, 2024.
119: 100.
https://www.ncbi.nlm.nih.gov/pubmed/37979707
737. Buyyounouski, M.K., et al. Noninferiority of Hypofractionated vs Conventional Postprostatectomy
Radiotherapy for Genitourinary and Gastrointestinal Symptoms: The NRG-GU003 Phase 3
Randomized Clinical Trial. JAMA Oncol, 2024. 10: 584.
https://www.ncbi.nlm.nih.gov/pubmed/38483412
738. Widmark, A., et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate
cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet, 2019.
394: 385.
https://www.ncbi.nlm.nih.gov/pubmed/31227373

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 201

739. van As, N., et al. Phase 3 Trial of Stereotactic Body Radiotherapy in Localized Prostate Cancer. N Engl
J Med, 2024. 391: 1413.
https://www.ncbi.nlm.nih.gov/pubmed/39413377
740. Jackson, W.C., et al. Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A
Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies. Int J
Radiat Oncol Biol Phys, 2019. 104: 778.
https://www.ncbi.nlm.nih.gov/pubmed/30959121
741. Cushman, T.R., et al. Stereotactic body radiation therapy for prostate cancer: systematic review and
meta-analysis of prospective trials. Oncotarget, 2019. 10: 5660.
https://www.ncbi.nlm.nih.gov/pubmed/31608141
742. Brand, D.H., et al. Intensity-modulated fractionated radiotherapy versus stereotactic body
radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised,
open-label, phase 3, non-inferiority trial. Lancet Oncol, 2019. 20: 1531.
https://www.ncbi.nlm.nih.gov/pubmed/31540791
743. Tree, A.C., et al. Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate
cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.
Lancet Oncol, 2022. 23: 1308.
https://www.ncbi.nlm.nih.gov/pubmed/36113498
744. Rasmusson, E., et al. Erectile Dysfunction and Absorbed Dose to Penile Base Structures in a
Randomized Trial Comparing Ultrahypofractionated and Conventionally Fractionated Radiation
Therapy for Prostate Cancer. Int J Radiat Oncol Biol Phys, 2020. 107: 143.
https://www.ncbi.nlm.nih.gov/pubmed/32004582
745. Greco, C., et al. Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in
Patients With Intermediate-Risk Prostate Cancer: Results From the PROSINT Phase 2 Randomized
Clinical Trial. JAMA Oncol, 2021. 7: 700.
https://www.ncbi.nlm.nih.gov/pubmed/33704378
746. Bolla, M., et al. External irradiation with or without long-term androgen suppression for prostate
cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol, 2010.
11: 1066.
https://www.ncbi.nlm.nih.gov/pubmed/20933466
747. Pilepich, M.V., et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--
long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys, 2005. 61: 1285.
https://www.ncbi.nlm.nih.gov/pubmed/15817329
748. Roach, M., 3rd, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam
radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol,
2008. 26: 585.
https://www.ncbi.nlm.nih.gov/pubmed/18172188
749. D’Amico, A.V., et al. Androgen suppression and radiation vs radiation alone for prostate cancer: a
randomized trial. JAMA, 2008. 299: 289.
https://www.ncbi.nlm.nih.gov/pubmed/18212313
750. Denham, J.W., et al. Short-term neoadjuvant androgen deprivation and radiotherapy for locally
advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol, 2011.
12: 451.
https://www.ncbi.nlm.nih.gov/pubmed/21440505
751. Lawton, C.A., et al. An update of the phase III trial comparing whole pelvic to prostate only
radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG
94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys,
2007. 69: 646.
https://www.ncbi.nlm.nih.gov/pubmed/17531401
752. Horwitz, E.M., et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III
trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol,
2008. 26: 2497.
https://www.ncbi.nlm.nih.gov/pubmed/18413638
753. Bolla, M., et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med,
2009. 360: 2516.
https://www.ncbi.nlm.nih.gov/pubmed/19516032
754. Pisansky, T.M., et al. Duration of androgen suppression before radiotherapy for localized prostate
cancer: radiation therapy oncology group randomized clinical trial 9910. J Clin Oncol, 2015. 33: 332.
https://www.ncbi.nlm.nih.gov/pubmed/25534388

202 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

755. Nabid, A., et al. Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A
randomised phase III trial. Eur J Cancer, 2021. 143: 64.
https://www.ncbi.nlm.nih.gov/pubmed/33279855
756. Krauss, D.J., et al. Dose-Escalated Radiotherapy Alone or in Combination With Short-Term Androgen
Deprivation for Intermediate-Risk Prostate Cancer: Results of a Phase III Multi-Institutional Trial. J
Clin Oncol, 2023. 41: 3203.
https://www.ncbi.nlm.nih.gov/pubmed/37104748
757. Kishan, A.U., et al. Androgen deprivation therapy use and duration with definitive radiotherapy for
localised prostate cancer: an individual patient data meta-analysis. Lancet Oncol, 2022. 23: 304.
https://www.ncbi.nlm.nih.gov/pubmed/35051385
758. Spratt, D.E., et al. Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT)
Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-
Analysis. J Clin Oncol, 2021. 39: 136.
https://www.ncbi.nlm.nih.gov/pubmed/33275486
759. Malone, S., et al. Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in
Localized Prostate Cancer: A Phase III Randomized Controlled Trial. J Clin Oncol, 2020. 38: 593.
https://www.ncbi.nlm.nih.gov/pubmed/31829912
760. Efstathiou, J.A., et al. Prostate Advanced Radiation Technologies Investigating Quality of Life
(PARTIQoL): Phase III Randomized Clinical Trial of Proton Therapy vs. IMRT for Localized Prostate
Cancer. Int J Radiat Oncol Biol Phys, 2024. 120: S1.
https://www.redjournal.org/article/S0360-3016(24)03237-1/fulltext
761. Lee, W.R., et al. NRG Oncology RTOG 0415: A randomized phase III non-inferiority study comparing
two fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol, 2024. 34: 1.
https://www.redjournal.org/article/S0360-3016(15)26644-8/abstract
762. de Vries, K.C., et al. Hyprofractionated Versus Conventionally Fractionated Radiation Therapy for
Patients with Intermediate- or High-Risk, Localized, Prostate Cancer: 7-Year Outcomes From the
Randomized, Multicenter, Open-Label, Phase 3 HYPRO Trial. Int J Radiat Oncol Biol Phys, 2020. 106:
108.
https://www.ncbi.nlm.nih.gov/pubmed/31593756
763. Fossa, S.D., et al. Ten- and 15-yr Prostate Cancer-specific Mortality in Patients with Nonmetastatic
Locally Advanced or Aggressive Intermediate Prostate Cancer, Randomized to Lifelong Endocrine
Treatment Alone or Combined with Radiotherapy: Final Results of The Scandinavian Prostate Cancer
Group-7. Eur Urol, 2016. 70: 684.
https://www.ncbi.nlm.nih.gov/pubmed/27025586
764. Mason, M.D., et al. Final Report of the Intergroup Randomized Study of Combined Androgen-
Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally
Advanced Prostate Cancer. J Clin Oncol, 2015. 33: 2143.
https://www.ncbi.nlm.nih.gov/pubmed/25691677
765. Sargos, P., et al. Long-term androgen deprivation, with or without radiotherapy, in locally advanced
prostate cancer: updated results from a phase III randomised trial. BJU Int, 2020. 125: 810.
https://www.ncbi.nlm.nih.gov/pubmed/30946523
766. Excellence, N.I.f.H.a.C. Biodegradable spacer insertion to reduce rectal toxicity during radiotherapy
for prostate cancer. Interventional procedures guidance [IPG590]. 2017. 2022.
https://www.nice.org.uk/guidance/ipg590
767. Miller, L.E., et al. Association of the Placement of a Perirectal Hydrogel Spacer With the Clinical
Outcomes of Men Receiving Radiotherapy for Prostate Cancer: A Systematic Review and Meta-
analysis. JAMA Netw Open, 2020. 3: e208221.
https://www.ncbi.nlm.nih.gov/pubmed/32585020
768. Hamstra, D.A., et al. Continued Benefit to Rectal Separation for Prostate Radiation Therapy: Final
Results of a Phase III Trial. Int J Radiat Oncol Biol Phys, 2017. 97: 976.
https://www.ncbi.nlm.nih.gov/pubmed/28209443
769. Aminsharifi, A., et al. Major Complications and Adverse Events Related to the Injection of the
SpaceOAR Hydrogel System Before Radiotherapy for Prostate Cancer: Review of the Manufacturer
and User Facility Device Experience Database. J Endourol, 2019. 33: 868.
https://www.ncbi.nlm.nih.gov/pubmed/31452385
770. Henry, A., et al. GEC-ESTRO ACROP prostate brachytherapy guidelines. Radiother Oncol, 2022. 167:
244.
https://www.ncbi.nlm.nih.gov/pubmed/34999134

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 203

771. Martens, C., et al. Relationship of the International Prostate Symptom score with urinary flow studies,
and catheterization rates following 125I prostate brachytherapy. Brachytherapy, 2006. 5: 9.
https://www.ncbi.nlm.nih.gov/pubmed/16563992
772. Michalski, J.M., et al. Effect of Brachytherapy With External Beam Radiation Therapy Versus
Brachytherapy Alone for Intermediate-Risk Prostate Cancer: NRG Oncology RTOG 0232 Randomized
Clinical Trial. J Clin Oncol, 2023. 41: 4035.
https://www.ncbi.nlm.nih.gov/pubmed/37315297
773. Le, H., et al. The influence of prostate volume on outcome after high-dose-rate brachytherapy alone
for localized prostate cancer. Int J Radiat Oncol Biol Phys, 2013. 87: 270.
https://www.ncbi.nlm.nih.gov/pubmed/23849693
774. Salembier, C., et al. A history of transurethral resection of the prostate should not be a contra-
indication for low-dose-rate (125)I prostate brachytherapy: results of a prospective Uro-GEC phase-II
trial. J Contemp Brachyther, 2020. 12: 1.
https://www.ncbi.nlm.nih.gov/pubmed/32190063
775. Salembier, C., et al. Prospective multi-center dosimetry study of low-dose Iodine-125 prostate
brachytherapy performed after transurethral resection. J Contemp Brachyther, 2013. 5: 63.
https://www.ncbi.nlm.nih.gov/pubmed/23878549
776. Stone, N.N., et al. Prostate brachytherapy in men with gland volume of 100cc or greater: Technique,
cancer control, and morbidity. Brachytherapy, 2013. 12: 217.
https://www.ncbi.nlm.nih.gov/pubmed/23384439
777. Crook, J.M., et al. Comparison of health-related quality of life 5 years after SPIRIT: Surgical
Prostatectomy Versus Interstitial Radiation Intervention Trial. J Clin Oncol, 2011. 29: 362.
https://www.ncbi.nlm.nih.gov/pubmed/21149658
778. Sylvester, J.E., et al. Fifteen-year biochemical relapse-free survival, cause-specific survival, and
overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle
experience. Int J Radiat Oncol Biol Phys, 2011. 81: 376.
https://www.ncbi.nlm.nih.gov/pubmed/20864269
779. Potters, L., et al. 12-year outcomes following permanent prostate brachytherapy in patients with
clinically localized prostate cancer. J Urol, 2005. 173: 1562.
https://www.ncbi.nlm.nih.gov/pubmed/15821486
780. Stone, N.N., et al. Intermediate term biochemical-free progression and local control following
125iodine brachytherapy for prostate cancer. J Urol, 2005. 173: 803.
https://www.ncbi.nlm.nih.gov/pubmed/15711273
781. Zelefsky, M.J., et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate
cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys, 2007. 67: 327.
https://www.ncbi.nlm.nih.gov/pubmed/17084558
782. Lawton, C.A., et al. Results of a phase II trial of transrectal ultrasound-guided permanent radioactive
implantation of the prostate for definitive management of localized adenocarcinoma of the prostate
(radiation therapy oncology group 98-05). Int J Radiat Oncol Biol Phys, 2007. 67: 39.
https://www.ncbi.nlm.nih.gov/pubmed/17084551
783. Stock, R.G., et al. Importance of post-implant dosimetry in permanent prostate brachytherapy. Eur
Urol, 2002. 41: 434.
https://www.ncbi.nlm.nih.gov/pubmed/12074816
784. Keyes, M., et al. American Brachytherapy Society Task Group Report: Use of androgen deprivation
therapy with prostate brachytherapy-A systematic literature review. Brachytherapy, 2017. 16: 245.
https://www.ncbi.nlm.nih.gov/pubmed/28110898
785. Morris, W.J., et al. Androgen Suppression Combined with Elective Nodal and Dose Escalated
Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial
Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for
High- and Intermediate-risk Prostate Cancer. Int J Radiat Oncol Biol Phys, 2017. 98: 275.
https://www.ncbi.nlm.nih.gov/pubmed/28262473
786. Oh, J., et al. An Updated Analysis of the Survival Endpoints of ASCENDE-RT. Int J Radiat Oncol Biol
Phys, 2023. 115: 1061.
https://www.ncbi.nlm.nih.gov/pubmed/36528488
787. Rodda, S., et al. ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial
Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated External Beam Boost for
High- and Intermediate-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys, 2017. 98: 286.
https://www.ncbi.nlm.nih.gov/pubmed/28433432

204 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

788. Hoskin, P.J., et al. GEC/ESTRO recommendations on high dose rate afterloading brachytherapy for
localised prostate cancer: an update. Radiother Oncol, 2013. 107: 325.
https://www.ncbi.nlm.nih.gov/pubmed/23773409
789. Galalae, R.M., et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local
dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat
Oncol Biol Phys, 2002. 52: 81.
https://www.ncbi.nlm.nih.gov/pubmed/11777625
790. Miszczyk, M., et al. Brachytherapy boost improves survival and decreases risk of developing distant
metastases compared to external beam radiotherapy alone in intermediate and high risk group
prostate cancer patients. Radiother Oncol, 2023. 183: 109632.
https://www.ncbi.nlm.nih.gov/pubmed/36963442
791. Pieters, B.R., et al. Comparison of three radiotherapy modalities on biochemical control and overall
survival for the treatment of prostate cancer: a systematic review. Radiother Oncol, 2009. 93: 168.
https://www.ncbi.nlm.nih.gov/pubmed/19748692
792. Parry, M.G., et al. Impact of High-Dose-Rate and Low-Dose-Rate Brachytherapy Boost on Toxicity,
Functional and Cancer Outcomes in Patients Receiving External Beam Radiation Therapy for Prostate
Cancer: A National Population-Based Study. Int J Radiat Oncol Biol Phys, 2021. 109: 1219.
https://www.ncbi.nlm.nih.gov/pubmed/33279595
793. Hoskin, P.J., et al. Randomised trial of external-beam radiotherapy alone or with high-dose-rate
brachytherapy for prostate cancer: Mature 12-year results. Radiother Oncol, 2021. 154: 214.
https://www.ncbi.nlm.nih.gov/pubmed/33011207
794. Joseph, D., et al. Radiation Dose Escalation or Longer Androgen Suppression to Prevent Distant
Progression in Men With Locally Advanced Prostate Cancer: 10-Year Data From the TROG 03.04
RADAR Trial. Int J Radiat Oncol Biol Phys, 2020. 106: 693.
https://www.ncbi.nlm.nih.gov/pubmed/32092343
795. Jackson, W.C., et al. Addition of Androgen-Deprivation Therapy or Brachytherapy Boost to External
Beam Radiotherapy for Localized Prostate Cancer: A Network Meta-Analysis of Randomized Trials. J
Clin Oncol, 2020. 38: 3024.
https://www.ncbi.nlm.nih.gov/pubmed/32396488
796. Viani, G.A., et al. HDR brachytherapy as monotherapy for prostate cancer: A systematic review with
meta-analysis. Brachytherapy, 2021. 20: 307.
https://www.ncbi.nlm.nih.gov/pubmed/33461894
797. Morton, G., et al. Prostate high dose-rate brachytherapy as monotherapy for low and intermediate risk
prostate cancer: Early toxicity and quality-of life results from a randomized phase II clinical trial of
one fraction of 19Gy or two fractions of 13.5Gy. Radiother Oncol, 2017. 122: 87.
https://www.ncbi.nlm.nih.gov/pubmed/27823821
798. Matzinger, O., et al. Acute toxicity of curative radiotherapy for intermediate- and high-risk localised
prostate cancer in the EORTC trial 22991. Eur J Cancer, 2009. 45: 2825.
https://www.ncbi.nlm.nih.gov/pubmed/19682889
799. Crook, J., et al. A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate
Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy. Int J Radiat Oncol Biol
Phys, 2024. 120: 59.
https://www.ncbi.nlm.nih.gov/pubmed/38493901
800. King, C.R., et al. Health-related quality of life after stereotactic body radiation therapy for localized
prostate cancer: results from a multi-institutional consortium of prospective trials. Int J Radiat Oncol
Biol Phys, 2013. 87: 939.
https://www.ncbi.nlm.nih.gov/pubmed/24119836
801. Fahmy, W.E., et al. Cryosurgery for prostate cancer. Arch Androl, 2003. 49: 397.
https://www.ncbi.nlm.nih.gov/pubmed/12893518
802. Rees, J., et al. Cryosurgery for prostate cancer. BJU Int, 2004. 93: 710.
https://www.ncbi.nlm.nih.gov/pubmed/15049977
803. Han, K.R., et al. Third-generation cryosurgery for primary and recurrent prostate cancer. BJU Int, 2004.
93: 14.
https://www.ncbi.nlm.nih.gov/pubmed/14678360
804. van der Poel, H.G., et al. Focal Therapy in Primary Localised Prostate Cancer: The European
Association of Urology Position in 2018. Eur Urol, 2018. 74: 84.
https://www.ncbi.nlm.nih.gov/pubmed/29373215
805. Valerio, M., et al. New and Established Technology in Focal Ablation of the Prostate: A Systematic
Review. Eur Urol, 2017. 71: 17.
https://www.ncbi.nlm.nih.gov/pubmed/27595377

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 205

806. Madersbacher, S., et al. High-energy shockwaves and extracorporeal high-intensity focused
ultrasound. J Endourol, 2003. 17: 667.
https://www.ncbi.nlm.nih.gov/pubmed/14622487
807. Ramsay, C.R., et al. Ablative therapy for people with localised prostate cancer: a systematic review
and economic evaluation. Health Technol Assess, 2015. 19: 1.
https://www.ncbi.nlm.nih.gov/pubmed/26140518
808. Pan, Y., et al. Whole-gland high-intensity focused ultrasound ablation and transurethral resection
of the prostate in the patients with prostate cancer: A systematic review and meta-analysis. Front
Oncol, 2022. 12: 988490.
https://www.ncbi.nlm.nih.gov/pubmed/36313706
809. Brundl, J., et al. Oncological Long-term Outcome After Whole-gland High-intensity Focused
Ultrasound for Prostate Cancer-21-yr Follow-up. Eur Urol Focus, 2022. 8: 134.
https://www.ncbi.nlm.nih.gov/pubmed/33483288
810. Dickinson, L., et al. Medium-term Outcomes after Whole-gland High-intensity Focused Ultrasound for
the Treatment of Nonmetastatic Prostate Cancer from a Multicentre Registry Cohort. Eur Urol, 2016.
70: 668.
https://www.ncbi.nlm.nih.gov/pubmed/26951947
811. Mouraviev, V., et al. Pathologic basis of focal therapy for early-stage prostate cancer. Nat Rev Urol,
2009. 6: 205.
https://www.ncbi.nlm.nih.gov/pubmed/19352395
812. Cooperberg, M.R., et al. Contemporary trends in low risk prostate cancer: risk assessment and
treatment. J Urol, 2007. 178: S14.
https://www.ncbi.nlm.nih.gov/pubmed/17644125
813. Polascik, T.J., et al. Pathologic stage T2a and T2b prostate cancer in the recent prostate-specific
antigen era: implications for unilateral ablative therapy. Prostate, 2008. 68: 1380.
https://www.ncbi.nlm.nih.gov/pubmed/18543281
814. Ahmed, H.U., et al. Will focal therapy become a standard of care for men with localized prostate
cancer? Nat Clin Pract Oncol, 2007. 4: 632.
https://www.ncbi.nlm.nih.gov/pubmed/17965641
815. Eggener, S.E., et al. Focal therapy for localized prostate cancer: a critical appraisal of rationale and
modalities. J Urol, 2007. 178: 2260.
https://www.ncbi.nlm.nih.gov/pubmed/17936815
816. Crawford, E.D., et al. Targeted focal therapy: a minimally invasive ablation technique for early prostate
cancer. Oncology (Williston Park), 2007. 21: 27.
https://www.ncbi.nlm.nih.gov/pubmed/17313155
817. Hopstaken, J.S., et al. An Updated Systematic Review on Focal Therapy in Localized Prostate Cancer:
What Has Changed over the Past 5 Years? Eur Urol, 2022. 81: 5.
https://www.ncbi.nlm.nih.gov/pubmed/34489140
818. Busby, D., et al. Biopsy and Erectile Functional Outcomes of Partial Prostate Ablation: A Systematic
Review and Meta-analysis of Prospective Studies. Urology, 2023. 182: 14.
https://www.ncbi.nlm.nih.gov/pubmed/37774854
819. Reddy, D., et al. Cancer Control Outcomes Following Focal Therapy Using High-intensity Focused
Ultrasound in 1379 Men with Nonmetastatic Prostate Cancer: A Multi-institute 15-year Experience.
Eur Urol, 2022. 81: 407.
https://www.ncbi.nlm.nih.gov/pubmed/35123819
820. Hamdy, F.C., et al. Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer:
the PART feasibility RCT. Health Technol Assess, 2018. 22: 1.
https://www.ncbi.nlm.nih.gov/pubmed/30264692
821. Baco, E., Vlakovic, L., Rud, E. , MP21-7901 Focal ablation versus radical prostatectomy for
intermediate-risk prostate cancer: interim analysis of a randomized controlled Trial, in AUA-2021.
2021, AUA: Las Vegas, USA.
https://static1.squarespace.com/static/567fcc1f40667a31535fc681/t/6238663f826ed01f1b359
ac7/1647863360447/Poster+AUA+2021+FARP.pdf
822. Reddy, D., et al. Comparative healthcare research outcomes of novel Surgery in prostate cancer (IP4-
CHRONOS): Pilot RCT assessing feasibility of randomization for focal therapy in localized prostate
cancer. J Clin Oncol, 2022. 40: 5086.
https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.5086
823. Shah, T.T., et al. Focal therapy compared to radical prostatectomy for non-metastatic prostate cancer:
a propensity score-matched study. Prostate Cancer Prostatic Dis, 2021. 24: 567.
https://www.ncbi.nlm.nih.gov/pubmed/33504940

206 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

824. van Son, M.J., et al. Conventional radical versus focal treatment for localised prostate cancer: a
propensity score weighted comparison of 6-year tumour control. Prostate Cancer Prostatic Dis, 2021.
24: 1120.
https://www.ncbi.nlm.nih.gov/pubmed/33934114
825. Lovegrove, C.E., et al. Evaluation of functional outcomes after a second focal high-intensity focused
ultrasonography (HIFU) procedure in men with primary localized, non-metastatic prostate cancer:
results from the HIFU Evaluation and Assessment of Treatment (HEAT) registry. BJU Int, 2020. 125:
853.
https://www.ncbi.nlm.nih.gov/pubmed/31971335
826. Marconi, L., et al. Robot-assisted Radical Prostatectomy After Focal Therapy: Oncological, Functional
Outcomes and Predictors of Recurrence. Eur Urol, 2019. 76: 27.
https://www.ncbi.nlm.nih.gov/pubmed/30904357
827. Spitznagel, T., et al. Salvage Robotic-assisted Laparoscopic Radical Prostatectomy Following Focal
High-Intensity Focused Ultrasound for ISUP 2/3 Cancer. Urology, 2021. 156: 147.
https://www.ncbi.nlm.nih.gov/pubmed/34186136
828. Zwergel, U., et al. Outcome of prostate cancer patients with initial PSA> or =20 ng/ml undergoing
radical prostatectomy. Eur Urol, 2007. 52: 1058.
https://www.ncbi.nlm.nih.gov/pubmed/17418938
829. Magheli, A., et al. Importance of tumor location in patients with high preoperative prostate specific
antigen levels (greater than 20 ng/ml) treated with radical prostatectomy. J Urol, 2007. 178: 1311.
https://www.ncbi.nlm.nih.gov/pubmed/17698095
830. Blank, F., et al. Salvage Radical Prostatectomy after Primary Focal Ablative Therapy: A Systematic
Review and Meta-Analysis. Cancers (Basel), 2023. 15.
https://www.ncbi.nlm.nih.gov/pubmed/37345064
831. Gill, I.S., et al. Randomized Trial of Partial Gland Ablation with Vascular Targeted Phototherapy versus
Active Surveillance for Low Risk Prostate Cancer: Extended Followup and Analyses of Effectiveness.
J Urol, 2018. 200: 786.
https://www.ncbi.nlm.nih.gov/pubmed/29864437
832. Marra, G., et al. Long-term Outcomes of Focal Cryotherapy for Low- to Intermediate-risk Prostate
Cancer: Results and Matched Pair Analysis with Active Surveillance. Eur Urol Focus, 2022. 8: 701.
https://www.ncbi.nlm.nih.gov/pubmed/33926838
833. MacLennan, S., et al. A core outcome set for localised prostate cancer effectiveness trials. BJU Int,
2017. 120: E64.
https://www.ncbi.nlm.nih.gov/pubmed/28346770
834. Guillaumier, S., et al. A Multicentre Study of 5-year Outcomes Following Focal Therapy in Treating
Clinically Significant Nonmetastatic Prostate Cancer. Eur Urol, 2018. 74: 422.
https://www.ncbi.nlm.nih.gov/pubmed/29960750
835. McLeod, D.G., et al. Bicalutamide 150 mg plus standard care vs standard care alone for early
prostate cancer. BJU Int, 2006. 97: 247.
https://www.ncbi.nlm.nih.gov/pubmed/16430622
836. Holmberg, L., et al. Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer. New Engl J
Med, 2024. 391: 1362.
https://www.nejm.org/doi/full/10.1056/NEJMc2406108
837. Luo, X., et al. Prostatectomy Versus Observation for Localized Prostate Cancer: A Meta-Analysis.
Scand J Surg, 2021. 110: 78.
https://www.ncbi.nlm.nih.gov/pubmed/31662032
838. Kuperus, J.M., et al. Pelvic Lymph Node Dissection at Radical Prostatectomy for Intermediate Risk
Prostate Cancer: Assessing Utility and Nodal Metastases Within a Statewide Quality Improvement
Consortium. Urology, 2022. 165: 227.
https://www.ncbi.nlm.nih.gov/pubmed/35263639
839. James, N.D., et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone
therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage,
platform randomised controlled trial. Lancet, 2016. 387: 1163.
https://www.ncbi.nlm.nih.gov/pubmed/26719232
840. Krauss, D., et al. Lack of benefit for the addition of androgen deprivation therapy to dose-escalated
radiotherapy in the treatment of intermediate- and high-risk prostate cancer. Int J Radiat Oncol Biol
Phys, 2011. 80: 1064.
https://www.ncbi.nlm.nih.gov/pubmed/20584576

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 207

841. Kupelian, P.A., et al. Effect of increasing radiation doses on local and distant failures in patients with
localized prostate cancer. Int J Radiat Oncol Biol Phys, 2008. 71: 16.
https://www.ncbi.nlm.nih.gov/pubmed/17996382
842. King, M.T., et al. Low dose rate brachytherapy for primary treatment of localized prostate cancer: A
systemic review and executive summary of an evidence-based consensus statement. Brachytherapy,
2021. 20: 1114.
https://www.ncbi.nlm.nih.gov/pubmed/34509378
843. Studer, U.E., et al. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0
prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol, 2008. 53: 941.
https://www.ncbi.nlm.nih.gov/pubmed/18191322
844. Joniau, S., et al. Stratification of high-risk prostate cancer into prognostic categories: a European
multi-institutional study. Eur Urol, 2015. 67: 157.
https://www.ncbi.nlm.nih.gov/pubmed/24486307
845. Donohue, J.F., et al. Poorly differentiated prostate cancer treated with radical prostatectomy: long-
term outcome and incidence of pathological downgrading. J Urol, 2006. 176: 991.
https://www.ncbi.nlm.nih.gov/pubmed/16890678
846. Laukhtina, E., et al. Oncologic impact of delaying radical prostatectomy in men with intermediate- and
high-risk prostate cancer: a systematic review. World J Urol, 2021. 39: 4085.
https://www.ncbi.nlm.nih.gov/pubmed/34047825
847. Nguyen, D.D., et al. Systematic Review of Time to Definitive Treatment for Intermediate Risk and High
Risk Prostate Cancer: Are Delays Associated with Worse Outcomes? J Urol, 2021. 205: 1263.
https://www.ncbi.nlm.nih.gov/pubmed/33443458
848. Kumar, S., et al. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced
prostate cancer. Cochrane Database Syst Rev, 2006. 2006: CD006019.
https://www.ncbi.nlm.nih.gov/pubmed/17054269
849. Roach, M., et al. Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised
prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial. Lancet Oncol,
2018. 19: 1504.
https://www.ncbi.nlm.nih.gov/pubmed/30316827
850. Murthy, V., et al. Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-
Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized Controlled Trial. J Clin Oncol,
2021. 39: 1234.
https://www.ncbi.nlm.nih.gov/pubmed/33497252
851. Murthy, V., et al. Late toxicity and quality of life with prostate only or whole pelvic radiation therapy in
high risk prostate cancer (POP-RT): A randomised trial. Radiother Oncol, 2020. 145: 71.
https://www.ncbi.nlm.nih.gov/pubmed/31923712
852. Moris, L., et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally
Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol, 2020. 77:
614.
https://www.ncbi.nlm.nih.gov/pubmed/32146018
853. Gongora, M., et al. Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical
Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally
Advanced Prostate Cancer. Eur Urol Open Sci, 2022. 41: 63.
https://www.ncbi.nlm.nih.gov/pubmed/35813256
854. Bastian, P.J., et al. Clinical and pathologic outcome after radical prostatectomy for prostate cancer
patients with a preoperative Gleason sum of 8 to 10. Cancer, 2006. 107: 1265.
https://www.ncbi.nlm.nih.gov/pubmed/16900523
855. Yossepowitch, O., et al. Radical prostatectomy for clinically localized, high risk prostate cancer:
critical analysis of risk assessment methods. J Urol, 2007. 178: 493.
https://www.ncbi.nlm.nih.gov/pubmed/17561152
856. Trails.gov, C. Surgery Versus Radiotherapy for Locally Advanced Prostate Cancer (SPCG-15). 2014.
2022.
https://clinicaltrials.gov/ct2/show/NCT02102477
857. Chang, K., et al. Comparison of two adjuvant hormone therapy regimens in patients with high-risk
localized prostate cancer after radical prostatectomy: primary results of study CU1005. Asian J
Androl, 2016. 18: 452.
https://www.ncbi.nlm.nih.gov/pubmed/26323560
858. Walz, J., et al. Pathological results and rates of treatment failure in high-risk prostate cancer patients
after radical prostatectomy. BJU Int, 2011. 107: 765.
https://www.ncbi.nlm.nih.gov/pubmed/20875089

208 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

859. Spahn, M., et al. Outcome predictors of radical prostatectomy in patients with prostate-specific
antigen greater than 20 ng/ml: a European multi-institutional study of 712 patients. Eur Urol, 2010.
58: 1.
https://www.ncbi.nlm.nih.gov/pubmed/20299147
860. Ward, J.F., et al. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent
of prostate-specific antigen testing: 15-year outcome. BJU Int, 2005. 95: 751.
https://www.ncbi.nlm.nih.gov/pubmed/15794776
861. Werner, R.A., et al. Prostate-specific Membrane Antigen Reporting and Data System Version 2.0. Eur
Urol, 2023. 84: 491.
https://www.ncbi.nlm.nih.gov/pubmed/37414701
862. Seifert, R., et al. Second Version of the Prostate Cancer Molecular Imaging Standardized Evaluation
Framework Including Response Evaluation for Clinical Trials (PROMISE V2). Eur Urol, 2023. 83: 405.
https://www.ncbi.nlm.nih.gov/pubmed/36935345
863. Stranne, J., et al. Use of Prostate-specific Membrane Antigen Positron Emission Tomography/
Computed Tomography for Nodal Staging in Prostate Cancer and Tailoring of Treatment: A
Continuing Conundrum. Eur Urol, 2024.
https://www.ncbi.nlm.nih.gov/pubmed/39701872
864. Yaow, C.Y.L., et al. Local Therapy on Clinically Lymph Node-positive Prostate Cancer: A Systematic
Review and Meta-analysis. Eur Urol Oncol, 2024. 7: 355.
https://www.ncbi.nlm.nih.gov/pubmed/37730526
865. James, N.D., et al. Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed
Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial.
JAMA Oncol, 2016. 2: 348.
https://www.ncbi.nlm.nih.gov/pubmed/26606329
866. James, N.D., et al. Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in
the STAMPEDE Randomized Controlled Trial. JNCI Cancer Spectr, 2022. 6: pkac043.
https://www.ncbi.nlm.nih.gov/pubmed/35877084
867. Attard, G., et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk
non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled
phase 3 trials of the STAMPEDE platform protocol. Lancet, 2022. 399: 447.
https://www.ncbi.nlm.nih.gov/pubmed/34953525
868. Fizazi, K., et al. Androgen deprivation therapy plus docetaxel and estramustine versus androgen
deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised
controlled trial. Lancet Oncol, 2015. 16: 787.
https://www.ncbi.nlm.nih.gov/pubmed/26028518
869. Vale, C.L., et al. Addition of docetaxel or bisphosphonates to standard of care in men with
localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses
of aggregate data. Lancet Oncol, 2016. 17: 243.
https://www.ncbi.nlm.nih.gov/pubmed/26718929
870. Bryant, A.K., et al. Definitive Radiation Therapy and Survival in Clinically Node-Positive Prostate
Cancer. Int J Radiat Oncol Biol Phys, 2018. 101: 1188.
https://www.ncbi.nlm.nih.gov/pubmed/29891203
871. Sarkar, R.R., et al. Association between Radical Prostatectomy and Survival in Men with Clinically
Node-positive Prostate Cancer. Eur Urol Oncol, 2019. 2: 584.
https://www.ncbi.nlm.nih.gov/pubmed/31411995
872. Lin, C.C., et al. Androgen deprivation with or without radiation therapy for clinically node-positive
prostate cancer. J Natl Cancer Inst, 2015. 107.
https://www.ncbi.nlm.nih.gov/pubmed/25957435
873. Tward, J.D., et al. Radiation therapy for clinically node-positive prostate adenocarcinoma is correlated
with improved overall and prostate cancer-specific survival. Pract Radiat Oncol, 2013. 3: 234.
https://www.ncbi.nlm.nih.gov/pubmed/24674370
874. Rusthoven, C.G., et al. The impact of definitive local therapy for lymph node-positive prostate cancer:
a population-based study. Int J Radiat Oncol Biol Phys, 2014. 88: 1064.
https://www.ncbi.nlm.nih.gov/pubmed/24661660
875. Seisen, T., et al. Efficacy of Local Treatment in Prostate Cancer Patients with Clinically Pelvic Lymph
Node-positive Disease at Initial Diagnosis. Eur Urol, 2018. 73: 452.
https://www.ncbi.nlm.nih.gov/pubmed/28890245
876. Chierigo, F., et al. Survival after radical prostatectomy versus radiation therapy in clinical node-
positive prostate cancer. Prostate, 2022. 82: 740.
https://www.ncbi.nlm.nih.gov/pubmed/35226380

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 209

877. Elumalai, T., et al. Impact of prostate radiotherapy on survival outcomes in clinically node-positive
prostate cancer: A multicentre retrospective analysis. Radiother Oncol, 2023. 186: 109746.
https://www.ncbi.nlm.nih.gov/pubmed/37330057
878. Studer, U.E., et al. Immediate or deferred androgen deprivation for patients with prostate cancer not
suitable for local treatment with curative intent: European Organisation for Research and Treatment
of Cancer (EORTC) Trial 30891. J Clin Oncol, 2006. 24: 1868.
https://www.ncbi.nlm.nih.gov/pubmed/16622261
879. Wurnschimmel, C., et al. Radical prostatectomy for localized prostate cancer: 20-year oncological
outcomes from a German high-volume center. Urol Oncol, 2021. 39: 830 e17.
https://www.ncbi.nlm.nih.gov/pubmed/34092484
880. Bader, P., et al. Is a limited lymph node dissection an adequate staging procedure for prostate
cancer? J Urol, 2002. 168: 514.
https://www.ncbi.nlm.nih.gov/pubmed/12131300
881. Briganti, A., et al. Two positive nodes represent a significant cut-off value for cancer specific survival
in patients with node positive prostate cancer. A new proposal based on a two-institution experience
on 703 consecutive N+ patients treated with radical prostatectomy, extended pelvic lymph node
dissection and adjuvant therapy. Eur Urol, 2009. 55: 261.
https://www.ncbi.nlm.nih.gov/pubmed/18838212
882. Schumacher, M.C., et al. Good outcome for patients with few lymph node metastases after radical
retropubic prostatectomy. Eur Urol, 2008. 54: 344.
https://www.ncbi.nlm.nih.gov/pubmed/18511183
883. Abdollah, F., et al. More extensive pelvic lymph node dissection improves survival in patients with
node-positive prostate cancer. Eur Urol, 2015. 67: 212.
https://www.ncbi.nlm.nih.gov/pubmed/24882672
884. Pound, C.R., et al. Natural history of progression after PSA elevation following radical prostatectomy.
JAMA, 1999. 281: 1591.
https://www.ncbi.nlm.nih.gov/pubmed/10235151
885. Aus, G., et al. Prognostic factors and survival in node-positive (N1) prostate cancer-a prospective
study based on data from a Swedish population-based cohort. Eur Urol, 2003. 43: 627.
https://www.ncbi.nlm.nih.gov/pubmed/12767363
886. Cheng, L., et al. Risk of prostate carcinoma death in patients with lymph node metastasis. Cancer,
2001. 91: 66.
https://www.ncbi.nlm.nih.gov/pubmed/11148561
887. Seiler, R., et al. Removal of limited nodal disease in patients undergoing radical prostatectomy: long-
term results confirm a chance for cure. J Urol, 2014. 191: 1280.
https://www.ncbi.nlm.nih.gov/pubmed/24262495
888. Passoni, N.M., et al. Prognosis of patients with pelvic lymph node (LN) metastasis after radical
prostatectomy: value of extranodal extension and size of the largest LN metastasis. BJU Int, 2014.
114: 503.
https://www.ncbi.nlm.nih.gov/pubmed/24053552
889. Daneshmand, S., et al. Prognosis of patients with lymph node positive prostate cancer following
radical prostatectomy: long-term results. J Urol, 2004. 172: 2252.
https://www.ncbi.nlm.nih.gov/pubmed/15538242
890. Touijer, K.A., et al. Long-term outcomes of patients with lymph node metastasis treated with radical
prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol, 2014. 65: 20.
https://www.ncbi.nlm.nih.gov/pubmed/23619390
891. Spratt, D.E., et al. Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic
Classifier in High-Risk Men After Prostatectomy to Predict Development of Metastatic Disease. J Clin
Oncol, 2017. 35: 1991.
https://www.ncbi.nlm.nih.gov/pubmed/28358655
892. Jairath, N.K., et al. A Systematic Review of the Evidence for the Decipher Genomic Classifier in
Prostate Cancer. Eur Urol, 2021. 79: 374.
https://www.ncbi.nlm.nih.gov/pubmed/33293078
893. Wiegel, T., et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year
follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol, 2014. 66: 243.
https://www.ncbi.nlm.nih.gov/pubmed/24680359
894. Fossati, N., et al. Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0
Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional
Series. Eur Urol, 2017. 71: 886.
https://www.ncbi.nlm.nih.gov/pubmed/27484843

210 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

895. Buscariollo, D.L., et al. Long-term results of adjuvant versus early salvage postprostatectomy
radiation: A large single-institutional experience. Pract Radiat Oncol, 2017. 7: e125.
https://www.ncbi.nlm.nih.gov/pubmed/28274403
896. Hwang, W.L., et al. Comparison Between Adjuvant and Early-Salvage Postprostatectomy
Radiotherapy for Prostate Cancer With Adverse Pathological Features. JAMA Oncol, 2018. 4:
e175230.
https://www.ncbi.nlm.nih.gov/pubmed/29372236
897. Parker, C.C., et al. Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes
in the RADICALS-RT trial (NCT00541047). Ann Oncol, 2024. 35: 656.
https://www.ncbi.nlm.nih.gov/pubmed/38583574
898. Kneebone, A., et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical
prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.
Lancet Oncol, 2020. 21: 1331.
https://www.ncbi.nlm.nih.gov/pubmed/33002437
899. Sargos, P., et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen
deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU
17): a randomised, phase 3 trial. Lancet Oncol, 2020. 21: 1341.
https://www.ncbi.nlm.nih.gov/pubmed/33002438
900. Vale, C.L., et al. Adjuvant or early salvage radiotherapy for the treatment of localised and locally
advanced prostate cancer: a prospectively planned systematic review and meta-analysis of
aggregate data. Lancet, 2020. 396: 1422.
https://www.ncbi.nlm.nih.gov/pubmed/33002431
901. Parker, C.C., et al. Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy
with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way
Comparison of RADICALS-HD (NCT00541047). Eur Urol, 2024. 86: 422.
https://www.ncbi.nlm.nih.gov/pubmed/39217077
902. Tilki, D., et al. Adjuvant Versus Early Salvage Radiation Therapy for Men at High Risk for Recurrence
Following Radical Prostatectomy for Prostate Cancer and the Risk of Death. J Clin Oncol, 2021. 39:
2284.
https://www.ncbi.nlm.nih.gov/pubmed/34086480
903. Tilki, D., et al. Timing of radiotherapy after radical prostatectomy. Lancet, 2020. 396: 1374.
https://www.ncbi.nlm.nih.gov/pubmed/33002430
904. Ghadjar, P., et al. Postoperative radiotherapy in prostate cancer. Lancet, 2021. 397: 1623.
https://www.ncbi.nlm.nih.gov/pubmed/33933203
905. Thompson, I.M., et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly
reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J
Urol, 2009. 181: 956.
https://www.ncbi.nlm.nih.gov/pubmed/19167731
906. Bolla, M., et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer:
long-term results of a randomised controlled trial (EORTC trial 22911). Lancet, 2012. 380: 2018.
https://www.ncbi.nlm.nih.gov/pubmed/23084481
907. Hackman, G., et al. Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy
Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or
Extracapsular Extension. Eur Urol, 2019. 76: 586.
https://www.ncbi.nlm.nih.gov/pubmed/31375279
908. Ahlgren, G.M., et al. Docetaxel Versus Surveillance After Radical Prostatectomy for High-risk Prostate
Cancer: Results from the Prospective Randomised, Open-label Phase 3 Scandinavian Prostate
Cancer Group 12 Trial. Eur Urol, 2018. 73: 870.
https://www.ncbi.nlm.nih.gov/pubmed/29395502
909. Schweizer, M.T., et al. Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate
cancer after radical prostatectomy (TAX-3501): important lessons for future trials. Cancer, 2013. 119:
3610.
https://www.ncbi.nlm.nih.gov/pubmed/23943299
910. Ghavamian, R., et al. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone
for pTxN+ prostate cancer: a matched comparison. J Urol, 1999. 161: 1223.
https://www.ncbi.nlm.nih.gov/pubmed/10081874
911. Messing, E.M., et al. Immediate versus deferred androgen deprivation treatment in patients with
node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet
Oncol, 2006. 7: 472.
https://www.ncbi.nlm.nih.gov/pubmed/16750497

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 211

912. Abdollah, F., et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate
cancer. J Clin Oncol, 2014. 32: 3939.
https://www.ncbi.nlm.nih.gov/pubmed/25245445
913. Tilki, D., et al. Adjuvant Versus Early Salvage Radiation Therapy After Radical Prostatectomy for pN1
Prostate Cancer and the Risk of Death. J Clin Oncol, 2022. 40: 2186.
https://www.ncbi.nlm.nih.gov/pubmed/35290082
914. Abdollah, F., et al. Impact of Adjuvant Radiotherapy in Node-positive Prostate Cancer Patients: The
Importance of Patient Selection. Eur Urol, 2018. 74: 253.
https://www.ncbi.nlm.nih.gov/pubmed/29720348
915. Gupta, M., et al. Adjuvant radiation with androgen-deprivation therapy for men with lymph node
metastases after radical prostatectomy: identifying men who benefit. BJU Int, 2019. 123: 252.
https://www.ncbi.nlm.nih.gov/pubmed/29626845
916. Marra, G., et al. Management of Patients with Node-positive Prostate Cancer at Radical
Prostatectomy and Pelvic Lymph Node Dissection: A Systematic Review. Eur Urol Oncol, 2020. 3:
565.
https://www.ncbi.nlm.nih.gov/pubmed/32933887
917. Tilki, D., et al. Adjuvant radiation therapy is associated with better oncological outcome
compared with salvage radiation therapy in patients with pN1 prostate cancer treated with radical
prostatectomy. BJU Int, 2017. 119: 717.
https://www.ncbi.nlm.nih.gov/pubmed/27743493
918. Mandel, P., et al. Long-term oncological outcomes in patients with limited nodal disease undergoing
radical prostatectomy and pelvic lymph node dissection without adjuvant treatment. World J Urol,
2017. 35: 1833.
https://www.ncbi.nlm.nih.gov/pubmed/28828530
919. Kimura, S., et al. Prognostic Significance of Prostate-Specific Antigen Persistence after Radical
Prostatectomy: A Systematic Review and Meta-Analysis. Cancers (Basel), 2021. 13.
https://www.ncbi.nlm.nih.gov/pubmed/33668270
920. Ploussard, G., et al. Management of Persistently Elevated Prostate-specific Antigen After Radical
Prostatectomy: A Systematic Review of the Literature. Eur Urol Oncol, 2021. 4: 150.
https://www.ncbi.nlm.nih.gov/pubmed/33574012
921. Wu, S., et al. Clinicopathological and oncological significance of persistent prostate-specific antigen
after radical prostatectomy: A systematic review and meta-analysis. Asian J Urol, 2023. 10: 317.
https://www.ncbi.nlm.nih.gov/pubmed/38583574
922. Sasaki, T., et al. Cribriform pattern 4/intraductal carcinoma of the prostate and persistent prostate-
specific antigen after radical prostatectomy. BJUI Compass, 2024. 5: 709.
https://www.ncbi.nlm.nih.gov/pubmed/39022662
923. Preisser, F., et al. Persistent Prostate-Specific Antigen After Radical Prostatectomy and Its Impact on
Oncologic Outcomes. Eur Urol, 2019. 76: 106.
https://www.ncbi.nlm.nih.gov/pubmed/30772034
924. Xiang, C., et al. Prediction of Biochemical Recurrence Following Radiotherapy among Patients with
Persistent PSA after Radical Prostatectomy: A Single-Center Experience. Urol Int, 2018. 101: 47.
https://www.ncbi.nlm.nih.gov/pubmed/29627830
925. Rogers, C.G., et al. Natural history of disease progression in patients who fail to achieve an
undetectable prostate-specific antigen level after undergoing radical prostatectomy. Cancer, 2004.
101: 2549.
https://www.ncbi.nlm.nih.gov/pubmed/15470681
926. Patel, A., et al. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of
prostate specific antigen doubling times and log slope prostate specific antigen. J Urol, 1997. 158:
1441.
https://www.ncbi.nlm.nih.gov/pubmed/9302139
927. Farolfi, A., et al. (68)Ga-PSMA-11 Positron Emission Tomography Detects Residual Prostate Cancer
after Prostatectomy in a Multicenter Retrospective Study. J Urol, 2019. 202: 1174.
https://www.ncbi.nlm.nih.gov/pubmed/31233369
928. Meijer, D., et al. Biochemical Persistence of Prostate-Specific Antigen After Robot-Assisted
Laparoscopic Radical Prostatectomy: Tumor Localizations Using PSMA PET/CT Imaging. J Nucl
Med, 2021. 62: 961.
https://www.ncbi.nlm.nih.gov/pubmed/33158904

212 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

929. Schmidt-Hegemann, N.S., et al. Outcome after PSMA PET/CT based radiotherapy in patients with
biochemical persistence or recurrence after radical prostatectomy. Radiat Oncol, 2018. 13: 37.
https://www.ncbi.nlm.nih.gov/pubmed/29499730
930. Sood, A., et al. Anti-Androgen Therapy Overcomes the Time Delay in Initiation of Salvage Radiation
Therapy and Rescues the Oncological Outcomes in Men with Recurrent Prostate Cancer After
Radical Prostatectomy: A Post Hoc Analysis of the RTOG-9601 Trial Data. Ann of Surg Oncol, 2022.
29: 7206.
https://link.springer.com/article/10.1245/s10434-022-11892-8
931. Wiegel, T., et al. Prostate-specific antigen persistence after radical prostatectomy as a predictive
factor of clinical relapse-free survival and overall survival: 10-year data of the ARO 96-02 trial. Int J
Radiat Oncol Biol Phys, 2015. 91: 288.
https://www.ncbi.nlm.nih.gov/pubmed/25445556
932. Bartkowiak, D., et al. The impact of prostate-specific antigen persistence after radical prostatectomy
on the efficacy of salvage radiotherapy in patients with primary N0 prostate cancer. BJU Int, 2019.
124: 785.
https://www.ncbi.nlm.nih.gov/pubmed/31220400
933. Van den Broeck, T., et al. Prognostic Value of Biochemical Recurrence Following Treatment with
Curative Intent for Prostate Cancer: A Systematic Review. Eur Urol, 2019. 75: 967.
https://www.ncbi.nlm.nih.gov/pubmed/30342843
934. Özman, O., et al. The Effect of Salvage Radiation Therapy on Survival, Functional Outcomes, and
Quality of Life in Men with Persistent Prostate-specific Antigen After Robot-Assisted Radical
Prostatectomy: Which Patient Benefits More? Pract Radiat Oncol, 2022. 12: e538.
https://www.ncbi.nlm.nih.gov/pubmed/35843543
935. Choo, R., et al. Prospective study evaluating postoperative radiotherapy plus 2-year androgen
suppression for post-radical prostatectomy patients with pathologic T3 disease and/or positive
surgical margins. Int J Radiat Oncol Biol Phys, 2009. 75: 407.
https://www.ncbi.nlm.nih.gov/pubmed/19211197
936. Gandaglia, G., et al. Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-
specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. Eur
Urol, 2017. 72: 910.
https://www.ncbi.nlm.nih.gov/pubmed/28622831
937. Garcia-Barreras, S., et al. Predictive factors and the important role of detectable prostate-specific
antigen for detection of clinical recurrence and cancer-specific mortality following robot-assisted
radical prostatectomy. Clin Transl Oncol, 2018. 20: 1004.
https://www.ncbi.nlm.nih.gov/pubmed/29243074
938. Lohm, G., et al. Salvage radiotherapy in patients with persistently detectable PSA or PSA rising from
an undetectable range after radical prostatectomy gives comparable results. World J Urol, 2013. 31:
423.
https://www.ncbi.nlm.nih.gov/pubmed/22460203
939. Ploussard, G., et al. Clinical outcomes after salvage radiotherapy without androgen deprivation
therapy in patients with persistently detectable PSA after radical prostatectomy: results from a
national multicentre study. World J Urol, 2014. 32: 1331.
https://www.ncbi.nlm.nih.gov/pubmed/24270970
940. Fossati, N., et al. Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or
Rising Prostate-specific Antigen After Radical Prostatectomy. Eur Urol, 2018. 73: 436.
https://www.ncbi.nlm.nih.gov/pubmed/28779974
941. Tanegashima, T., et al. Prognosis based on postoperative PSA levels and treatment in prostate
cancer with lymph node involvement. Int J Clin Oncol, 2024. 29: 1586.
https://www.ncbi.nlm.nih.gov/pubmed/38976182
942. Komori, T., et al. Long-Term Prognosis and Treatment Strategy of Persistent PSA After Radical
Prostatectomy. Ann Surg Oncol, 2023. 30: 6936.
https://www.ncbi.nlm.nih.gov/pubmed/37418130
943. Milonas, D., et al. Benefits of early salvage therapy on oncological outcomes in high-risk prostate
cancer with persistent PSA after radical prostatectomy. Clin Transl Oncol, 2022. 24: 371.
https://www.ncbi.nlm.nih.gov/pubmed/34453699
944. Guerif, S.G., et al. The acute toxicity results of the GETUG-AFU 22 study: A multicenter randomized
phase II trial comparing the efficacy of a short hormone therapy in combination with radiotherapy
to radiotherapy alone as a salvage treatment for patients with detectable PSA after radical
prostatectomy. J Clin Oncol, 2017. 35: 16.
https://ascopubs.org/doi/abs/10.1200/JCO.2017.35.6_suppl.16

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 213

945. Arlen, P.M., et al. Prostate Specific Antigen Working Group guidelines on prostate specific antigen
doubling time. J Urol, 2008. 179: 2181.
https://www.ncbi.nlm.nih.gov/pubmed/18423743
946. Vickers, A.J., et al. PSA Velocity and Doubling Time in Diagnosis and Prognosis of Prostate Cancer.
Br J Med Surg Urol, 2012. 5: 162.
https://www.ncbi.nlm.nih.gov/pubmed/22712027
947. O’Brien, M.F., et al. Pretreatment prostate-specific antigen (PSA) velocity and doubling time are
associated with outcome but neither improves prediction of outcome beyond pretreatment PSA
alone in patients treated with radical prostatectomy. J Clin Oncol, 2009. 27: 3591.
https://www.ncbi.nlm.nih.gov/pubmed/19506163
948. Ramirez, M.L., et al. Current applications for prostate-specific antigen doubling time. Eur Urol, 2008.
54: 291.
https://www.ncbi.nlm.nih.gov/pubmed/18439749
949. Vickers, A.J., et al. Systematic review of pretreatment prostate-specific antigen velocity and doubling
time as predictors for prostate cancer. J Clin Oncol, 2009. 27: 398.
https://www.ncbi.nlm.nih.gov/pubmed/19064972
950. Lee, A.K., et al. Utility of prostate-specific antigen kinetics in addition to clinical factors in the
selection of patients for salvage local therapy. J Clin Oncol, 2005. 23: 8192.
https://www.ncbi.nlm.nih.gov/pubmed/16278472
951. Campbell, S.R., et al. Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive
Nomograms of Salvage Radiotherapy After Radical Prostatectomy. Eur Urol Oncol, 2022. 5: 304.
https://www.ncbi.nlm.nih.gov/pubmed/34016556
952. Smith, M.R., et al. Natural history of rising serum prostate-specific antigen in men with castrate
nonmetastatic prostate cancer. J Clin Oncol, 2005. 23: 2918.
https://www.ncbi.nlm.nih.gov/pubmed/15860850
953. Toussi, A., et al. Standardizing the Definition of Biochemical Recurrence after Radical Prostatectomy-
What Prostate Specific Antigen Cut Point Best Predicts a Durable Increase and Subsequent Systemic
Progression? J Urol, 2016. 195: 1754.
https://www.ncbi.nlm.nih.gov/pubmed/26721226
954. Roach, M., 3rd, et al. Defining biochemical failure following radiotherapy with or without hormonal
therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO
Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys, 2006. 65: 965.
https://www.ncbi.nlm.nih.gov/pubmed/16798415
955. Jackson, W.C., et al. Intermediate Endpoints After Postprostatectomy Radiotherapy: 5-Year Distant
Metastasis to Predict Overall Survival. Eur Urol, 2018. 74: 413.
https://www.ncbi.nlm.nih.gov/pubmed/29306514
956. Choueiri, T.K., et al. Impact of postoperative prostate-specific antigen disease recurrence and the use
of salvage therapy on the risk of death. Cancer, 2010. 116: 1887.
https://www.ncbi.nlm.nih.gov/pubmed/20162710
957. Freiberger, C., et al. Long-term prognostic significance of rising PSA levels following radiotherapy for
localized prostate cancer - focus on overall survival. Radiat Oncol, 2017. 12: 98.
https://www.ncbi.nlm.nih.gov/pubmed/28615058
958. Royce, T.J., et al. Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable-
Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen
Deprivation Therapy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol, 2017. 3: 652.
https://www.ncbi.nlm.nih.gov/pubmed/28097317
959. Tilki, D., et al. External Validation of the European Association of Urology Biochemical Recurrence
Risk Groups to Predict Metastasis and Mortality After Radical Prostatectomy in a European Cohort.
Eur Urol, 2019. 75: 896.
https://www.ncbi.nlm.nih.gov/pubmed/30955970
960. Zagars, G.K., et al. Kinetics of serum prostate-specific antigen after external beam radiation for
clinically localized prostate cancer. Radiother Oncol, 1997. 44: 213.
https://www.ncbi.nlm.nih.gov/pubmed/9380819
961. Rouviere, O., et al. Imaging of prostate cancer local recurrences: why and how? Eur Radiol, 2010. 20:
1254.
https://www.ncbi.nlm.nih.gov/pubmed/19921202
962. Beresford, M.J., et al. A systematic review of the role of imaging before salvage radiotherapy for
post-prostatectomy biochemical recurrence. Clin Oncol (R Coll Radiol), 2010. 22: 46.
https://www.ncbi.nlm.nih.gov/pubmed/19948393

214 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

963. Gomez, P., et al. Radionuclide bone scintigraphy in patients with biochemical recurrence after radical
prostatectomy: when is it indicated? BJU Int, 2004. 94: 299.
https://www.ncbi.nlm.nih.gov/pubmed/15291855
964. Kane, C.J., et al. Limited value of bone scintigraphy and computed tomography in assessing
biochemical failure after radical prostatectomy. Urology, 2003. 61: 607.
https://www.ncbi.nlm.nih.gov/pubmed/12639656
965. Evangelista, L., et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a
systematic review and meta-analysis. Clin Nucl Med, 2013. 38: 305.
https://www.ncbi.nlm.nih.gov/pubmed/23486334
966. Fanti, S., et al. PET/CT with (11)C-choline for evaluation of prostate cancer patients with biochemical
recurrence: meta-analysis and critical review of available data. Eur J Nucl Med Mol Imaging, 2016.
43: 55.
https://www.ncbi.nlm.nih.gov/pubmed/26450693
967. Fuccio, C., et al. Role of 11C-choline PET/CT in the restaging of prostate cancer patients showing a
single lesion on bone scintigraphy. Ann Nucl Med, 2010. 24: 485.
https://www.ncbi.nlm.nih.gov/pubmed/20544323
968. Fuccio, C., et al. Role of 11C-choline PET/CT in the re-staging of prostate cancer patients with
biochemical relapse and negative results at bone scintigraphy. Eur J Radiol, 2012. 81: e893.
https://www.ncbi.nlm.nih.gov/pubmed/22621862
969. Castellucci, P., et al. Early biochemical relapse after radical prostatectomy: which prostate cancer
patients may benefit from a restaging 11C-Choline PET/CT scan before salvage radiation therapy? J
Nucl Med, 2014. 55: 1424.
https://www.ncbi.nlm.nih.gov/pubmed/24935990
970. Treglia, G., et al. Relationship between prostate-specific antigen kinetics and detection rate of
radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. Clin Chem Lab
Med, 2014. 52: 725.
https://www.ncbi.nlm.nih.gov/pubmed/24310773
971. Mitchell, C.R., et al. Operational characteristics of (11)c-choline positron emission tomography/
computerized tomography for prostate cancer with biochemical recurrence after initial treatment. J
Urol, 2013. 189: 1308.
https://www.ncbi.nlm.nih.gov/pubmed/23123372
972. Soyka, J.D., et al. Clinical impact of 18F-choline PET/CT in patients with recurrent prostate cancer.
Eur J Nucl Med Mol Imaging, 2012. 39: 936.
https://www.ncbi.nlm.nih.gov/pubmed/22415598
973. Ceci, F., et al. Impact of 11C-choline PET/CT on clinical decision making in recurrent prostate cancer:
results from a retrospective two-centre trial. Eur J Nucl Med Mol Imaging, 2014. 41: 2222.
https://www.ncbi.nlm.nih.gov/pubmed/25182750
974. Beer, A.J., et al. Radionuclide and hybrid imaging of recurrent prostate cancer. Lancet Oncol, 2011.
12: 181.
https://www.ncbi.nlm.nih.gov/pubmed/20599424
975. Beheshti, M., et al. Detection of bone metastases in patients with prostate cancer by 18F
fluorocholine and 18F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging, 2008. 35:
1766.
https://www.ncbi.nlm.nih.gov/pubmed/18465129
976. Songmen, S., et al. Axumin Positron Emission Tomography: Novel Agent for Prostate Cancer
Biochemical Recurrence. J Clin Imaging Sci, 2019. 9: 49.
https://www.ncbi.nlm.nih.gov/pubmed/31819826
977. FDA approves new diagnostic imaging agent to detect recurrent prostate cancer - axumin. 2016.
2022.
https://www.fda.gov/news-events/press-announcements/fda-approves-new-diagnostic-imaging-
agent-detect-recurrent-prostate-cancer
978. EMA. Axumin 2017. 2021.
https://www.ema.europa.eu/en/medicines/human/EPAR/axumin
979. Nanni, C., et al. (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)
C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol
Imaging, 2016. 43: 1601.
https://www.ncbi.nlm.nih.gov/pubmed/26960562

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 215

980. Bach-Gansmo, T., et al. Multisite Experience of the Safety, Detection Rate and Diagnostic
Performance of Fluciclovine ((18)F) Positron Emission Tomography/Computerized Tomography
Imaging in the Staging of Biochemically Recurrent Prostate Cancer. J Urol, 2017. 197: 676.
https://www.ncbi.nlm.nih.gov/pubmed/27746282
981. Abiodun-Ojo, O.A., et al. Salvage Radiotherapy Management Decisions in Postprostatectomy Patients
with Recurrent Prostate Cancer Based on (18)F-Fluciclovine PET/CT Guidance. J Nucl Med, 2021. 62:
1089.
https://www.ncbi.nlm.nih.gov/pubmed/33517323
982. Yang, Y.Y., et al. Diagnostic performance of 18F-labeled PSMA PET/CT in patients with biochemical
recurrence of prostate cancer: a systematic review and meta-analysis. Acta Radiol, 2023. 64: 2791.
https://www.ncbi.nlm.nih.gov/pubmed/37545168
983. Morigi, J.J., et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in
Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered
for Targeted Therapy. J Nucl Med, 2015. 56: 1185.
https://www.ncbi.nlm.nih.gov/pubmed/26112024
984. Afshar-Oromieh, A., et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)
F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging,
2014. 41: 11.
https://www.ncbi.nlm.nih.gov/pubmed/24072344
985. Caroli, P., et al. (68)Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical
treatment: prospective results in 314 patients. Eur J Nucl Med Mol Imaging, 2018. 45: 2035.
https://www.ncbi.nlm.nih.gov/pubmed/29922948
986. Panagiotidis, E., et al. Comparison of 18F-PSMA-1007 and 18F-Choline PET/CT in prostate cancer
patients with biochemical recurrence: a phase 3, prospective, multicenter, randomized study. Nucl
Med Commun, 2023. 44: 1126.
https://www.ncbi.nlm.nih.gov/pubmed/37779440
987. Morris, M.J., et al. Diagnostic Performance of (18)F-DCFPyL-PET/CT in Men with Biochemically
Recurrent Prostate Cancer: Results from the CONDOR Phase III, Multicenter Study. Clin Cancer Res,
2021. 27: 3674.
https://www.ncbi.nlm.nih.gov/pubmed/33622706
988. Giesel, F.L., et al. Intraindividual Comparison of (18)F-PSMA-1007 and (18)F-DCFPyL PET/CT in the
Prospective Evaluation of Patients with Newly Diagnosed Prostate Carcinoma: A Pilot Study. J Nucl
Med, 2018. 59: 1076.
https://www.ncbi.nlm.nih.gov/pubmed/29269569
989. Oprea-Lager, D.E., et al. [(18)F]DCFPyL PET/CT versus [(18)F]fluoromethylcholine PET/CT
in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over,
comparative study. Eur J Nucl Med Mol Imaging, 2023. 50: 3439.
https://www.ncbi.nlm.nih.gov/pubmed/37341747
990. Olivier, P., et al. Phase III Study of (18)F-PSMA-1007 Versus (18)F-Fluorocholine PET/CT for
Localization of Prostate Cancer Biochemical Recurrence: A Prospective, Randomized, Crossover
Multicenter Study. J Nucl Med, 2023. 64: 579.
https://www.ncbi.nlm.nih.gov/pubmed/36418170
991. Perera, M., et al. Sensitivity, Specificity, and Predictors of Positive (68)Ga-Prostate-specific
Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic
Review and Meta-analysis. Eur Urol, 2016. 70: 926.
https://www.ncbi.nlm.nih.gov/pubmed/27363387
992. Eiber, M., et al. Whole-body MRI including diffusion-weighted imaging (DWI) for patients with
recurring prostate cancer: technical feasibility and assessment of lesion conspicuity in DWI. J Magn
Reson Imaging, 2011. 33: 1160.
https://www.ncbi.nlm.nih.gov/pubmed/21509875
993. Zacho, H.D., et al. Prospective comparison of (68)Ga-PSMA PET/CT, (18)F-sodium fluoride PET/
CT and diffusion weighted-MRI at for the detection of bone metastases in biochemically recurrent
prostate cancer. Eur J Nucl Med Mol Imaging, 2018. 45: 1884.
https://www.ncbi.nlm.nih.gov/pubmed/29876619
994. Renard-Penna, R., et al. Targeting Local Recurrence After Surgery With MRI Imaging for Prostate
Cancer in the Setting of Salvage Radiation Therapy. Front Oncol, 2022. 12: 775387.
https://www.ncbi.nlm.nih.gov/pubmed/35242702
995. Song, W., et al. Prognostic factors after salvage radiotherapy alone in patients with biochemical
recurrence after radical prostatectomy. Int J Urol, 2016. 23: 56.
https://www.ncbi.nlm.nih.gov/pubmed/26502086

216 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

996. Sharma, V., et al. Multiparametric Magnetic Resonance Imaging Is an Independent Predictor of
Salvage Radiotherapy Outcomes After Radical Prostatectomy. Eur Urol, 2018. 73: 879.
https://www.ncbi.nlm.nih.gov/pubmed/29195777
997. Farneti, A., et al. The Prognostic Value of DCE-MRI Findings before Salvage Radiotherapy after
Radical Prostatectomy. Cancers (Basel), 2023. 15.
https://www.ncbi.nlm.nih.gov/pubmed/36831588
998. Panebianco, V., et al. Prostate Magnetic Resonance Imaging for Local Recurrence Reporting (PI-
RR): International Consensus -based Guidelines on Multiparametric Magnetic Resonance Imaging
for Prostate Cancer Recurrence after Radiation Therapy and Radical Prostatectomy. Eur Urol Oncol,
2021. 4: 868.
https://www.ncbi.nlm.nih.gov/pubmed/33582104
999. Abreu-Gomez, J., et al. PI-RR: The Prostate Imaging for Recurrence Reporting System
for MRI Assessment of Local Prostate Cancer Recurrence After Radiation Therapy or Radical
Prostatectomy-A Review. AJR Am J Roentgenol, 2023. 220: 852.
https://www.ncbi.nlm.nih.gov/pubmed/36722763
1000. Achard, V., et al. Recurrent prostate cancer after radical prostatectomy: restaging performance of
18F-choline hybrid PET/MRI. Med Oncol, 2019. 36: 67.
https://www.ncbi.nlm.nih.gov/pubmed/31190232
1001. Luiting, H.B., et al. Use of gallium-68 prostate-specific membrane antigen positron-emission
tomography for detecting lymph node metastases in primary and recurrent prostate cancer and
location of recurrence after radical prostatectomy: an overview of the current literature. BJU Int,
2020. 125: 206.
https://www.ncbi.nlm.nih.gov/pubmed/31680398
1002. Boreta, L., et al. Location of Recurrence by Gallium-68 PSMA-11 PET Scan in Prostate Cancer
Patients Eligible for Salvage Radiotherapy. Urology, 2019. 129: 165.
https://www.ncbi.nlm.nih.gov/pubmed/30928607
1003. Farolfi, A., et al. (68)Ga-PSMA-11 PET/CT in prostate cancer patients with biochemical recurrence
after radical prostatectomy and PSA <0.5 ng/ml. Efficacy and impact on treatment strategy. Eur J
Nucl Med Mol Imaging, 2019. 46: 11.
https://www.ncbi.nlm.nih.gov/pubmed/29905907
1004. Guberina, N., et al. Whole-Body Integrated [(68)Ga]PSMA-11-PET/MR Imaging in Patients with
Recurrent Prostate Cancer: Comparison with Whole-Body PET/CT as the Standard of Reference. Mol
Imaging Biol, 2020. 22: 788.
https://www.ncbi.nlm.nih.gov/pubmed/31482413
1005. Metser, U., et al. The Contribution of Multiparametric Pelvic and Whole-Body MRI to Interpretation of
(18)F-Fluoromethylcholine or (68)Ga-HBED-CC PSMA-11 PET/CT in Patients with Biochemical Failure
After Radical Prostatectomy. J Nucl Med, 2019. 60: 1253.
https://www.ncbi.nlm.nih.gov/pubmed/30902875
1006. Freitag, M.T., et al. Local recurrence of prostate cancer after radical prostatectomy is at risk to be
missed in (68)Ga-PSMA-11-PET of PET/CT and PET/MRI: comparison with mpMRI integrated in
simultaneous PET/MRI. Eur J Nucl Med Mol Imaging, 2017. 44: 776.
https://www.ncbi.nlm.nih.gov/pubmed/27988802
1007. Jani, A.B., et al. (18)F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide
postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label,
phase 2/3 randomised controlled trial. Lancet, 2021. 397: 1895.
https://www.ncbi.nlm.nih.gov/pubmed/33971152
1008. Dinis Fernandes, C., et al. Quantitative 3T multiparametric MRI of benign and malignant prostatic
tissue in patients with and without local recurrent prostate cancer after external-beam radiation
therapy. J Magn Reson Imaging, 2019. 50: 269.
https://www.ncbi.nlm.nih.gov/pubmed/30585368
1009. Donati, O.F., et al. Multiparametric prostate MR imaging with T2-weighted, diffusion-weighted, and
dynamic contrast-enhanced sequences: are all pulse sequences necessary to detect locally recurrent
prostate cancer after radiation therapy? Radiology, 2013. 268: 440.
https://www.ncbi.nlm.nih.gov/pubmed/23481164
1010. Dinis Fernandes, C., et al. Quantitative 3-T multi-parametric MRI and step-section pathology of
recurrent prostate cancer patients after radiation therapy. Eur Radiol, 2019. 29: 4160.
https://www.ncbi.nlm.nih.gov/pubmed/30421016
1011. Rasing, M., et al. Value of Targeted Biopsies and Combined PSMA PET/CT and mp-MRI Imaging in
Locally Recurrent Prostate Cancer after Primary Radiotherapy. Cancers (Basel), 2022. 14.
https://www.ncbi.nlm.nih.gov/pubmed/35159048

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 217

1012. Boorjian, S.A., et al. Radiation therapy after radical prostatectomy: impact on metastasis and survival.
J Urol, 2009. 182: 2708.
https://www.ncbi.nlm.nih.gov/pubmed/19836762
1013. Kneebone, A., et al. A Phase III Multi-Centre Randomised Trial comparing adjuvant versus early
salvage Radiotherapy following a Radical Prostatectomy: Results of the TROG 08.03 and ANZUP
“RAVES” Trial. Int J Radiat Oncol Biol Phys, 2019. 105: S37.
https://www.redjournal.org/article/S0360-3016(19)31291-X/fulltext
1014. Tilki, D., et al. Salvage Radiotherapy versus Observation for Biochemical Recurrence following Radical
Prostatectomy for Prostate Cancer: A Matched Pair Analysis. Cancers (Basel), 2022. 14.
https://www.ncbi.nlm.nih.gov/pubmed/35159007
1015. Stish, B.J., et al. Improved Metastasis-Free and Survival Outcomes With Early Salvage Radiotherapy
in Men With Detectable Prostate-Specific Antigen After Prostatectomy for Prostate Cancer. J Clin
Oncol, 2016. 34: 3864.
https://www.ncbi.nlm.nih.gov/pubmed/27480153
1016. Pfister, D., et al. Early salvage radiotherapy following radical prostatectomy. Eur Urol, 2014. 65: 1034.
https://www.ncbi.nlm.nih.gov/pubmed/23972524
1017. Ohri, N., et al. Can early implementation of salvage radiotherapy for prostate cancer improve the
therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling.
Eur J Cancer, 2012. 48: 837.
https://www.ncbi.nlm.nih.gov/pubmed/21945099
1018. Wiegel, T., et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after
radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective
study. Int J Radiat Oncol Biol Phys, 2009. 73: 1009.
https://www.ncbi.nlm.nih.gov/pubmed/18963539
1019. Trock, B.J., et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in
men with biochemical recurrence after radical prostatectomy. JAMA, 2008. 299: 2760.
https://www.ncbi.nlm.nih.gov/pubmed/18560003
1020. Tilki, D., et al. Prostate-Specific Antigen Level at the Time of Salvage Therapy After Radical
Prostatectomy for Prostate Cancer and the Risk of Death. J Clin Oncol, 2023. 41: 2428.
https://www.ncbi.nlm.nih.gov/pubmed/36857638
1021. Group, I.C.W., et al. The Development of Intermediate Clinical Endpoints in Cancer of the Prostate
(ICECaP). J Natl Cancer Inst, 2015. 107: djv261.
https://www.ncbi.nlm.nih.gov/pubmed/26409187
1022. Xie, W., et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate
Cancer. J Clin Oncol, 2017. 35: 3097.
https://www.ncbi.nlm.nih.gov/pubmed/28796587
1023. Shipley, W., et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Eng
J Med, 2017. 376: 417.
https://www.ncbi.nlm.nih.gov/pubmed/28146658
1024. Carrie, C., et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage
treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of
a phase 3, randomised trial. Lancet Oncol, 2019. 20: 1740.
https://www.ncbi.nlm.nih.gov/pubmed/31629656
1025. Pollack, A., et al. The addition of androgen deprivation therapy and pelvic lymph node treatment
to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international,
multicentre, randomised phase 3 trial. Lancet, 2022. 399: 1886.
https://www.ncbi.nlm.nih.gov/pubmed/35569466
1026. Ramey, S.J., et al. Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen
Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer. Eur Urol,
2018. 74: 99.
https://www.ncbi.nlm.nih.gov/pubmed/29128208
1027. Parker, C.C., et al. Adding 6 months of androgen deprivation therapy to postoperative radiotherapy
for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the
RADICALS-HD randomised controlled trial. Lancet, 2024. 403: 2405.
https://www.ncbi.nlm.nih.gov/pubmed/38763154
1028. Parker, C.C., et al. Duration of androgen deprivation therapy with postoperative radiotherapy for
prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in
the RADICALS-HD randomised trial. Lancet, 2024. 403: 2416.
https://www.ncbi.nlm.nih.gov/pubmed/38763153

218 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1029. Parker, C.C., et al. Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy
with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way
Comparison of RADICALS-HD (NCT00541047). Eur Urol, 2024. 86: 422.
https://www.ncbi.nlm.nih.gov/pubmed/39217077
1030. Pollack, A., et al. Androgen deprivation therapy combined with postoperative radiotherapy for
prostate cancer management. Lancet, 2024. 403: 2353.
https://www.ncbi.nlm.nih.gov/pubmed/38763152
1031. Nabid, A., et al. Testosterone recovery after androgen deprivation therapy in localised prostate
cancer: Long-term data from two randomised trials. Radiother Oncol, 2024. 195: 110256.
https://www.ncbi.nlm.nih.gov/pubmed/38552845
1032. Dess, R.T., et al. Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With
Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer. JAMA Oncol, 2020. 6:
735.
https://www.ncbi.nlm.nih.gov/pubmed/32215583
1033. Spratt, D.E., et al. A Systematic Review and Framework for the Use of Hormone Therapy with Salvage
Radiation Therapy for Recurrent Prostate Cancer. Eur Urol, 2018. 73: 156.
https://www.ncbi.nlm.nih.gov/pubmed/28716370
1034. Malone, S., et al. Postoperative radiotherapy for prostate cancer: a comparison of four consensus
guidelines and dosimetric evaluation of 3D-CRT versus tomotherapy IMRT. Int J Radiat Oncol Biol
Phys, 2012. 84: 725.
https://www.ncbi.nlm.nih.gov/pubmed/22444999
1035. Dal Pra, A., et al. ESTRO ACROP guideline on prostate bed delineation for postoperative radiotherapy
in prostate cancer. Clin Transl Radiat Oncol, 2023. 41: 100638.
https://www.ncbi.nlm.nih.gov/pubmed/37251620
1036. Pisansky, T.M., et al. Salvage Radiation Therapy Dose Response for Biochemical Failure of Prostate
Cancer After Prostatectomy-A Multi-Institutional Observational Study. Int J Radiat Oncol Biol Phys,
2016. 96: 1046.
https://www.ncbi.nlm.nih.gov/pubmed/27745980
1037. King, C.R. The dose-response of salvage radiotherapy following radical prostatectomy: A systematic
review and meta-analysis. Radiother Oncol, 2016. 121: 199.
https://www.ncbi.nlm.nih.gov/pubmed/27863963
1038. Fossati, N., et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with
Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol, 2016. 69: 728.
https://www.ncbi.nlm.nih.gov/pubmed/26497924
1039. Fiorino, C., et al. Predicting the 5-Year Risk of Biochemical Relapse After Postprostatectomy
Radiation Therapy in >/=PT2, pN0 Patients With a Comprehensive Tumor Control Probability Model.
Int J Radiat Oncol Biol Phys, 2016. 96: 333.
https://www.ncbi.nlm.nih.gov/pubmed/27497691
1040. Tendulkar, R.D., et al. Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage
Radiotherapy After Radical Prostatectomy. J Clin Oncol, 2016. 34: 3648.
https://www.ncbi.nlm.nih.gov/pubmed/27528718
1041. Ghadjar, P., et al. Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically
Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial. Eur Urol,
2021. 80: 306.
https://www.ncbi.nlm.nih.gov/pubmed/34140144
1042. Li, H.Z., et al. Dose-Intensified Postoperative Radiation Therapy for Prostate Cancer: Long-Term
Results From the PKUFH Randomized Phase 3 Trial. Int J Radiat Oncol Biol Phys, 2024. 118: 697.
https://www.ncbi.nlm.nih.gov/pubmed/37717784
1043. Bartkowiak, D., et al. Prostate-specific antigen after salvage radiotherapy for postprostatectomy
biochemical recurrence predicts long-term outcome including overall survival. Acta Oncol, 2018. 57:
362.
https://www.ncbi.nlm.nih.gov/pubmed/28816074
1044. Ghadjar, P., et al. Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy
for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized
Trial SAKK 09/10. J Clin Oncol, 2015. 33: 4158.
https://www.ncbi.nlm.nih.gov/pubmed/26527774
1045. Ghadjar, P., et al. Impact of dose intensified salvage radiation therapy on urinary continence recovery
after radical prostatectomy: Results of the randomized trial SAKK 09/10. Radiother Oncol, 2018. 126:
257.
https://www.ncbi.nlm.nih.gov/pubmed/29103826

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 219

1046. Goenka, A., et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation
therapy with intensity-modulated radiation therapy. Eur Urol, 2011. 60: 1142.
https://www.ncbi.nlm.nih.gov/pubmed/21855208
1047. Ost, P., et al. High-dose salvage intensity-modulated radiotherapy with or without androgen
deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year
results. Eur Urol, 2011. 60: 842.
https://www.ncbi.nlm.nih.gov/pubmed/21514039
1048. Qi, X., et al. Toxicity and Biochemical Outcomes of Dose-Intensified Postoperative Radiation Therapy
for Prostate Cancer: Results of a Randomized Phase III Trial. Int J Radiat Oncol Biol Phys, 2020. 106:
282.
https://www.ncbi.nlm.nih.gov/pubmed/31669564
1049. Jackson, W.C., et al. Combining prostate-specific antigen nadir and time to nadir allows for early
identification of patients at highest risk for development of metastasis and death following salvage
radiation therapy. Pract Radiat Oncol, 2014. 4: 99.
https://www.ncbi.nlm.nih.gov/pubmed/24890350
1050. Roach, P.J., et al. The Impact of (68)Ga-PSMA PET/CT on Management Intent in Prostate Cancer:
Results of an Australian Prospective Multicenter Study. J Nucl Med, 2018. 59: 82.
https://www.ncbi.nlm.nih.gov/pubmed/28646014
1051. Rauscher, I., et al. Efficacy, Predictive Factors, and Prediction Nomograms for (68)Ga-labeled
Prostate-specific Membrane Antigen-ligand Positron-emission Tomography/Computed Tomography
in Early Biochemical Recurrent Prostate Cancer After Radical Prostatectomy. Eur Urol, 2018. 73: 656.
https://www.ncbi.nlm.nih.gov/pubmed/29358059
1052. Meijer, D., et al. Prostate-specific Membrane Antigen Positron Emission Tomography/Computed
Tomography Is Associated with Improved Oncological Outcome in Men Treated with Salvage
Radiation Therapy for Biochemically Recurrent Prostate Cancer. Eur Urol Oncol, 2022. 5: 146.
https://www.ncbi.nlm.nih.gov/pubmed/35074282
1053. Steuber, T., et al. Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal
Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control
Study. Eur Urol Focus, 2019. 5: 1007.
https://www.ncbi.nlm.nih.gov/pubmed/29530632
1054. De Bleser, E., et al. Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A
Multi-institutional Analysis Comparing the Outcome and Toxicity of Stereotactic Body Radiotherapy
and Elective Nodal Radiotherapy. Eur Urol, 2019. 76: 732.
https://www.ncbi.nlm.nih.gov/pubmed/31331782
1055. Fodor, A., et al. Extended nodal radiotherapy for prostate cancer relapse guided with [11C]-choline
PET/CT: ten-year results in patients enrolled in a prospective trial. Eur J Nucl Med Mol Imaging, 2024.
51: 590.
https://www.ncbi.nlm.nih.gov/pubmed/37747578
1056. Vaugier, L., et al. Long-term Outcomes and Patterns of Relapse Following High-dose Elective Salvage
Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes in Prostate Cancer: OLIGOPELVIS
(GETUG-P07). Eur Urol, 2025. 87: 73.
https://www.ncbi.nlm.nih.gov/pubmed/38490854
1057. Suardi, N., et al. Long-term outcomes of salvage lymph node dissection for clinically recurrent
prostate cancer: results of a single-institution series with a minimum follow-up of 5 years. Eur Urol,
2015. 67: 299.
https://www.ncbi.nlm.nih.gov/pubmed/24571959
1058. Tilki, D., et al. Salvage lymph node dissection for nodal recurrence of prostate cancer after radical
prostatectomy. J Urol, 2015. 193: 484.
https://www.ncbi.nlm.nih.gov/pubmed/25180792
1059. Fossati, N., et al. Identifying the Optimal Candidate for Salvage Lymph Node Dissection for Nodal
Recurrence of Prostate Cancer: Results from a Large, Multi-institutional Analysis. Eur Urol, 2019. 75:
176.
https://www.ncbi.nlm.nih.gov/pubmed/30301694
1060. Ploussard, G., et al. Salvage Lymph Node Dissection for Nodal Recurrent Prostate Cancer: A
Systematic Review. Eur Urol, 2019. 76: 493.
https://www.ncbi.nlm.nih.gov/pubmed/30391078
1061. Ost, P., et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment
of prostate cancer: a systematic review of the literature. Eur Urol, 2015. 67: 852.
https://www.ncbi.nlm.nih.gov/pubmed/25240974

220 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1062. Rischke, H.C., et al. Adjuvant radiotherapy after salvage lymph node dissection because of nodal
relapse of prostate cancer versus salvage lymph node dissection only. Strahlenther Onkol, 2015. 191:
310.
https://www.ncbi.nlm.nih.gov/pubmed/25326142
1063. Bravi, C.A., et al. Long-term Outcomes of Salvage Lymph Node Dissection for Nodal Recurrence of
Prostate Cancer After Radical Prostatectomy: Not as Good as Previously Thought. Eur Urol, 2020. 78:
661.
https://www.ncbi.nlm.nih.gov/pubmed/32624288
1064. Knipper, S., et al. Cohort Study of Oligorecurrent Prostate Cancer Patients: Oncological Outcomes
of Patients Treated with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen-
radioguided Surgery. Eur Urol, 2023. 83: 62.
https://www.ncbi.nlm.nih.gov/pubmed/35718637
1065. Valle, L.F., et al. A Systematic Review and Meta-analysis of Local Salvage Therapies After
Radiotherapy for Prostate Cancer (MASTER). Eur Urol, 2021. 80: 280.
https://www.ncbi.nlm.nih.gov/pubmed/33309278
1066. Gontero, P., et al. Salvage Radical Prostatectomy for Recurrent Prostate Cancer: Morbidity and
Functional Outcomes from a Large Multicenter Series of Open versus Robotic Approaches. J Urol,
2019. 202: 725.
https://www.ncbi.nlm.nih.gov/pubmed/31075058
1067. Saouli, A., et al. Salvage Radical Prostatectomy for Recurrent Prostate Cancer: A Systematic Review
(French ccAFU). Cancers (Basel), 2023. 15: 5485.
https://www.ncbi.nlm.nih.gov/pubmed/38001745
1068. Chade, D.C., et al. Cancer control and functional outcomes of salvage radical prostatectomy for
radiation-recurrent prostate cancer: a systematic review of the literature. Eur Urol, 2012. 61: 961.
https://www.ncbi.nlm.nih.gov/pubmed/22280856
1069. Marra, G., et al. Oncological outcomes of salvage radical prostatectomy for recurrent prostate cancer
in the contemporary era: A multicenter retrospective study. Urol Oncol, 2021. 39: 296 e21.
https://www.ncbi.nlm.nih.gov/pubmed/33436329
1070. Calleris, G., et al. Salvage Radical Prostatectomy for Recurrent Prostate Cancer Following First-
line Nonsurgical Treatment: Validation of the European Association of Urology Criteria in a Large,
Multicenter, Contemporary Cohort. Eur Urol Focus, 2023. 9: 645.
https://www.ncbi.nlm.nih.gov/pubmed/36682962
1071. Thakker, P.U., et al. A Comprehensive Review of the Current State of Robot-assisted Laparoscopic
Salvage Prostatectomy. Int Braz J Urol, 2024. 50: 398.
https://www.ncbi.nlm.nih.gov/pubmed/38701186
1072. Preisser, F., et al. Oncologic Outcomes of Lymph Node Dissection at Salvage Radical Prostatectomy.
Cancers (Basel), 2023. 15.
https://www.ncbi.nlm.nih.gov/pubmed/37370733
1073. Preisser, F., et al. Impact of persistent PSA after salvage radical prostatectomy: a multicenter study.
Prostate Cancer Prostatic Dis, 2024. 27: 686.
https://www.ncbi.nlm.nih.gov/pubmed/37803241
1074. Gotto, G.T., et al. Impact of prior prostate radiation on complications after radical prostatectomy. J
Urol, 2010. 184: 136.
https://www.ncbi.nlm.nih.gov/pubmed/20478594
1075. Mandel, P., et al. Salvage radical prostatectomy for recurrent prostate cancer: verification of European
Association of Urology guideline criteria. BJU Int, 2016. 117: 55.
https://www.ncbi.nlm.nih.gov/pubmed/25711672
1076. Ginsburg, K.B., et al. Avoidance of androgen deprivation therapy in radiorecurrent prostate cancer as
a clinically meaningful endpoint for salvage cryoablation. Prostate, 2017. 77: 1446.
https://www.ncbi.nlm.nih.gov/pubmed/28856702
1077. Spiess, P.E., et al. A pretreatment nomogram predicting biochemical failure after salvage cryotherapy
for locally recurrent prostate cancer. BJU Int, 2010. 106: 194.
https://www.ncbi.nlm.nih.gov/pubmed/19922545
1078. Li, R., et al. The Effect of Androgen Deprivation Therapy Before Salvage Whole-gland Cryoablation
After Primary Radiation Failure in Prostate Cancer Treatment. Urology, 2015. 85: 1137.
https://www.ncbi.nlm.nih.gov/pubmed/25799176
1079. Kovac, E., et al. Five-Year Biochemical Progression-Free Survival Following Salvage Whole-Gland
Prostate Cryoablation: Defining Success with Nadir Prostate-Specific Antigen. J Endourol, 2016. 30:
624.
https://www.ncbi.nlm.nih.gov/pubmed/26915721

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 221

1080. Ahmad, I., et al. Prostate gland lengths and iceball dimensions predict micturition functional outcome
following salvage prostate cryotherapy in men with radiation recurrent prostate cancer. PLoS One,
2013. 8: e69243.
https://www.ncbi.nlm.nih.gov/pubmed/23950886
1081. Pisters, L.L., et al. Salvage prostate cryoablation: initial results from the cryo on-line data registry. J
Urol, 2008. 180: 559.
https://www.ncbi.nlm.nih.gov/pubmed/18554664
1082. Henriquez Lopez, I., et al. Salvage brachytherapy for locally-recurrent prostate cancer after radiation
therapy: A comparison of efficacy and toxicity outcomes with high-dose rate and low-dose rate
brachytherapy. Radiother Oncol, 2019. 141: 156.
https://www.ncbi.nlm.nih.gov/pubmed/31570236
1083. Crook, J.M., et al. A Prospective Phase 2 Trial of Transperineal Ultrasound-Guided Brachytherapy for
Locally Recurrent Prostate Cancer After External Beam Radiation Therapy (NRG Oncology/RTOG-
0526). Int J Radiat Oncol Biol Phys, 2019. 103: 335.
https://www.ncbi.nlm.nih.gov/pubmed/30312717
1084. Smith, W.H., et al. Salvage low dose rate brachytherapy for prostate cancer recurrence following
definitive external beam radiation therapy. Radiother Oncol, 2021. 155: 42.
https://www.ncbi.nlm.nih.gov/pubmed/33075391
1085. Lyczek, J., et al. HDR brachytherapy as a solution in recurrences of locally advanced prostate cancer.
J Contemp Brachyther, 2009. 1: 105.
https://www.ncbi.nlm.nih.gov/pubmed/27795720
1086. Pasquier, D., et al. Salvage Stereotactic Body Radiation Therapy for Local Prostate Cancer Recurrence
After Radiation Therapy: A Retrospective Multicenter Study of the GETUG. Int J Radiat Oncol Biol
Phys, 2019. 105: 727.
https://www.ncbi.nlm.nih.gov/pubmed/31344433
1087. Fuller, D., et al. Retreatment for Local Recurrence of Prostatic Carcinoma After Prior Therapeutic
Irradiation: Efficacy and Toxicity of HDR-Like SBRT. Int J Radiat Oncol Biol Phys, 2020. 106: 291.
https://www.ncbi.nlm.nih.gov/pubmed/31629838
1088. Bergamin, S., et al. Interim Results of a Prospective Prostate-Specific Membrane Antigen-Directed
Focal Stereotactic Reirradiation Trial for Locally Recurrent Prostate Cancer. Int J Radiat Oncol Biol
Phys, 2020. 108: 1172.
https://www.ncbi.nlm.nih.gov/pubmed/32659332
1089. Yang, J., et al. Nonsurgical salvage options for locally recurrent prostate cancer after primary
definitive radiotherapy: a systematic review and meta-analysis. Int J Surg, 2024. 110: 3008.
https://www.ncbi.nlm.nih.gov/pubmed/38348896
1090. Crouzet, S., et al. Salvage high-intensity focused ultrasound (HIFU) for locally recurrent prostate
cancer after failed radiation therapy: Multi-institutional analysis of 418 patients. BJU Int, 2017. 119:
896.
https://www.ncbi.nlm.nih.gov/pubmed/28063191
1091. Murat, F.J., et al. Mid-term results demonstrate salvage high-intensity focused ultrasound (HIFU)
as an effective and acceptably morbid salvage treatment option for locally radiorecurrent prostate
cancer. Eur Urol, 2009. 55: 640.
https://www.ncbi.nlm.nih.gov/pubmed/18508188
1092. Kanthabalan, A., et al. Focal salvage high-intensity focused ultrasound in radiorecurrent prostate
cancer. BJU Int, 2017. 120: 246.
https://www.ncbi.nlm.nih.gov/pubmed/28258616
1093. Jones, T.A., et al. High Intensity Focused Ultrasound for Radiorecurrent Prostate Cancer: A North
American Clinical Trial. J Urol, 2018. 199: 133.
https://www.ncbi.nlm.nih.gov/pubmed/28652121
1094. van den Bergh, R.C., et al. Role of Hormonal Treatment in Prostate Cancer Patients with
Nonmetastatic Disease Recurrence After Local Curative Treatment: A Systematic Review. Eur Urol,
2016. 69: 802.
https://www.ncbi.nlm.nih.gov/pubmed/26691493
1095. Duchesne, G.M., et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a
rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase
3 trial. Lancet Oncol, 2016. 17: 727.
https://www.ncbi.nlm.nih.gov/pubmed/27155740

222 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1096. Siddiqui, S.A., et al. Timing of androgen deprivation therapy and its impact on survival after radical
prostatectomy: a matched cohort study. J Urol, 2008. 179: 1830.
https://www.ncbi.nlm.nih.gov/pubmed/18353378
1097. Levine, G.N., et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science
advisory from the American Heart Association, American Cancer Society, and American Urological
Association: endorsed by the American Society for Radiation Oncology. Circulation, 2010. 121: 833.
https://www.ncbi.nlm.nih.gov/pubmed/20124128
1098. O’Farrell, S., et al. Risk and timing of cardiovascular disease after androgen-deprivation therapy in
men with prostate cancer. J Clin Oncol, 2015. 33: 1243.
https://www.ncbi.nlm.nih.gov/pubmed/25732167
1099. Boorjian, S.A., et al. Long-term risk of clinical progression after biochemical recurrence following
radical prostatectomy: the impact of time from surgery to recurrence. Eur Urol, 2011. 59: 893.
https://www.ncbi.nlm.nih.gov/pubmed/21388736
1100. Freedland, S.J., et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate
Cancer. New Engl J Med, 2023. 389: 1453.
https://www.nejm.org/doi/full/10.1056/NEJMoa2303974
1101. FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. 2019. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-
metastatic-castration-sensitive-prostate-cancer
1102. Aparicio, A. Biochemical Recurrence in Prostate Cancer — Tilting the Scale. New Engl J Med, 2023.
389: 1522.
https://www.nejm.org/doi/full/10.1056/NEJMe2309502
1103. Aggarwal, R., et al. PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in
Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19). J Clin
Oncol, 2024. 42: 1114.
https://www.ncbi.nlm.nih.gov/pubmed/38261983
1104. Josefsson, A., et al. Effect of docetaxel added to bicalutamide in Hormone-Naïve non-metastatic
prostate cancer with rising PSA, a randomized clinical trial (SPCG-14). Acta Oncol, 2023. 62: 372.
https://www.ncbi.nlm.nih.gov/pubmed/37073813
1105. Bubley, G.J. Is the flare phenomenon clinically significant? Urology, 2001. 58: 5.
https://www.ncbi.nlm.nih.gov/pubmed/11502435
1106. Krakowsky, Y., et al. Risk of Testosterone Flare in the Era of the Saturation Model: One More
Historical Myth. Eur Urol Focus, 2019. 5: 81.
https://www.ncbi.nlm.nih.gov/pubmed/28753828
1107. Klotz, L., et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label,
parallel-group phase III study in patients with prostate cancer. BJU Int, 2008. 102: 1531.
https://www.ncbi.nlm.nih.gov/pubmed/19035858
1108. Seidenfeld, J., et al. Single-therapy androgen suppression in men with advanced prostate cancer: a
systematic review and meta-analysis. Ann Intern Med, 2000. 132: 566.
https://www.ncbi.nlm.nih.gov/pubmed/10744594
1109. Ostergren, P.B., et al. Luteinizing Hormone-Releasing Hormone Agonists are Superior to Subcapsular
Orchiectomy in Lowering Testosterone Levels of Men with Prostate Cancer: Results from a
Randomized Clinical Trial. J Urol, 2017. 197: 1441.
https://www.ncbi.nlm.nih.gov/pubmed/27939836
1110. Shore, N.D. Experience with degarelix in the treatment of prostate cancer. Ther Adv Urol, 2013. 5: 11.
https://www.ncbi.nlm.nih.gov/pubmed/23372607
1111. Sciarra, A., et al. A meta-analysis and systematic review of randomized controlled trials with
degarelix versus gonadotropin-releasing hormone agonists for advanced prostate cancer. Medicine
(Baltimore), 2016. 95: e3845.
https://www.ncbi.nlm.nih.gov/pubmed/27399062
1112. Cirne, F., et al. The cardiovascular effects of gonadotropin-releasing hormone antagonists in men
with prostate cancer. Eur Heart J Cardiovasc Pharmacother, 2022. 8: 253.
https://www.ncbi.nlm.nih.gov/pubmed/33470403
1113. Abufaraj, M., et al. Differential Impact of Gonadotropin-releasing Hormone Antagonist Versus Agonist
on Clinical Safety and Oncologic Outcomes on Patients with Metastatic Prostate Cancer: A Meta-
analysis of Randomized Controlled Trials. Eur Urol, 2021. 79: 44.
https://www.ncbi.nlm.nih.gov/pubmed/32605859
1114. Shore, N.D., et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N
Engl J Med, 2020. 382: 2187.
https://www.ncbi.nlm.nih.gov/pubmed/32469183

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 223

1115. FDA approves relugolix for advanced prostate cancer. 2020. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-relugolix-advanced-
prostate-cancer
1116. EMA. Orgovyx approved for advanced prostate cancer. 2022. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/orgovyx
1117. Moffat, L.E. Comparison of Zoladex, diethylstilbestrol and cyproterone acetate treatment in advanced
prostate cancer. Eur Urol, 1990. 18 Suppl 3: 26.
https://www.ncbi.nlm.nih.gov/pubmed/2151272
1118. Schroder, F.H., et al. Metastatic prostate cancer treated by flutamide versus cyproterone acetate.
Final analysis of the “European Organization for Research and Treatment of Cancer” (EORTC)
Protocol 30892. Eur Urol, 2004. 45: 457.
https://www.ncbi.nlm.nih.gov/pubmed/15041109
1119. Smith, M.R., et al. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer:
effects on bone mineral density and body composition. J Clin Oncol, 2004. 22: 2546.
https://www.ncbi.nlm.nih.gov/pubmed/15226323
1120. Iversen, P. Antiandrogen monotherapy: indications and results. Urology, 2002. 60: 64.
https://www.ncbi.nlm.nih.gov/pubmed/12231053
1121. Wadhwa, V.K., et al. Long-term changes in bone mineral density and predicted fracture risk in patients
receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on
presenting values. BJU Int, 2009. 104: 800.
https://www.ncbi.nlm.nih.gov/pubmed/19338564
1122. Montgomery, R.B., et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a
mechanism for castration-resistant tumor growth. Cancer Res, 2008. 68: 4447.
https://www.ncbi.nlm.nih.gov/pubmed/18519708
1123. EMA. Nubeqa (darolutamide). 2020. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/nubeqa
1124. EMA. Xtandi (enzalutamide). 2013. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/xtandi
1125. Chi, K.N., et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med, 2019.
381: 13.
https://www.ncbi.nlm.nih.gov/pubmed/31150574
1126. Armstrong, A.J., et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With
Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol,
2019. 37: 2974.
https://www.ncbi.nlm.nih.gov/pubmed/31329516
1127. Fizazi, K., et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N
Engl J Med, 2017. 377: 352.
https://www.ncbi.nlm.nih.gov/pubmed/28578607
1128. Saad, F., et al. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With
Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol,
2024: JCO2401798.
https://www.ncbi.nlm.nih.gov/pubmed/39279580
1129. FDA approves abiraterone acetate in combination with prednisone for high-risk metastatic
castration-sensitive prostate cancer. 2018. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abiraterone-
acetate-combination-prednisone-high-risk-metastatic-castration-sensitive
1130. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. 2019. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-
metastatic-castration-sensitive-prostate-cancer
1131. EMA. Zytiga. 2011. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/zytiga
1132. EMA. Erleada (apalutamide). 2019. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/erleada
1133. Keam, S.J. Rezvilutamide: First Approval. Drugs, 2023. 83: 189.
https://www.ncbi.nlm.nih.gov/pubmed/36630077
1134. Moilanen, A.M., et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting
resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep, 2015. 5:
12007.
https://www.ncbi.nlm.nih.gov/pubmed/26137992

224 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1135. Zurth, C., et al. Blood-brain barrier penetration of [14C]darolutamide compared with [14C]
enzalutamide in rats using whole body autoradiography. J Clin Oncol, 2018. 36: 345.
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.345
1136. Sousa-Pimenta, M., et al. Chemotherapeutic properties and side-effects associated with the clinical
practice of terpene alkaloids: paclitaxel, docetaxel, and cabazitaxel. Front Pharmacol, 2023. 14:
1157306.
https://www.ncbi.nlm.nih.gov/pubmed/37229270
1137. Xue, B., et al. Synthesis of Taxol and Docetaxel by Using 10-Deacetyl-7-xylosyltaxanes. Chem
Biodivers, 2020. 17: e1900631.
https://www.ncbi.nlm.nih.gov/pubmed/31967396
1138. Geng, C.X., et al. Docetaxel inhibits SMMC-7721 human hepatocellular carcinoma cells growth and
induces apoptosis. World J Gastroenterol, 2003. 9: 696.
https://www.ncbi.nlm.nih.gov/pubmed/12679913
1139. Lord, C.J., et al. PARP inhibitors: Synthetic lethality in the clinic. Science, 2017. 355: 1152.
https://www.ncbi.nlm.nih.gov/pubmed/28302823
1140. Hargadon, K.M., et al. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved
immune checkpoint inhibitors. Int Immunopharmacol, 2018. 62: 29.
https://www.ncbi.nlm.nih.gov/pubmed/29990692
1141. Le, D.T., et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015. 372:
2509.
https://www.ncbi.nlm.nih.gov/pubmed/26028255
1142. Sgouros, G., et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev
Drug Discov, 2020. 19: 589.
https://www.ncbi.nlm.nih.gov/pubmed/32728208
1143. FDA approval of Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for the treatment of adult patients
with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer
who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy.
2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-
approval-pluvicto-lutetium-lu-177-vipivotide-tetraxetan-treatment-adult
1144. EMA. Summary of product characteristics - Pluvicto 2022.
https://www.ema.europa.eu/en/documents/product-information/pluvicto-epar-product-information_
en.pdf
1145. Napoli, G., et al. A Systematic Review and a Meta-analysis of Randomized Controlled Trials’ Control
Groups in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC). Curr Oncol Rep, 2022. 24: 1633.
https://www.ncbi.nlm.nih.gov/pubmed/35953601
1146. Glass, T.R., et al. Metastatic carcinoma of the prostate: identifying prognostic groups using recursive
partitioning. J Urol, 2003. 169: 164.
https://www.ncbi.nlm.nih.gov/pubmed/12478127
1147. Gravis, G., et al. Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation
of the Glass Model and Development of a Novel Simplified Prognostic Model. Eur Urol, 2015. 68: 196.
https://www.ncbi.nlm.nih.gov/pubmed/25277272
1148. Gravis, G., et al. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic
Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the
Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol, 2016. 70: 256.
https://www.ncbi.nlm.nih.gov/pubmed/26610858
1149. Sweeney, C.J., et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N
Engl J Med, 2015. 373: 737.
https://www.ncbi.nlm.nih.gov/pubmed/26244877
1150. Kyriakopoulos, C.E., et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate
Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin
Oncol, 2018. 36: 1080.
https://www.ncbi.nlm.nih.gov/pubmed/29384722
1151. Gravis, G., et al. Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More
Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies.
Eur Urol, 2018. 73: 847.
https://www.ncbi.nlm.nih.gov/pubmed/29475737
1152. Parker, C.C., et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate
cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet, 2018. 392: 2353.
https://www.ncbi.nlm.nih.gov/pubmed/30355464

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 225

1153. Francini, E., et al. Time of metastatic disease presentation and volume of disease are prognostic for
metastatic hormone sensitive prostate cancer (mHSPC). Prostate, 2018. 78: 889.
https://www.ncbi.nlm.nih.gov/pubmed/29707790
1154. Hussain, M., et al. Absolute prostate-specific antigen value after androgen deprivation is a strong
independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology
Group Trial 9346 (INT-0162). J Clin Oncol, 2006. 24: 3984.
https://www.ncbi.nlm.nih.gov/pubmed/16921051
1155. Harshman, L.C., et al. Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone-
Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel. J Clin
Oncol, 2018. 36: 376.
https://www.ncbi.nlm.nih.gov/pubmed/29261442
1156. Matsubara, N., et al. Correlation of Prostate-specific Antigen Kinetics with Overall Survival and
Radiological Progression-free Survival in Metastatic Castration-sensitive Prostate Cancer Treated
with Abiraterone Acetate plus Prednisone or Placebos Added to Androgen Deprivation Therapy: Post
Hoc Analysis of Phase 3 LATITUDE Study. Eur Urol, 2020. 77: 494.
https://www.ncbi.nlm.nih.gov/pubmed/31843335
1157. Chowdhury, S., et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus
androgen deprivation therapy is associated with longer survival and improved clinical outcomes in
TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol, 2023. 34: 477.
https://www.ncbi.nlm.nih.gov/pubmed/36858151
1158. Pagliarulo, V., et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol,
2012. 61: 11.
https://www.ncbi.nlm.nih.gov/pubmed/21871711
1159. Davey, P., et al. Cardiovascular risk profiles of GnRH agonists and antagonists: real-world analysis
from UK general practice. World J Urol, 2021. 39: 307.
https://www.ncbi.nlm.nih.gov/pubmed/32979057
1160. Boland, J., et al. Cardiovascular Toxicity of Androgen Deprivation Therapy. Curr Cardiol Rep, 2021. 23:
109.
https://www.ncbi.nlm.nih.gov/pubmed/34216282
1161. Gu, L., et al. Adverse cardiovascular effect following gonadotropin-releasing hormone antagonist
versus GnRH agonist for prostate cancer treatment: A systematic review and meta-analysis. Front
Endocrinol (Lausanne), 2023. 14: 1157857.
https://www.ncbi.nlm.nih.gov/pubmed/37065739
1162. Kunath, F., et al. Non-steroidal antiandrogen monotherapy compared with luteinising hormone-
releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer.
Cochrane Database Syst Rev, 2014. 6: CD009266.
https://www.ncbi.nlm.nih.gov/pubmed/24979481
1163. Niraula, S., et al. Treatment of prostate cancer with intermittent versus continuous androgen
deprivation: a systematic review of randomized trials. J Clin Oncol, 2013. 31: 2029.
https://www.ncbi.nlm.nih.gov/pubmed/23630216
1164. Botrel, T.E., et al. Intermittent versus continuous androgen deprivation for locally advanced, recurrent
or metastatic prostate cancer: a systematic review and meta-analysis. BMC Urol, 2014. 14: 9.
https://www.ncbi.nlm.nih.gov/pubmed/24460605
1165. Tsai, H.T., et al. Efficacy of intermittent androgen deprivation therapy vs conventional continuous
androgen deprivation therapy for advanced prostate cancer: a meta-analysis. Urology, 2013. 82: 327.
https://www.ncbi.nlm.nih.gov/pubmed/23896094
1166. Brungs, D., et al. Intermittent androgen deprivation is a rational standard-of-care treatment for all
stages of progressive prostate cancer: results from a systematic review and meta-analysis. Prostate
Cancer Prostatic Dis, 2014. 17: 105.
https://www.ncbi.nlm.nih.gov/pubmed/24686773
1167. Magnan, S., et al. Intermittent vs Continuous Androgen Deprivation Therapy for Prostate Cancer: A
Systematic Review and Meta-analysis. JAMA Oncol, 2015. 1: 1261.
https://www.ncbi.nlm.nih.gov/pubmed/26378418
1168. Hussain, M., et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J
Med, 2013. 368: 1314.
https://www.ncbi.nlm.nih.gov/pubmed/23550669
1169. Kunath, F., et al. Early versus deferred standard androgen suppression therapy for advanced
hormone-sensitive prostate cancer. Cochrane Database Syst Rev, 2019. 6: CD003506.
https://www.ncbi.nlm.nih.gov/pubmed/31194882

226 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1170. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials.
Prostate Cancer Trialists’ Collaborative Group. Lancet, 2000. 355: 1491.
https://www.ncbi.nlm.nih.gov/pubmed/10801170
1171. Schmitt, B., et al. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst
Rev, 2000: CD001526.
https://www.ncbi.nlm.nih.gov/pubmed/10796804
1172. Davis, I.D., et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl
J Med, 2019. 381: 121.
https://www.ncbi.nlm.nih.gov/pubmed/31157964
1173. Gu, W., et al. Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in
patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised,
open-label, phase 3 trial. Lancet Oncol, 2022. 23: 1249.
https://www.ncbi.nlm.nih.gov/pubmed/36075260
1174. James, N.D., et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N
Engl J Med, 2017. 377: 338.
https://www.ncbi.nlm.nih.gov/pubmed/28578639
1175. Rydzewska, L.H.M., et al. Adding abiraterone to androgen deprivation therapy in men with metastatic
hormone-sensitive prostate cancer: A systematic review and meta-analysis. Eur J Cancer, 2017. 84:
88.
https://www.ncbi.nlm.nih.gov/pubmed/28800492
1176. Hoyle, A.P., et al. Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer.
Eur Urol, 2019. 76: 719.
https://www.ncbi.nlm.nih.gov/pubmed/31447077
1177. Armstrong, A.J., et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-
Sensitive Prostate Cancer. J Clin Oncol, 2022. 40: 1616.
https://www.ncbi.nlm.nih.gov/pubmed/35420921
1178. Sweeney, C.J., et al. Testosterone suppression plus enzalutamide versus testosterone suppression
plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET):
an international, open-label, randomised, phase 3 trial. Lancet Oncol, 2023. 24: 323.
https://www.ncbi.nlm.nih.gov/pubmed/36990608
1179. Chi, K.N., et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final
Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol, 2021. 39:
2294.
https://www.ncbi.nlm.nih.gov/pubmed/33914595
1180. Fukuokaya, W., et al. Radiographic Progression Without Corresponding Prostate-specific Antigen
Progression in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving Apalutamide:
Secondary Analysis of the TITAN Trial. Eur Urol Oncol, 2024.
https://www.ncbi.nlm.nih.gov/pubmed/38688767
1181. Sweeney, C.J., et al. Overall Survival of Men with Metachronous Metastatic Hormone-sensitive
Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy. Eur Urol, 2021. 80:
275.
https://www.ncbi.nlm.nih.gov/pubmed/34030924
1182. Merseburger, A.S., et al. Apalutamide plus androgen deprivation therapy in clinical subgroups of
patients with metastatic castration-sensitive prostate cancer: A subgroup analysis of the randomised
clinical TITAN study. Eur J Cancer, 2023. 193: 113290.
https://www.ncbi.nlm.nih.gov/pubmed/37708629
1183. Gravis, G., et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic
prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol, 2013. 14:
149.
https://www.ncbi.nlm.nih.gov/pubmed/23306100
1184. Smith, T.J., et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical
Oncology Clinical Practice Guideline Update. J Clin Oncol, 2015. 33: 3199.
https://www.ncbi.nlm.nih.gov/pubmed/26169616
1185. Sathianathen, N.J., et al. Taxane-based chemohormonal therapy for metastatic hormone-sensitive
prostate cancer. Cochrane Database Syst Rev, 2018. 10: CD012816.
https://www.ncbi.nlm.nih.gov/pubmed/30320443
1186. Clarke, N.W., et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic
hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol,
2019. 30: 1992.
https://www.ncbi.nlm.nih.gov/pubmed/31560068

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 227

1187. Vale, C.L., et al. Which patients with metastatic hormone-sensitive prostate cancer benefit from
docetaxel: a systematic review and meta-analysis of individual participant data from randomised
trials. Lancet Oncol, 2023. 24: 783.
https://www.ncbi.nlm.nih.gov/pubmed/37414011
1188. Fizazi, K., et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel
in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label,
randomised, phase 3 study with a 2 x 2 factorial design. Lancet, 2022. 399: 1695.
https://www.ncbi.nlm.nih.gov/pubmed/35405085
1189. Fizazi, K., et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/
or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC):
First results of PEACE-1. J Clin Oncol, 2021. 39: 5000.
https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.5000
1190. Smith, M.R., et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N
Engl J Med, 2022. 386: 1132.
https://www.ncbi.nlm.nih.gov/pubmed/35179323
1191. Hussain, M., et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic
Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III
ARASENS Trial. J Clin Oncol, 2023. 41: 3595.
https://www.ncbi.nlm.nih.gov/pubmed/36795843
1192. Jian, T., et al. Systemic triplet therapy for metastatic hormone-sensitive prostate cancer: A systematic
review and network meta-analysis. Front Pharmacol, 2022. 13: 955925.
https://www.ncbi.nlm.nih.gov/pubmed/36278154
1193. Fiorica, F., et al. Addition of New Androgen Receptor Pathway Inhibitors to Docetaxel and Androgen
Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and
Metanalysis. Curr Oncol, 2022. 29: 9511.
https://www.ncbi.nlm.nih.gov/pubmed/36547161
1194. Riaz, I.B., et al. First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate
Cancer: A Living Systematic Review and Network Meta-analysis. JAMA Oncol, 2023. 9: 635.
https://www.ncbi.nlm.nih.gov/pubmed/36862387
1195. Chen, X., et al. Comparative efficacy of second-generation androgen receptor inhibitors for treating
prostate cancer: A systematic review and network meta-analysis. Front Endocrinol (Lausanne), 2023.
14: 1134719.
https://www.ncbi.nlm.nih.gov/pubmed/36967752
1196. Fallara, G., et al. Chemotherapy and advanced androgen blockage, alone or combined, for metastatic
hormone-sensitive prostate cancer a systematic review and meta-analysis. Cancer Treat Rev, 2022.
110: 102441.
https://www.ncbi.nlm.nih.gov/pubmed/35939976
1197. Hoeh, B., et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer: Updated
Network Meta-analysis Stratified by Disease Volume. Eur Urol Focus, 2023. 9: 838.
https://www.ncbi.nlm.nih.gov/pubmed/37055323
1198. Ramos-Esquivel, A., et al. A systematic review and meta-analysis on overall survival, failure-free
survival and safety outcomes in patients with metastatic hormone-sensitive prostate cancer treated
with new anti-androgens. Anticancer Drugs, 2023. 34: 405.
https://www.ncbi.nlm.nih.gov/pubmed/36730553
1199. Rajwa, P., et al. Association between age and efficacy of combination systemic therapies in patients
with metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis. Prostate
Cancer Prostatic Dis, 2023. 26: 170.
https://www.ncbi.nlm.nih.gov/pubmed/36284192
1200. Boeve, L.M.S., et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen
Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with
Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the
HORRAD Trial. Eur Urol, 2019. 75: 410.
https://www.ncbi.nlm.nih.gov/pubmed/30266309
1201. Parker, C.C., et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and
Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Med, 2022. 19:
e1003998.
https://www.ncbi.nlm.nih.gov/pubmed/35671327

228 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1202. Ali, A., et al. Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy
in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a
Randomized Clinical Trial. JAMA Oncol, 2021. 7: 555.
https://www.ncbi.nlm.nih.gov/pubmed/33599706
1203. Roy, S., et al. Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A
Network Meta-analysis. Eur Urol, 2024. 86: 10.
https://www.ncbi.nlm.nih.gov/pubmed/38570246
1204. Burdett, S., et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A
STOPCAP Systematic Review and Meta-analysis. Eur Urol, 2019. 76: 115.
https://www.ncbi.nlm.nih.gov/pubmed/30826218
1205. Bossi, A., et al. Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive
prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial
design. Lancet, 2024. 404: 2065.
https://www.ncbi.nlm.nih.gov/pubmed/39580202
1206. Milenkovic, U., et al. Predictors of Recurrence After Metastasis-directed Therapy in Oligorecurrent
Prostate Cancer Following Radical Prostatectomy. Eur Urol Oncol, 2023. 6: 582.
https://www.ncbi.nlm.nih.gov/pubmed/36878753
1207. Ost, P., et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer
Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol, 2018. 36: 446.
https://www.ncbi.nlm.nih.gov/pubmed/29240541
1208. Phillips, R., et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic
Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol, 2020. 6: 650.
https://www.ncbi.nlm.nih.gov/pubmed/32215577
1209. Deek, M.P., et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed
Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE
Trials. J Clin Oncol, 2022. 40: 3377.
https://www.ncbi.nlm.nih.gov/pubmed/36001857
1210. Glicksman, R.M., et al. Curative-intent Metastasis-directed Therapies for Molecularly-defined
Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.
Eur Urol, 2021. 80: 374.
https://www.ncbi.nlm.nih.gov/pubmed/33685838
1211. Tang, C., et al. Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for
Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial. JAMA Oncol,
2023. 9: 825.
https://www.ncbi.nlm.nih.gov/pubmed/37022702
1212. Nikitas, J., et al. Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer
(SATURN): Primary Endpoint Results from a Phase 2 Clinical Trial. Eur Urol, 2024. 85: 517.
https://www.ncbi.nlm.nih.gov/pubmed/38494380
1213. Battaglia, A., et al. Novel Insights into the Management of Oligometastatic Prostate Cancer: A
Comprehensive Review. Eur Urol Oncol, 2019. 2: 174.
https://www.ncbi.nlm.nih.gov/pubmed/31017094
1214. Connor, M.J., et al. Targeting Oligometastasis with Stereotactic Ablative Radiation Therapy or Surgery
in Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review of Prospective Clinical Trials.
Eur Urol Oncol, 2020. 3: 582.
https://www.ncbi.nlm.nih.gov/pubmed/32891600
1215. Marvaso, G., et al. Oligorecurrent Prostate Cancer and Stereotactic Body Radiotherapy: Where Are We
Now? A Systematic Review and Meta-analysis of Prospective Studies. Eur Urol Open Sci, 2021. 27:
19.
https://www.ncbi.nlm.nih.gov/pubmed/34337513
1216. Devos, G., et al. Oncological Outcomes of Metastasis-Directed Therapy in Oligorecurrent Prostate
Cancer Patients Following Radical Prostatectomy. Cancers (Basel), 2020. 12.
https://www.ncbi.nlm.nih.gov/pubmed/32823690
1217. Miszczyk, M., et al. The Efficacy and Safety of Metastasis-directed Therapy in Patients with Prostate
Cancer: A Systematic Review and Meta-analysis of Prospective Studies. Eur Urol, 2024. 85: 125.
https://www.ncbi.nlm.nih.gov/pubmed/37945451
1218. Scher, H.I., et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated
Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol, 2016. 34:
1402.
https://www.ncbi.nlm.nih.gov/pubmed/26903579

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 229

1219. Eisenhauer, E.A., et al. New response evaluation criteria in solid tumours: revised RECIST guideline
(version 1.1). Eur J Cancer, 2009. 45: 228.
https://www.ncbi.nlm.nih.gov/pubmed/19097774
1220. FDA approves liquid biopsy NGS companion diagnostic test for multiple cancers and biomarkers.
2020. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-liquid-biopsy-ngs-
companion-diagnostic-test-multiple-cancers-and-biomarkers
1221. Lotan, T.L., et al. Report From the International Society of Urological Pathology (ISUP) Consultation
Conference on Molecular Pathology of Urogenital Cancers. I. Molecular Biomarkers in Prostate
Cancer. Am J Surg Pathol, 2020. 44: e15.
https://www.ncbi.nlm.nih.gov/pubmed/32044806
1222. Dienstmann, R., et al. Standardized decision support in next generation sequencing reports of
somatic cancer variants. Mol Oncol, 2014. 8: 859.
https://www.ncbi.nlm.nih.gov/pubmed/24768039
1223. Beer, T.M., et al. Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant
Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol, 2017. 71: 151.
https://www.ncbi.nlm.nih.gov/pubmed/27477525
1224. Hussain, M., et al. LBA8 - PROfound: Phase III study of olaparib versus enzalutamide or abiraterone
for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair
(HRR) gene alterations. Ann Oncol, 2019. 30: v881.
https://www.annalsofoncology.org/article/S0923-7534(19)58212-6/fulltext
1225. Hussain, M., et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J
Med, 2020. 383: 2345.
https://www.ncbi.nlm.nih.gov/pubmed/32955174
1226. Clarke, N.W., et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer.
NEJM Evidence, 2022. 1: EVIDoa2200043.
https://www.ncbi.nlm.nih.gov/pubmed/38319800
1227. Saad, F., et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-
resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised,
double-blind, phase 3 trial. Lancet Oncol, 2023. 24: 1094.
https://www.ncbi.nlm.nih.gov/pubmed/37714168
1228. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated
metastatic castration-resistant prostate cancer. 2023.
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-
prednisone-or-prednisolone-brca-mutated-metastatic-castration
1229. FDA D.I.S.C.O. Burst Edition: FDA approval of Lynparza (olaparib), with abiraterone and prednisone,
for BRCA-mutated metastatic castration-resistant prostate cancer. 2023.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-
approval-lynparza-olaparib-abiraterone-and-prednisone-brca-mutated
1230. Chi, K.N., et al. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate
and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant
prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations.
J Clin Oncol, 2022. 40: 12.
https://ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.012
1231. Chi, K.N., et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic
castration-resistant prostate cancer and homologous recombination repair gene alterations: second
interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol, 2023. 34: 772.
https://www.ncbi.nlm.nih.gov/pubmed/37399894
1232. EMA. Akeega. 2023.
https://www.ema.europa.eu/en/medicines/human/EPAR/akeega
1233. Agarwal, N., et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant
prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet, 2023. 402:
291.
https://www.ncbi.nlm.nih.gov/pubmed/37285865
1234. Fizazi, K., et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-
resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nature Med, 2023.
https://www.nature.com/articles/s41591-023-02704-x

230 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1235. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant
prostate cancer. 2023.
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-
hrr-gene-mutated-metastatic-castration-resistant-prostate
1236. FDA. Pembrolizumab (KEYTRUDA). 2016. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda
1237. de Wit, R., et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N
Engl J Med, 2019. 381: 2506.
https://www.ncbi.nlm.nih.gov/pubmed/31566937
1238. Loriot, Y., et al. Prior long response to androgen deprivation predicts response to next-generation
androgen receptor axis targeted drugs in castration resistant prostate cancer. Eur J Cancer, 2015. 51:
1946.
https://www.ncbi.nlm.nih.gov/pubmed/26208462
1239. de Bono, J.S., et al. Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic
Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone
for >/=24 weeks in Europe. Eur Urol, 2018. 74: 37.
https://www.ncbi.nlm.nih.gov/pubmed/28844372
1240. Heiss, B.L., et al. US Food and Drug Administration Approval Summary: Talazoparib in Combination
With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated
Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol, 2024. 42: 1851.
https://www.ncbi.nlm.nih.gov/pubmed/38452327
1241. Fallah, J., et al. FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of
Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol, 2024. 42:
605.
https://www.ncbi.nlm.nih.gov/pubmed/38127780
1242. Fallah, J., et al. Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in
Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer:
A US Food and Drug Administration Pooled Analysis. J Clin Oncol, 2024. 42: 1687.
https://www.ncbi.nlm.nih.gov/pubmed/38484203
1243. Fizazi, K., et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Engl J Med, 2023.
388: 719.
https://www.ncbi.nlm.nih.gov/pubmed/36795891
1244. Smith, M.R., et al. Disease and host characteristics as predictors of time to first bone metastasis and
death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer, 2011. 117:
2077.
https://www.ncbi.nlm.nih.gov/pubmed/21523719
1245. Crawford, E.D., et al. Challenges and recommendations for early identification of metastatic disease
in prostate cancer. Urology, 2014. 83: 664.
https://www.ncbi.nlm.nih.gov/pubmed/24411213
1246. Fendler, W.P., et al. Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in
Men with Nonmetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res, 2019. 25: 7448.
https://www.ncbi.nlm.nih.gov/pubmed/31511295
1247. Hussain, M., et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N
Engl J Med, 2018. 378: 2465.
https://www.ncbi.nlm.nih.gov/pubmed/29949494
1248. Smith, M.R., et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J
Med, 2018. 378: 1408.
https://www.ncbi.nlm.nih.gov/pubmed/29420164
1249. Fizazi, K., et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med,
2019. 380: 1235.
https://www.ncbi.nlm.nih.gov/pubmed/30763142
1250. Hussain, M., et al. Effects of continued androgen-deprivation therapy and other prognostic factors
on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a
Southwest Oncology Group report. J Clin Oncol, 1994. 12: 1868.
https://www.ncbi.nlm.nih.gov/pubmed/8083710
1251. Taylor, C.D., et al. Importance of continued testicular suppression in hormone-refractory prostate
cancer. J Clin Oncol, 1993. 11: 2167.
https://www.ncbi.nlm.nih.gov/pubmed/8229130
1252. Ryan, C.J., et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 231

 Med, 2013. 368: 138.
https://www.ncbi.nlm.nih.gov/pubmed/23228172
1253. Ryan, C.J., et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in
chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final
overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet
Oncol, 2015. 16: 152.
https://www.ncbi.nlm.nih.gov/pubmed/25601341
1254. Roviello, G., et al. Targeting the androgenic pathway in elderly patients with castration-resistant
prostate cancer: A meta-analysis of randomized trials. Medicine (Baltimore), 2016. 95: e4636.
https://www.ncbi.nlm.nih.gov/pubmed/27787354
1255. Beer, T.M., et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med,
2014. 371: 424.
https://www.ncbi.nlm.nih.gov/pubmed/24881730
1256. Graff, J.N., et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-
naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol, 2016. 27:
286.
https://www.ncbi.nlm.nih.gov/pubmed/26578735
1257. Evans, C.P., et al. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease
for Enzalutamide-treated Men with Chemotherapy-naive Metastatic Castration-resistant Prostate
Cancer. Eur Urol, 2016. 70: 675.
https://www.ncbi.nlm.nih.gov/pubmed/27006332
1258. Shore, N.D., et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with
metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol,
2016. 17: 153.
https://www.ncbi.nlm.nih.gov/pubmed/26774508
1259. de Bono, J.S., et al. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in
Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur
Urol, 2017. 71: 656.
https://www.ncbi.nlm.nih.gov/pubmed/27402060
1260. Tannock, I.F., et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate
cancer. N Engl J Med, 2004. 351: 1502.
https://www.ncbi.nlm.nih.gov/pubmed/15470213
1261. Berthold, D.R., et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced
prostate cancer: updated survival in the TAX 327 study. J Clin Oncol, 2008. 26: 242.
https://www.ncbi.nlm.nih.gov/pubmed/18182665
1262. Armstrong, A.J., et al. Prediction of survival following first-line chemotherapy in men with castration-
resistant metastatic prostate cancer. Clin Cancer Res, 2010. 16: 203.
https://www.ncbi.nlm.nih.gov/pubmed/20008841
1263. Italiano, A., et al. Docetaxel-based chemotherapy in elderly patients (age 75 and older) with
castration-resistant prostate cancer. Eur Urol, 2009. 55: 1368.
https://www.ncbi.nlm.nih.gov/pubmed/18706755
1264. Horgan, A.M., et al. Tolerability and efficacy of docetaxel in older men with metastatic castrate-
resistant prostate cancer (mCRPC) in the TAX 327 trial. J Geriatr Oncol, 2014. 5: 119.
https://www.ncbi.nlm.nih.gov/pubmed/24495703
1265. Kellokumpu-Lehtinen, P.L., et al. 2-Weekly versus 3-weekly docetaxel to treat castration-resistant
advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol, 2013. 14: 117.
https://www.ncbi.nlm.nih.gov/pubmed/23294853
1266. Kantoff, P.W., et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J
Med, 2010. 363: 411.
https://www.ncbi.nlm.nih.gov/pubmed/20818862
1267. Hussain, M., et al. Abiraterone, Olaparib, or Abiraterone + Olaparib in First-Line Metastatic Castration-
Resistant Prostate Cancer with DNA Repair Defects (BRCAAway). Clin Cancer Res, 2024. 30: 4318.
https://www.ncbi.nlm.nih.gov/pubmed/39115414
1268. Fizazi, K., et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-
resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat Med, 2024. 30: 257.
https://www.ncbi.nlm.nih.gov/pubmed/38049622
1269. EMA. Talzenna - opinion on variation to marketing authorisation. 2023.
https://www.ema.europa.eu/en/medicines/human/variation/talzenna

232 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1270. Yazgan, S.C., et al. Thromboembolic risk in prostate cancer patients treated with PARP inhibitors: A
systematic review and meta-analysis. Crit Rev Oncol Hematol, 2024. 198: 104376.
https://www.ncbi.nlm.nih.gov/pubmed/38685459
1271. Morice, P.M., et al. Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with
PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of
the WHO pharmacovigilance database. Lancet Haematol, 2021. 8: e122.
https://www.ncbi.nlm.nih.gov/pubmed/33347814
1272. de Bono, J.S., et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant
prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet, 2010.
376: 1147.
https://www.ncbi.nlm.nih.gov/pubmed/20888992
1273. Sartor, A., et al. Cabazitaxel vs docetaxel in chemotherapy-naive (CN) patients with metastatic
castration-resistant prostate cancer (mCRPC): A three-arm phase III study (FIRSTANA). J Clin Oncol
2016. 34: Abstract 5006.
https://ascopubs.org/doi/10.1200/JCO.2016.34.15_suppl.5006
1274. Eisenberger, M., et al. Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m(2)) and
the Currently Approved Dose (25 mg/m(2)) in Postdocetaxel Patients With Metastatic Castration-
Resistant Prostate Cancer-PROSELICA. J Clin Oncol, 2017. 35: 3198.
https://www.ncbi.nlm.nih.gov/pubmed/28809610
1275. Di Lorenzo, G., et al. Peg-filgrastim and cabazitaxel in prostate cancer patients. Anticancer Drugs,
2013. 24: 84.
https://www.ncbi.nlm.nih.gov/pubmed/23044721
1276. de Bono, J.S., et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med,
2011. 364: 1995.
https://www.ncbi.nlm.nih.gov/pubmed/21612468
1277. Fizazi, K., et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer:
final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase
3 study. Lancet Oncol, 2012. 13: 983.
https://www.ncbi.nlm.nih.gov/pubmed/22995653
1278. Scher, H.I., et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl
J Med, 2012. 367: 1187.
https://www.ncbi.nlm.nih.gov/pubmed/22894553
1279. Parker, C., et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med,
2013. 369: 213.
https://www.ncbi.nlm.nih.gov/pubmed/23863050
1280. Hoskin, P., et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant
prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a
prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet
Oncol, 2014. 15: 1397.
https://www.ncbi.nlm.nih.gov/pubmed/25439694
1281. EMA restricts use of prostate cancer medicine Xofigo. 2018. 2022.
https://www.ema.europa.eu/en/news/ema-restricts-use-prostate-cancer-medicine-xofigo
1282. Smith, M., et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in
patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised,
double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2019. 20: 408.
https://www.ncbi.nlm.nih.gov/pubmed/30738780
1283. Bryce, A.H., et al. Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3
interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen
pathway inhibitor therapy. J Clin Oncol, 2023. 41: 18.
https://ascopubs.org/doi/pdf/10.1200/JCO.2023.41.6_suppl.18
1284. Morris, M.J., et al. (177)Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor
therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer
(PSMAfore): a phase 3, randomised, controlled trial. Lancet, 2024. 404: 1227.
https://www.ncbi.nlm.nih.gov/pubmed/39293462
1285. Rubin, K.H., et al. Comparison of different screening tools (FRAX(R), OST, ORAI, OSIRIS, SCORE and
age alone) to identify women with increased risk of fracture. A population-based prospective study.
Bone, 2013. 56: 16.
https://www.ncbi.nlm.nih.gov/pubmed/23669650
1286. Conde, F.A., et al. Risk factors for male osteoporosis. Urol Oncol, 2003. 21: 380.
https://www.ncbi.nlm.nih.gov/pubmed/14670549

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 233

1287. Mateo, J., et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med, 2015.
373: 1697.
https://www.ncbi.nlm.nih.gov/pubmed/26510020
1288. de Bono, J.S., et al. Final overall survival (OS) analysis of PROfound: Olaparib vs physician’s choice
of enzalutamide or abiraterone in patients (pts) with metastatic castration-resistant prostate cancer
(mCRPC) and homologous recombination repair (HRR) gene alterations. Ann Oncol 2020. 31: S507.
https://www.annalsofoncology.org/article/S0923-7534(20)40866-X/fulltext
1289. Badrising, S., et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with
metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone
treatment. Cancer, 2014. 120: 968.
https://www.ncbi.nlm.nih.gov/pubmed/24382803
1290. Zhang, T., et al. Enzalutamide versus abiraterone acetate for the treatment of men with metastatic
castration-resistant prostate cancer. Expert Opin Pharmacother, 2015. 16: 473.
https://www.ncbi.nlm.nih.gov/pubmed/25534660
1291. Antonarakis, E.S., et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N
Engl J Med, 2014. 371: 1028.
https://www.ncbi.nlm.nih.gov/pubmed/25184630
1292. Attard, G., et al. Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-
Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment. J
Clin Oncol, 2018. 36: 2639.
https://www.ncbi.nlm.nih.gov/pubmed/30028657
1293. Serafini, A.N. Current status of systemic intravenous radiopharmaceuticals for the treatment of
painful metastatic bone disease. Int J Radiat Oncol Biol Phys, 1994. 30: 1187.
https://www.ncbi.nlm.nih.gov/pubmed/7525518
1294. Ballinger, J.R. Theranostic radiopharmaceuticals: established agents in current use. Br J Radiol,
2018. 91: 20170969.
https://www.ncbi.nlm.nih.gov/pubmed/29474096
1295. Emmett, L., et al. Lutetium (177) PSMA radionuclide therapy for men with prostate cancer: a review of
the current literature and discussion of practical aspects of therapy. J Med Radiat Sci, 2017. 64: 52.
https://www.ncbi.nlm.nih.gov/pubmed/28303694
1296. Calopedos, R.J.S., et al. Lutetium-177-labelled anti-prostate-specific membrane antigen antibody and
ligands for the treatment of metastatic castrate-resistant prostate cancer: a systematic review and
meta-analysis. Prostate Cancer Prostatic Dis, 2017. 20: 352.
https://www.ncbi.nlm.nih.gov/pubmed/28440324
1297. Hofman, M.S., et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic
castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study.
Lancet Oncol, 2018. 19: 825.
https://www.ncbi.nlm.nih.gov/pubmed/29752180
1298. Emmett, L., et al. Results of a Prospective Phase 2 Pilot Trial of (177)Lu-PSMA-617 Therapy
for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of Treatment
Response and Patterns of Progression. Clin Genitourin Cancer, 2019. 17: 15.
https://www.ncbi.nlm.nih.gov/pubmed/30425003
1299. Hofman, M.S., et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-
resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet, 2021. 397: 797.
https://www.ncbi.nlm.nih.gov/pubmed/33581798
1300. Hofman, M.S., et al. TheraP: 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-
resistant prostate cancer (mCRPC) progressing after docetaxel—Overall survival after median follow-
up of 3 years (ANZUP 1603). J Clin Oncol, 2022. 40: 5000.
https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.5000
1301. Hofman, M.S., et al. Overall survival with [(177)Lu]Lu-PSMA-617 versus cabazitaxel in metastatic
castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label,
phase 2 trial. Lancet Oncol, 2024. 25: 99.
https://www.ncbi.nlm.nih.gov/pubmed/38043558
1302. Sartor, O., et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl
J Med, 2021. 385: 1091.
https://www.ncbi.nlm.nih.gov/pubmed/34161051
1303. Sadaghiani, M.S., et al. (177) Lu-PSMA radioligand therapy effectiveness in metastatic castration-
resistant prostate cancer: An updated systematic review and meta-analysis. Prostate, 2022. 82: 826.
https://www.ncbi.nlm.nih.gov/pubmed/35286735

234 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1304. Lee, D.Y., et al. Effects of (225)Ac-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy
in Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis. J Nucl Med, 2022. 63: 840.
https://www.ncbi.nlm.nih.gov/pubmed/34503960
1305. Sathekge, M.M., et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant
prostate cancer (WARMTH Act): a multicentre, retrospective study. Lancet Oncol, 2024. 25: 175.
https://www.ncbi.nlm.nih.gov/pubmed/38218192
1306. Ballal, S., et al. Long-term survival outcomes of salvage [(225)Ac]Ac-PSMA-617 targeted alpha
therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer:
a real-world study. Eur J Nucl Med Mol Imaging, 2023. 50: 3777.
https://www.ncbi.nlm.nih.gov/pubmed/37462775
1307. Emmett, L., et al. [(177)Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-
resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet
Oncol, 2024. 25: 563.
https://www.ncbi.nlm.nih.gov/pubmed/38621400
1308. EMA. Lynparza (olaparib). 2014. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/lynparza
1309. Abida, W., et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a
BRCA1 or BRCA2 Gene Alteration. J Clin Oncol, 2020. 38: 3763.
https://www.ncbi.nlm.nih.gov/pubmed/32795228
1310. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant
prostate cancer. 2020. 2022.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-
rucaparib-brca-mutated-metastatic-castration-resistant-prostate
1311. Khalaf, D.J., et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone
in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2,
crossover trial. Lancet Oncol, 2019. 20: 1730.
https://www.ncbi.nlm.nih.gov/pubmed/31727538
1312. Miyake, H., et al. Comparative Assessment of Efficacies Between 2 Alternative Therapeutic
Sequences With Novel Androgen Receptor-Axis-Targeted Agents in Patients With Chemotherapy-
Naive Metastatic Castration-Resistant Prostate Cancer. Clin Genitourin Cancer, 2017. 15: e591.
https://www.ncbi.nlm.nih.gov/pubmed/28063845
1313. Terada, N., et al. Exploring the optimal sequence of abiraterone and enzalutamide in patients with
chemotherapy-naive castration-resistant prostate cancer: The Kyoto-Baltimore collaboration. Int J
Urol, 2017. 24: 441.
https://www.ncbi.nlm.nih.gov/pubmed/28455853
1314. Azad, A.A., et al. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive
metastatic castration-resistant prostate cancer patients. Eur Urol, 2015. 67: 23.
https://www.ncbi.nlm.nih.gov/pubmed/25018038
1315. Kobayashi, T., et al. Sequential Use of Androgen Receptor Axis-targeted Agents in Chemotherapy-
naive Castration-resistant Prostate Cancer: A Multicenter Retrospective Analysis With 3-Year Follow-
up. Clin Genitourin Cancer, 2020. 18: e46.
https://www.ncbi.nlm.nih.gov/pubmed/31759831
1316. Komura, K., et al. Comparison of Radiographic Progression-Free Survival and PSA Response on
Sequential Treatment Using Abiraterone and Enzalutamide for Newly Diagnosed Castration-Resistant
Prostate Cancer: A Propensity Score Matched Analysis from Multicenter Cohort. J Clin Med, 2019. 8.
https://www.ncbi.nlm.nih.gov/pubmed/31430900
1317. Matsubara, N., et al. Abiraterone Followed by Enzalutamide Versus Enzalutamide Followed by
Abiraterone in Chemotherapy-naive Patients With Metastatic Castration-resistant Prostate Cancer.
Clin Genitourin Cancer, 2018. 16: 142.
https://www.ncbi.nlm.nih.gov/pubmed/29042308
1318. Maughan, B.L., et al. Comparing Sequencing of Abiraterone and Enzalutamide in Men With Metastatic
Castration-Resistant Prostate Cancer: A Retrospective Study. Prostate, 2017. 77: 33.
https://www.ncbi.nlm.nih.gov/pubmed/27527643
1319. Mori, K., et al. Sequential therapy of abiraterone and enzalutamide in castration-resistant prostate
cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis, 2020. 23: 539.
https://www.ncbi.nlm.nih.gov/pubmed/32152435
1320. Lavaud, P., et al. Anticancer Activity and Tolerance of Treatments Received Beyond Progression in
Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic
Castration-naive Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial. Eur Urol, 2018. 73: 696.
https://www.ncbi.nlm.nih.gov/pubmed/29074061

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 235

1321. Hager, S., et al. Anti-tumour activity of platinum compounds in advanced prostate cancer-a
systematic literature review. Ann Oncol, 2016. 27: 975.
https://www.ncbi.nlm.nih.gov/pubmed/27052650
1322. Corn, P.G., et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-
resistant prostate cancers: a randomised, open-label, phase 1-2 trial. Lancet Oncol, 2019. 20: 1432.
https://www.ncbi.nlm.nih.gov/pubmed/31515154
1323. Aparicio, A.M., et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin
Cancer Res, 2013. 19: 3621.
https://www.ncbi.nlm.nih.gov/pubmed/23649003
1324. Mota, J.M., et al. Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair
Gene Alterations. JCO Precis Oncol, 2020. 4: 355.
https://www.ncbi.nlm.nih.gov/pubmed/32856010
1325. Fazekas, T., et al. Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum
Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A
Systematic Review and Meta-analysis. Eur Urol Oncol, 2024. 7: 365.
https://www.ncbi.nlm.nih.gov/pubmed/37722977
1326. Fizazi, K., et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide.
N Engl J Med, 2020. 383: 1040.
https://www.ncbi.nlm.nih.gov/pubmed/32905676
1327. Sternberg, C.N., et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate
Cancer. N Engl J Med, 2020. 382: 2197.
https://www.ncbi.nlm.nih.gov/pubmed/32469184
1328. Smith, M.R., et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol, 2021. 79: 150.
https://www.ncbi.nlm.nih.gov/pubmed/32907777
1329. Petrylak, D.P., et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for
advanced refractory prostate cancer. N Engl J Med, 2004. 351: 1513.
https://www.ncbi.nlm.nih.gov/pubmed/15470214
1330. Rathkopf, D.E., et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in
metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302).
Eur Urol, 2014. 66: 815.
https://www.ncbi.nlm.nih.gov/pubmed/24647231
1331. Small, E.J., et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T
(APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin
Oncol, 2006. 24: 3089.
https://www.ncbi.nlm.nih.gov/pubmed/16809734
1332. Chi, K.N., et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate
Cancer. J Clin Oncol, 2023. 41: 3339.
https://www.ncbi.nlm.nih.gov/pubmed/36952634
1333. Bahl, A., et al. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men
with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Ann Oncol, 2013. 24:
2402.
https://www.ncbi.nlm.nih.gov/pubmed/23723295
1334. Gillessen, S., et al. Management of patients with advanced prostate cancer: recommendations of the
St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann Oncol, 2015. 26:
1589.
https://www.ncbi.nlm.nih.gov/pubmed/26041764
1335. Saad, F., et al. Prostate-specific Antigen Progression in Enzalutamide-treated Men with
Nonmetastatic Castration-resistant Prostate Cancer: Any Rise in Prostate-specific Antigen May
Require Closer Monitoring. Eur Urol, 2020. 78: 847.
https://www.ncbi.nlm.nih.gov/pubmed/33010985
1336. Aggarwal, R., et al. Heterogeneous Flare in Prostate-specific Membrane Antigen Positron Emission
Tomography Tracer Uptake with Initiation of Androgen Pathway Blockade in Metastatic Prostate
Cancer. Eur Urol Oncol, 2018. 1: 78.
https://www.ncbi.nlm.nih.gov/pubmed/31100231
1337. Payne, H., et al. Prostate-specific antigen: an evolving role in diagnosis, monitoring, and treatment
evaluation in prostate cancer. Urol Oncol, 2011. 29: 593.
https://www.ncbi.nlm.nih.gov/pubmed/20060331
1338. Pezaro, C., et al. Visceral disease in castration-resistant prostate cancer. Eur Urol, 2014. 65: 270.
https://www.ncbi.nlm.nih.gov/pubmed/24295792

236 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1339. Gillessen, S., et al. Management of Patients with Advanced Prostate Cancer: Report of the Advanced
Prostate Cancer Consensus Conference 2019. Eur Urol, 2020. 77: 508.
https://www.ncbi.nlm.nih.gov/pubmed/32001144
1340. Gillessen, S., et al. Management of patients with advanced prostate cancer-metastatic and/or
castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference
(APCCC) 2022. Eur J Cancer, 2023. 185: 178.
https://www.ncbi.nlm.nih.gov/pubmed/37003085
1341. Rao, K., et al. Uro-oncology multidisciplinary meetings at an Australian tertiary referral centre--impact
on clinical decision-making and implications for patient inclusion. BJU Int, 2014. 114 Suppl 1: 50.
https://www.ncbi.nlm.nih.gov/pubmed/25070295
1342. Cereceda, L.E., et al. Management of vertebral metastases in prostate cancer: a retrospective
analysis in 119 patients. Clin Prostate Cancer, 2003. 2: 34.
https://www.ncbi.nlm.nih.gov/pubmed/15046682
1343. Chaichana, K.L., et al. Outcome following decompressive surgery for different histological types of
metastatic tumors causing epidural spinal cord compression. Clinical article. J Neurosurg Spine,
2009. 11: 56.
https://www.ncbi.nlm.nih.gov/pubmed/19569942
1344. Hoskin, P., et al. A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose
Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer. J Natl Cancer Inst, 2015. 107.
https://www.ncbi.nlm.nih.gov/pubmed/26242893
1345. Frankel, B.M., et al. Percutaneous vertebral augmentation: an elevation in adjacent-level fracture risk
in kyphoplasty as compared with vertebroplasty. Spine J, 2007. 7: 575.
https://www.ncbi.nlm.nih.gov/pubmed/17905320
1346. Dutka, J., et al. Time of survival and quality of life of the patients operatively treated due to
pathological fractures due to bone metastases. Ortop Traumatol Rehabil, 2003. 5: 276.
https://www.ncbi.nlm.nih.gov/pubmed/18034018
1347. Frankel, B.M., et al. Segmental polymethylmethacrylate-augmented pedicle screw fixation in patients
with bone softening caused by osteoporosis and metastatic tumor involvement: a clinical evaluation.
Neurosurgery, 2007. 61: 531.
https://www.ncbi.nlm.nih.gov/pubmed/17881965
1348. Lawton, A.J., et al. Assessment and Management of Patients With Metastatic Spinal Cord
Compression: A Multidisciplinary Review. J Clin Oncol, 2019. 37: 61.
https://www.ncbi.nlm.nih.gov/pubmed/30395488
1349. Saad, F., et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-
refractory metastatic prostate carcinoma. J Natl Cancer Inst, 2002. 94: 1458.
https://www.ncbi.nlm.nih.gov/pubmed/12359855
1350. Fizazi, K., et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with
castration-resistant prostate cancer: a randomised, double-blind study. Lancet, 2011. 377: 813.
https://www.ncbi.nlm.nih.gov/pubmed/21353695
1351. Smith, M.R., et al. Denosumab and bone-metastasis-free survival in men with castration-resistant
prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet, 2012. 379: 39.
https://www.ncbi.nlm.nih.gov/pubmed/22093187
1352. Marco, R.A., et al. Functional and oncological outcome of acetabular reconstruction for the treatment
of metastatic disease. J Bone Joint Surg Am, 2000. 82: 642.
https://www.ncbi.nlm.nih.gov/pubmed/10819275
1353. Stopeck, A.T., et al. Safety of long-term denosumab therapy: results from the open label extension
phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care
Cancer, 2016. 24: 447.
https://www.ncbi.nlm.nih.gov/pubmed/26335402
1354. Aapro, M., et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an
international expert panel. Ann Oncol, 2008. 19: 420.
https://www.ncbi.nlm.nih.gov/pubmed/17906299
1355. Medication-Related Osteonecrosis of the Jaws, ed. S. Otto. 2015, Berlin Heidelberg.
1356. EMA. Xgeva. 2019. 2022.
https://www.ema.europa.eu/en/medicines/human/EPAR/xgeva
1357. Stopeck, A.T., et al. Denosumab compared with zoledronic acid for the treatment of bone metastases
in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol, 2010. 28:
5132.
https://www.ncbi.nlm.nih.gov/pubmed/21060033

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 237

1358. Body, J.J., et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab.
Eur J Cancer, 2015. 51: 1812.
https://www.ncbi.nlm.nih.gov/pubmed/26093811
1359. Rice, S.M., et al. Depression and Prostate Cancer: Examining Comorbidity and Male-Specific
Symptoms. Am J Mens Health, 2018. 12: 1864.
https://www.ncbi.nlm.nih.gov/pubmed/29957106
1360. van Stam, M.A., et al. Prevalence and correlates of mental health problems in prostate cancer
survivors: A case-control study comparing survivors with general population peers. Urol Oncol, 2017.
35: 531 e1.
https://www.ncbi.nlm.nih.gov/pubmed/28457651
1361. Stephenson, A.J., et al. Defining biochemical recurrence of prostate cancer after radical
prostatectomy: a proposal for a standardized definition. J Clin Oncol, 2006. 24: 3973.
https://www.ncbi.nlm.nih.gov/pubmed/16921049
1362. Horwitz, E.M., et al. Definitions of biochemical failure that best predict clinical failure in patients with
prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis. J
Urol, 2005. 173: 797.
https://www.ncbi.nlm.nih.gov/pubmed/15711272
1363. Stamey, T.A., et al. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of
the prostate. II. Radical prostatectomy treated patients. J Urol, 1989. 141: 1076.
https://www.ncbi.nlm.nih.gov/pubmed/2468795
1364. Jackson, W.C., et al. Impact of Biochemical Failure After Salvage Radiation Therapy on Prostate
Cancer-specific Mortality: Competition Between Age and Time to Biochemical Failure. Eur Urol Oncol,
2018. 1: 276.
https://www.ncbi.nlm.nih.gov/pubmed/31100248
1365. Grivas, N., et al. Ultrasensitive prostate-specific antigen level as a predictor of biochemical
progression after robot-assisted radical prostatectomy: Towards risk adapted follow-up. J Clin Lab
Anal, 2019. 33: e22693.
https://www.ncbi.nlm.nih.gov/pubmed/30365194
1366. Shen, S., et al. Ultrasensitive serum prostate specific antigen nadir accurately predicts the risk of
early relapse after radical prostatectomy. J Urol, 2005. 173: 777.
https://www.ncbi.nlm.nih.gov/pubmed/15711268
1367. Zakaria, A.S., et al. Detectable Prostate-specific antigen value between 0.01 and 0.1 ng/ml following
robotic-assisted radical prostatectomy (RARP): does it correlate with future biochemical recurrence?
World J Urol, 2021. 39: 1853.
https://www.ncbi.nlm.nih.gov/pubmed/32696130
1368. Ray, M.E., et al. PSA nadir predicts biochemical and distant failures after external beam radiotherapy
for prostate cancer: a multi-institutional analysis. Int J Radiat Oncol Biol Phys, 2006. 64: 1140.
https://www.ncbi.nlm.nih.gov/pubmed/16198506
1369. Oefelein, M.G., et al. The incidence of prostate cancer progression with undetectable serum prostate
specific antigen in a series of 394 radical prostatectomies. J Urol, 1995. 154: 2128.
https://www.ncbi.nlm.nih.gov/pubmed/7500474
1370. Doneux, A., et al. The utility of digital rectal examination after radical radiotherapy for prostate cancer.
Clin Oncol (R Coll Radiol), 2005. 17: 172.
https://www.ncbi.nlm.nih.gov/pubmed/15901001
1371. Chaplin, B.J., et al. Digital rectal examination is no longer necessary in the routine follow-up of men
with undetectable prostate specific antigen after radical prostatectomy: the implications for follow-
up. Eur Urol, 2005. 48: 906.
https://www.ncbi.nlm.nih.gov/pubmed/16126322
1372. Warren, K.S., et al. Is routine digital rectal examination required for the followup of prostate cancer? J
Urol, 2007. 178: 115.
https://www.ncbi.nlm.nih.gov/pubmed/17499293
1373. Wilt, T.J., et al. Follow-up of Prostatectomy versus Observation for Early Prostate Cancer. N Engl J
Med, 2017. 377: 132.
https://www.ncbi.nlm.nih.gov/pubmed/28700844
1374. Beesley, L.J., et al. Individual and Population Comparisons of Surgery and Radiotherapy Outcomes in
Prostate Cancer Using Bayesian Multistate Models. JAMA Netw Open, 2019. 2: e187765.
https://www.ncbi.nlm.nih.gov/pubmed/30707231
1375. Marshall, C.H., et al. Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent
Prostate Cancer in the Context of Novel Therapies. J Urol, 2021. 206: 623.
https://www.ncbi.nlm.nih.gov/pubmed/34003011

238 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1376. Loblaw, A., et al. Follow-up Care for Survivors of Prostate Cancer - Clinical Management: a Program
in Evidence-Based Care Systematic Review and Clinical Practice Guideline. Clin Oncol (R Coll Radiol),
2017. 29: 711.
https://www.ncbi.nlm.nih.gov/pubmed/28928084
1377. Thorstenson, A., et al. Incidence of fractures causing hospitalisation in prostate cancer patients:
results from the population-based PCBaSe Sweden. Eur J Cancer, 2012. 48: 1672.
https://www.ncbi.nlm.nih.gov/pubmed/22386317
1378. Franck Lissbrant, I., et al. Set-up and preliminary results from the Patient-overview Prostate Cancer.
Longitudinal registration of treatment of advanced prostate cancer in the National Prostate Cancer
Register of Sweden. Scand J Urol, 2020. 54: 227.
https://www.ncbi.nlm.nih.gov/pubmed/32363988
1379. Saad, F., et al. Testosterone Breakthrough Rates during Androgen Deprivation Therapy for Castration
Sensitive Prostate Cancer. J Urol, 2020. 204: 416.
https://www.ncbi.nlm.nih.gov/pubmed/32096678
1380. Rouleau, M., et al. Discordance between testosterone measurement methods in castrated prostate
cancer patients. Endocr Connect, 2019. 8: 132.
https://www.ncbi.nlm.nih.gov/pubmed/30673630
1381. Morote, J., et al. Serum Testosterone Levels in Prostate Cancer Patients Undergoing Luteinizing
Hormone-Releasing Hormone Agonist Therapy. Clin Genitourin Cancer, 2018. 16: e491.
https://www.ncbi.nlm.nih.gov/pubmed/29198640
1382. Long, M.E., et al. Decreased testosterone recovery after androgen deprivation therapy for prostate
cancer. Can J Urol, 2021. 28: 10738.
https://www.ncbi.nlm.nih.gov/pubmed/34378507
1383. Nascimento, B., et al. Testosterone Recovery Profiles After Cessation of Androgen Deprivation
Therapy for Prostate Cancer. J Sex Med, 2019. 16: 872.
https://www.ncbi.nlm.nih.gov/pubmed/31080102
1384. Beer, T.M., et al. Hepatic effects assessed by review of safety data in enzalutamide castration-
resistant prostate cancer (CRPC) trials. J Clin Oncol, 2018. 36: 199.
https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.199
1385. Yanagisawa, T., et al. Abiraterone acetate versus nonsteroidal antiandrogen with androgen
deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer. Prostate, 2022. 82: 3.
https://www.ncbi.nlm.nih.gov/pubmed/34559410
1386. Beer, T.M., et al. The prognostic value of hemoglobin change after initiating androgen-deprivation
therapy for newly diagnosed metastatic prostate cancer: A multivariate analysis of Southwest
Oncology Group Study 8894. Cancer, 2006. 107: 489.
https://www.ncbi.nlm.nih.gov/pubmed/16804926
1387. Ebbinge, M., et al. Clinical and prognostic significance of changes in haemoglobin concentration
during 1 year of androgen-deprivation therapy for hormone-naive bone-metastatic prostate cancer.
BJU Int, 2018. 122: 583.
https://www.ncbi.nlm.nih.gov/pubmed/29611275
1388. Sini, C., et al. Dose-volume effects for pelvic bone marrow in predicting hematological toxicity in
prostate cancer radiotherapy with pelvic node irradiation. Radiother Oncol, 2016. 118: 79.
https://www.ncbi.nlm.nih.gov/pubmed/26702990
1389. Turner, P.G., et al. Toxicity and Efficacy of Concurrent Androgen Deprivation Therapy, Pelvic
Radiotherapy, and Radium-223 in Patients with De Novo Metastatic Hormone-Sensitive Prostate
Cancer. Clin Cancer Res, 2021. 27: 4549.
https://www.ncbi.nlm.nih.gov/pubmed/34187853
1390. Iacovelli, R., et al. The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer.
Clin Genitourin Cancer, 2018. 16: e645.
https://www.ncbi.nlm.nih.gov/pubmed/29339044
1391. Rizzo, A., et al. Risk of cardiovascular toxicities and hypertension in nonmetastatic castration-
resistant prostate cancer patients treated with novel hormonal agents: a systematic review and
meta-analysis. Expert Opin Drug Metab Toxicol, 2021. 17: 1237.
https://www.ncbi.nlm.nih.gov/pubmed/34407702
1392. Gong, J., et al. Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After
Prolonged Androgen Deprivation Therapy for Prostate Cancer. JACC CardioOncol, 2020. 2: 553.
https://www.ncbi.nlm.nih.gov/pubmed/34396266

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 239

1393. Attard, G., et al. Assessment of the Safety of Glucocorticoid Regimens in Combination With
Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer: A Randomized, Open-label
Phase 2 Study. JAMA Oncol, 2019. 5: 1159.
https://www.ncbi.nlm.nih.gov/pubmed/31246234
1394. James, N., et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-
effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony
metastatic castration-refractory prostate cancer. Health Technol Assess, 2016. 20: 1.
https://www.ncbi.nlm.nih.gov/pubmed/27434595
1395. Ng, H.S., et al. Development of comorbidities in men with prostate cancer treated with androgen
deprivation therapy: an Australian population-based cohort study. Prostate Cancer Prostatic Dis,
2018. 21: 403.
https://www.ncbi.nlm.nih.gov/pubmed/29720722
1396. Kanis, J.A., et al. Case finding for the management of osteoporosis with FRAX--assessment and
intervention thresholds for the UK. Osteoporos Int, 2008. 19: 1395.
https://www.ncbi.nlm.nih.gov/pubmed/18751937
1397. Cianferotti, L., et al. The prevention of fragility fractures in patients with non-metastatic prostate
cancer: a position statement by the international osteoporosis foundation. Oncotarget, 2017. 8:
75646.
https://www.ncbi.nlm.nih.gov/pubmed/29088899
1398. Hamdy, R.C., et al. Algorithm for the management of osteoporosis. South Med J, 2010. 103: 1009.
https://www.ncbi.nlm.nih.gov/pubmed/20818296
1399. Higano, C.S. Bone loss and the evolving role of bisphosphonate therapy in prostate cancer. Urol
Oncol, 2003. 21: 392.
https://www.ncbi.nlm.nih.gov/pubmed/14670551
1400. Sharma, A., et al. A prospective longitudinal study to evaluate bone health, implication of FRAX tool
and impact on quality of life (FACT-P) in advanced prostate cancer patients. Am J Clin Exp Urol, 2021.
9: 211.
https://www.ncbi.nlm.nih.gov/pubmed/34327260
1401.r Edmunds, K., et al. Incidence of the adverse effects of androgen deprivation therapy for prostate
cancer: a systematic literature review. Support Care Cancer, 2020. 28: 2079.
https://www.ncbi.nlm.nih.gov/pubmed/31912360
1402. Daniell, H.W. Osteoporosis due to androgen deprivation therapy in men with prostate cancer. Urology,
2001. 58: 101.
https://www.ncbi.nlm.nih.gov/pubmed/11502461
1403. Edmunds, K., et al. The role of exercise in the management of adverse effects of androgen
deprivation therapy for prostate cancer: a rapid review. Support Care Cancer, 2020. 28: 5661.
https://www.ncbi.nlm.nih.gov/pubmed/32699997
1404. Thomas, H.R., et al. Association Between Androgen Deprivation Therapy and Patient-reported
Depression in Men With Recurrent Prostate Cancer. Clin Genitourin Cancer, 2018. 16: 313.
https://www.ncbi.nlm.nih.gov/pubmed/29866496
1405. Hoogland, A.I., et al. Systemic inflammation and symptomatology in patients with prostate cancer
treated with androgen deprivation therapy: Preliminary findings. Cancer, 2021. 127: 1476.
https://www.ncbi.nlm.nih.gov/pubmed/33378113
1406. Gonzalez, B.D., et al. Course and Predictors of Cognitive Function in Patients With Prostate Cancer
Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol, 2015. 33: 2021.
https://www.ncbi.nlm.nih.gov/pubmed/25964245
1407. Duthie, C.J., et al. Maintenance of sexual activity following androgen deprivation in males. Crit Rev
Oncol Hematol, 2020. 153: 103064.
https://www.ncbi.nlm.nih.gov/pubmed/32712517
1408. Miller, P.D., et al. Prostate specific antigen and bone scan correlation in the staging and monitoring of
patients with prostatic cancer. Br J Urol, 1992. 70: 295.
https://www.ncbi.nlm.nih.gov/pubmed/1384920
1409. Bryce, A.H., et al. Patterns of Cancer Progression of Metastatic Hormone-sensitive Prostate Cancer
in the ECOG3805 CHAARTED Trial. Eur Urol Oncol, 2020. 3: 717.
https://www.ncbi.nlm.nih.gov/pubmed/32807727
1410. Padhani, A.R., et al. Rationale for Modernising Imaging in Advanced Prostate Cancer. Eur Urol Focus,
2017. 3: 223.
https://www.ncbi.nlm.nih.gov/pubmed/28753774

240 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1411. Lecouvet, F.E., et al. Monitoring the response of bone metastases to treatment with Magnetic
Resonance Imaging and nuclear medicine techniques: a review and position statement by the
European Organisation for Research and Treatment of Cancer imaging group. Eur J Cancer, 2014. 50:
2519.
https://www.ncbi.nlm.nih.gov/pubmed/25139492
1412. Ulmert, D., et al. A novel automated platform for quantifying the extent of skeletal tumour
involvement in prostate cancer patients using the Bone Scan Index. Eur Urol, 2012. 62: 78.
https://www.ncbi.nlm.nih.gov/pubmed/22306323
1413. Padhani, A.R., et al. METastasis Reporting and Data System for Prostate Cancer: Practical Guidelines
for Acquisition, Interpretation, and Reporting of Whole-body Magnetic Resonance Imaging-based
Evaluations of Multiorgan Involvement in Advanced Prostate Cancer. Eur Urol, 2017. 71: 81.
https://www.ncbi.nlm.nih.gov/pubmed/27317091
1414. Trabulsi, E.J., et al. Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline. J
Clin Oncol, 2020. 38: 1963.
https://www.ncbi.nlm.nih.gov/pubmed/31940221
1415. Bryce, A.H., et al. Radiographic progression with nonrising PSA in metastatic castration-resistant
prostate cancer: post hoc analysis of PREVAIL. Prostate Cancer Prostatic Dis, 2017. 20: 221.
https://www.ncbi.nlm.nih.gov/pubmed/28117385
1416. Bourke, L., et al. Survivorship and improving quality of life in men with prostate cancer. Eur Urol, 2015.
68: 374.
https://www.ncbi.nlm.nih.gov/pubmed/25941049
1417. Prashar, J., et al. Supportive care needs of men with prostate cancer: A systematic review update. Eur
J Cancer Care (Engl), 2022. 31: e13541.
https://www.ncbi.nlm.nih.gov/pubmed/35038783
1418. Resnick, M.J., et al. Prostate cancer survivorship care guideline: American Society of Clinical
Oncology Clinical Practice Guideline endorsement. J Clin Oncol, 2015. 33: 1078.
https://www.ncbi.nlm.nih.gov/pubmed/25667275
1419. Yiannopoulou, K.G., et al. Cognitive and Psychological Impacts of Different Treatment Options for
Prostate Cancer: A Critical Analysis. Curr Urol, 2020. 14: 169.
https://www.ncbi.nlm.nih.gov/pubmed/33488334
1420. Venderbos, L.D.F., et al. Europa Uomo Patient Reported Outcome Study (EUPROMS): Descriptive
Statistics of a Prostate Cancer Survey from Patients for Patients. Eur Urol Focus, 2021. 7: 987.
https://www.ncbi.nlm.nih.gov/pubmed/33281109
1421. Downing, A., et al. Quality of life in men living with advanced and localised prostate cancer in the UK:
a population-based study. Lancet Oncol, 2019. 20: 436.
https://www.ncbi.nlm.nih.gov/pubmed/30713036
1422. Luckenbaugh, A.N., et al. Association between Treatment for Localized Prostate Cancer and Mental
Health Outcomes. J Urol, 2022. 207: 1029.
https://www.ncbi.nlm.nih.gov/pubmed/34978488
1423. Thompson, D., et al. Long-term Health-related Quality of Life in Patients on Active Surveillance for
Prostate Cancer: A Systematic Review. Eur Urol Oncol, 2023. 6: 4.
https://www.ncbi.nlm.nih.gov/pubmed/36156268
1424. Marzouk, K., et al. Long-Term Cancer Specific Anxiety in Men Undergoing Active Surveillance of
Prostate Cancer: Findings from a Large Prospective Cohort. J Urol, 2018. 200: 1250.
https://www.ncbi.nlm.nih.gov/pubmed/29886089
1425. Carlsson, S., et al. Surgery-related complications in 1253 robot-assisted and 485 open retropubic
radical prostatectomies at the Karolinska University Hospital, Sweden. Urology, 2010. 75: 1092.
https://www.ncbi.nlm.nih.gov/pubmed/20022085
1426. Ficarra, V., et al. Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic
review and cumulative analysis of comparative studies. Eur Urol, 2009. 55: 1037.
https://www.ncbi.nlm.nih.gov/pubmed/19185977
1427. Rabbani, F., et al. Comprehensive standardized report of complications of retropubic and
laparoscopic radical prostatectomy. Eur Urol, 2010. 57: 371.
https://www.ncbi.nlm.nih.gov/pubmed/19945779
1428. Resnick, M.J., et al. Long-term functional outcomes after treatment for localized prostate cancer. N
Engl J Med, 2013. 368: 436.
https://www.ncbi.nlm.nih.gov/pubmed/23363497
1429. Parekh, A., et al. Reduced penile size and treatment regret in men with recurrent prostate cancer after
surgery, radiotherapy plus androgen deprivation, or radiotherapy alone. Urology, 2013. 81: 130.
https://www.ncbi.nlm.nih.gov/pubmed/23273077

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 241

1430. Msezane, L.P., et al. Bladder neck contracture after robot-assisted laparoscopic radical
prostatectomy: evaluation of incidence and risk factors and impact on urinary function. J Endourol,
2008. 22: 377.
https://www.ncbi.nlm.nih.gov/pubmed/18095861
1431. Haglind, E., et al. Corrigendum re: “Urinary Incontinence and Erectile Dysfunction After Robotic
Versus Open Radical Prostatectomy: A Prospective, Controlled, Nonrandomised Trial” [Eur Urol
2015;68:216-25]. Eur Urol, 2017. 72: e81.
https://www.ncbi.nlm.nih.gov/pubmed/28552613
1432. Park, M.Y., et al. Comparison of biopsy strategies for prostate biopsy according to lesion size and
PSA density in MRI-directed biopsy pathway. Abdom Radiol (NY), 2020. 45: 4166.
https://www.ncbi.nlm.nih.gov/pubmed/32737545
1433. Coughlin, G.D., et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic
prostatectomy: 24-month outcomes from a randomised controlled study. Lancet Oncol, 2018. 19:
1051.
https://www.ncbi.nlm.nih.gov/pubmed/30017351
1434. Alder, R., et al. Incidence of Inguinal Hernia after Radical Prostatectomy: A Systematic Review and
Meta-Analysis. J Urol, 2020. 203: 265.
https://www.ncbi.nlm.nih.gov/pubmed/31039101
1435. Fernando, H., et al. Incidence, Predictive Factors and Preventive Measures for Inguinal Hernia
following Robotic and Laparoscopic Radical Prostatectomy: A Systematic Review. J Urol, 2019. 201:
1072.
https://www.ncbi.nlm.nih.gov/pubmed/30730406
1436. Chiong, E., et al. Port-site hernias occurring after the use of bladeless radially expanding trocars.
Urology, 2010. 75: 574.
https://www.ncbi.nlm.nih.gov/pubmed/19854489
1437. Clinckaert, A., et al. The Prevalence of Lower Limb and Genital Lymphedema after Prostate Cancer
Treatment: A Systematic Review. Cancers (Basel), 2022. 14.
https://www.ncbi.nlm.nih.gov/pubmed/36428759
1438. Donovan, J.L., et al. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for
Prostate Cancer. N Engl J Med, 2016. 375: 1425.
https://www.ncbi.nlm.nih.gov/pubmed/27626365
1439. Barocas, D.A., et al. Association Between Radiation Therapy, Surgery, or Observation for Localized
Prostate Cancer and Patient-Reported Outcomes After 3 Years. JAMA, 2017. 317: 1126.
https://www.ncbi.nlm.nih.gov/pubmed/28324093
1440. Wallis, C.J., et al. Second malignancies after radiotherapy for prostate cancer: systematic review and
meta-analysis. BMJ, 2016. 352: i851.
https://www.ncbi.nlm.nih.gov/pubmed/26936410
1441. Movsas, B., et al. Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen
Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation
Therapy Oncology Group 0815 Randomized Trial. J Clin Oncol, 2023. 41: 3217.
https://www.ncbi.nlm.nih.gov/pubmed/37104723
1442. Budaus, L., et al. Functional outcomes and complications following radiation therapy for prostate
cancer: a critical analysis of the literature. Eur Urol, 2012. 61: 112.
https://www.ncbi.nlm.nih.gov/pubmed/22001105
1443. Donovan, K.A., et al. Psychological effects of androgen-deprivation therapy on men with prostate
cancer and their partners. Cancer, 2015. 121: 4286.
https://www.ncbi.nlm.nih.gov/pubmed/26372364
1444. Nguyen, P.L., et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them.
Eur Urol, 2015. 67: 825.
https://www.ncbi.nlm.nih.gov/pubmed/25097095
1445. Cherrier, M.M., et al. Cognitive and mood changes in men undergoing intermittent combined
androgen blockade for non-metastatic prostate cancer. Psychooncology, 2009. 18: 237.
https://www.ncbi.nlm.nih.gov/pubmed/18636420
1446. Alibhai, S.M., et al. Effects of long-term androgen deprivation therapy on cognitive function over 36
months in men with prostate cancer. Cancer, 2017. 123: 237.
https://www.ncbi.nlm.nih.gov/pubmed/27583806
1447. Herr, H.W., et al. Quality of life of asymptomatic men with nonmetastatic prostate cancer on
androgen deprivation therapy. J Urol, 2000. 163: 1743.
https://www.ncbi.nlm.nih.gov/pubmed/10799173

242 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1448. Tombal, B.F., et al. A Phase 2 Randomized Open-label Study of Oral Darolutamide Monotherapy
Versus Androgen Deprivation Therapy in Men with Hormone-sensitive Prostate Cancer (EORTC-GUCG
1532). Eur Urol Oncol, 2024. 7: 1051.
https://www.ncbi.nlm.nih.gov/pubmed/38272747
1449. Becker, B., et al. Comparison of Intermittent and Continuous Androgen Deprivation Therapy in
Prostate Cancer Patients: An Up-to-Date Meta-analysis for Urologists and Medical Providers. Urol
Pract, 2023. 10: 424.
https://www.ncbi.nlm.nih.gov/pubmed/37505912
1450. O’Sullivan, N.J., et al. Surgical versus medical castration in the treatment of metastatic prostate
cancer: A systematic review and meta-analysis. J Clin Urol, 2023.
https://journals.sagepub.com/doi/10.1177/20514158231212534
1451. Potosky, A.L., et al. Quality-of-life outcomes after primary androgen deprivation therapy: results from
the Prostate Cancer Outcomes Study. J Clin Oncol, 2001. 19: 3750.
https://www.ncbi.nlm.nih.gov/pubmed/11533098
1452. Saad, F., et al. Relugolix vs. Leuprolide Effects on Castration Resistance-Free Survival from the Phase
3 HERO Study in Men with Advanced Prostate Cancer. Cancers (Basel), 2023. 15.
https://www.ncbi.nlm.nih.gov/pubmed/37835548
1453. Mell, L.K., et al. Effects of Androgen Deprivation Therapy on Prostate Cancer Outcomes According to
Competing Event Risk: Secondary Analysis of a Phase 3 Randomised Trial. Eur Urol, 2024. 85: 373.
https://www.ncbi.nlm.nih.gov/pubmed/36710205
1454. Yanagisawa, T., et al. Impact of performance status on efficacy of systemic therapy for prostate
cancer: a meta-analysis. BJU Int, 2023. 132: 365.
https://www.ncbi.nlm.nih.gov/pubmed/37395151
1455. Walker, L.M., et al. Luteinizing hormone--releasing hormone agonists: a quick reference for
prevalence rates of potential adverse effects. Clin Genitourin Cancer, 2013. 11: 375.
https://www.ncbi.nlm.nih.gov/pubmed/23891497
1456. Elliott, S., et al. Androgen deprivation therapy for prostate cancer: recommendations to improve
patient and partner quality of life. J Sex Med, 2010. 7: 2996.
https://www.ncbi.nlm.nih.gov/pubmed/20626600
1457. Iversen, P., et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic
locally advanced prostate cancer: 6.3 years of followup. J Urol, 2000. 164: 1579.
https://www.ncbi.nlm.nih.gov/pubmed/11025708
1458. Iversen, P., et al. Nonsteroidal antiandrogens: a therapeutic option for patients with advanced
prostate cancer who wish to retain sexual interest and function. BJU Int, 2001. 87: 47.
https://www.ncbi.nlm.nih.gov/pubmed/11121992
1459. Boccardo, F., et al. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer
patients: results of an Italian Prostate Cancer Project study. J Clin Oncol, 1999. 17: 2027.
https://www.ncbi.nlm.nih.gov/pubmed/10561254
1460. Irani, J., et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the
treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for
prostate cancer: a double-blind, randomised trial. Lancet Oncol, 2010. 11: 147.
https://www.ncbi.nlm.nih.gov/pubmed/19963436
1461. Russell, N., et al. Effects of oestradiol treatment on hot flushes in men undergoing androgen
deprivation therapy for prostate cancer: a randomised placebo-controlled trial. Eur J Endocrinol,
2022. 187: 617.
https://www.ncbi.nlm.nih.gov/pubmed/36806623
1462. Sloan, J.A., et al. Methodologic lessons learned from hot flash studies. J Clin Oncol, 2001. 19: 4280.
https://www.ncbi.nlm.nih.gov/pubmed/11731510
1463. Moraska, A.R., et al. Gabapentin for the management of hot flashes in prostate cancer survivors: a
longitudinal continuation Study-NCCTG Trial N00CB. J Support Oncol, 2010. 8: 128.
https://www.ncbi.nlm.nih.gov/pubmed/20552926
1464. Frisk, J., et al. Two modes of acupuncture as a treatment for hot flushes in men with prostate cancer-
-a prospective multicenter study with long-term follow-up. Eur Urol, 2009. 55: 156.
https://www.ncbi.nlm.nih.gov/pubmed/18294761
1465. Smith, M.R., et al. Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for
prostate cancer. J Urol, 2006. 175: 136.
https://www.ncbi.nlm.nih.gov/pubmed/16406890
1466. Cree, M., et al. Mortality and institutionalization following hip fracture. J Am Geriatr Soc, 2000. 48:
283.
https://www.ncbi.nlm.nih.gov/pubmed/10733054

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 243

1467. Compston, J.E., et al. Osteoporosis. Lancet, 2019. 393: 364.
https://www.ncbi.nlm.nih.gov/pubmed/30696576
1468. Saylor, P.J., et al. Metabolic complications of androgen deprivation therapy for prostate cancer. J
Urol, 2009. 181: 1998.
https://www.ncbi.nlm.nih.gov/pubmed/19286225
1469. Stelmach-Mardas, M., et al. Influence of Androgen Deprivation Therapy on the Development of
Sarcopenia in Patients with Prostate Cancer: A Systematic Review. Nutrients, 2024. 16.
https://www.ncbi.nlm.nih.gov/pubmed/38474784
1470. Gonnelli, S., et al. Obesity and fracture risk. Clin Cases Miner Bone Metab, 2014. 11: 9.
https://www.ncbi.nlm.nih.gov/pubmed/25002873
1471. Myint, Z.W., et al. Evaluation of Fall and Fracture Risk Among Men With Prostate Cancer Treated With
Androgen Receptor Inhibitors: A Systematic Review and Meta-analysis. JAMA Netw Open, 2020. 3:
e2025826.
https://www.ncbi.nlm.nih.gov/pubmed/33201234
1472. Sieber, P.R., et al. Bicalutamide 150 mg maintains bone mineral density during monotherapy for
localized or locally advanced prostate cancer. J Urol, 2004. 171: 2272.
https://www.ncbi.nlm.nih.gov/pubmed/15126801
1473. Wadhwa, V.K., et al. Bicalutamide monotherapy preserves bone mineral density, muscle strength and
has significant health-related quality of life benefits for osteoporotic men with prostate cancer. BJU
Int, 2011. 107: 1923.
https://www.ncbi.nlm.nih.gov/pubmed/20950306
1474. Higano, C., et al. Bone mineral density in patients with prostate cancer without bone metastases
treated with intermittent androgen suppression. Urology, 2004. 64: 1182.
https://www.ncbi.nlm.nih.gov/pubmed/15596194
1475. Nobes, J.P., et al. A prospective, randomized pilot study evaluating the effects of metformin and
lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU
Int, 2012. 109: 1495.
https://www.ncbi.nlm.nih.gov/pubmed/21933330
1476. Grundy, S.M., et al. Diagnosis and management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 2005. 112:
2735.
https://www.ncbi.nlm.nih.gov/pubmed/16157765
1477. Braga-Basaria, M., et al. Metabolic syndrome in men with prostate cancer undergoing long-term
androgen-deprivation therapy. J Clin Oncol, 2006. 24: 3979.
https://www.ncbi.nlm.nih.gov/pubmed/16921050
1478. Cheung, A.S., et al. Muscle and bone effects of androgen deprivation therapy: current and emerging
therapies. Endocr Relat Cancer, 2014. 21: R371.
https://www.ncbi.nlm.nih.gov/pubmed/25056176
1479. Smith, M.R., et al. Sarcopenia during androgen-deprivation therapy for prostate cancer. J Clin Oncol,
2012. 30: 3271.
https://www.ncbi.nlm.nih.gov/pubmed/22649143
1480. Papadopoulos, E., et al. The impact of sarcopenia on clinical outcomes in men with metastatic
castrate-resistant prostate cancer. PLoS One, 2023. 18: e0286381.
https://www.ncbi.nlm.nih.gov/pubmed/37262068
1481. Lu-Yao, G., et al. Changing patterns in competing causes of death in men with prostate cancer: a
population based study. J Urol, 2004. 171: 2285.
https://www.ncbi.nlm.nih.gov/pubmed/15126804
1482. Saigal, C.S., et al. Androgen deprivation therapy increases cardiovascular morbidity in men with
prostate cancer. Cancer, 2007. 110: 1493.
https://www.ncbi.nlm.nih.gov/pubmed/17657815
1483. Keating, N.L., et al. Diabetes and cardiovascular disease during androgen deprivation therapy:
observational study of veterans with prostate cancer. J Natl Cancer Inst, 2010. 102: 39.
https://www.ncbi.nlm.nih.gov/pubmed/19996060
1484. Efstathiou, J.A., et al. Cardiovascular mortality and duration of androgen deprivation for locally
advanced prostate cancer: analysis of RTOG 92-02. Eur Urol, 2008. 54: 816.
https://www.ncbi.nlm.nih.gov/pubmed/18243498
1485. Jones, C.U., et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N
Engl J Med, 2011. 365: 107.
https://www.ncbi.nlm.nih.gov/pubmed/21751904

244 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1486. Mak, K.S., et al. Cardiovascular Mortality and Duration of Androgen Deprivation in Locally Advanced
Prostate Cancer: Long-term Update of NRG/RTOG 9202. Eur Urol Focus, 2024. 10: 271.
https://www.ncbi.nlm.nih.gov/pubmed/38307806
1487. Butler, S.S., et al. Risk of cardiovascular mortality with androgen deprivation therapy in prostate
cancer: A secondary analysis of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Randomized
Controlled Trial. Cancer, 2021. 127: 2213.
https://www.ncbi.nlm.nih.gov/pubmed/33905530
1488. Nguyen, P.L., et al. Association of androgen deprivation therapy with cardiovascular death in patients
with prostate cancer: a meta-analysis of randomized trials. JAMA, 2011. 306: 2359.
https://www.ncbi.nlm.nih.gov/pubmed/22147380
1489. Bourke, L., et al. Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and cost-
effectiveness? Br J Cancer, 2013. 108: 9.
https://www.ncbi.nlm.nih.gov/pubmed/23321508
1490. Blankfield, R.P. Androgen deprivation therapy for prostate cancer and cardiovascular death. JAMA,
2012. 307: 1252; author reply 1252.
https://www.ncbi.nlm.nih.gov/pubmed/22453560
1491. Bosco, C., et al. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular
disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur Urol, 2015.
68: 386.
https://www.ncbi.nlm.nih.gov/pubmed/25484142
1492. Swaby, J., et al. Association of Androgen Deprivation Therapy with Metabolic Disease in Prostate
Cancer Patients: An Updated Meta-Analysis. Clin Genitourin Cancer, 2023. 21: e182.
https://www.ncbi.nlm.nih.gov/pubmed/36621463
1493. Nguyen, P.L., et al. Influence of androgen deprivation therapy on all-cause mortality in men with high-
risk prostate cancer and a history of congestive heart failure or myocardial infarction. Int J Radiat
Oncol Biol Phys, 2012. 82: 1411.
https://www.ncbi.nlm.nih.gov/pubmed/21708431
1494. Tsai, H.K., et al. Androgen deprivation therapy for localized prostate cancer and the risk of
cardiovascular mortality. J Natl Cancer Inst, 2007. 99: 1516.
https://www.ncbi.nlm.nih.gov/pubmed/17925537
1495. Lopes, R.D., et al. Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate
Cancer: The Primary Results of the PRONOUNCE Randomized Trial. Circulation, 2021. 144: 1295.
https://www.ncbi.nlm.nih.gov/pubmed/34459214
1496. Tisseverasinghe, S., et al. Should Prostate Cancer Patients With History of Cardiovascular Events
Be Preferentially Treated With Luteinizing Hormone-Releasing Hormone Antagonists? J Clin Oncol,
2022. 40: 4173.
https://www.ncbi.nlm.nih.gov/pubmed/35862876
1497. Nelson, A.J., et al. Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate
Cancer: A Systematic Review. JACC CardioOncol, 2023. 5: 613.
https://www.ncbi.nlm.nih.gov/pubmed/37969642
1498. Gilbert, S.E., et al. Effects of a lifestyle intervention on endothelial function in men on long-term
androgen deprivation therapy for prostate cancer. Br J Cancer, 2016. 114: 401.
https://www.ncbi.nlm.nih.gov/pubmed/26766737
1499. Cao, B., et al. Adverse Events and Androgen Receptor Signaling Inhibitors in the Treatment of
Prostate Cancer: A Systematic Review and Multivariate Network Meta-analysis. Eur Urol Oncol, 2023.
6: 237.
https://www.ncbi.nlm.nih.gov/pubmed/36682938
1500. Wilding, S., et al. Cancer-related symptoms, mental well-being, and psychological distress in men
diagnosed with prostate cancer treated with androgen deprivation therapy. Qual Life Res, 2019. 28:
2741.
https://www.ncbi.nlm.nih.gov/pubmed/31115843
1501. Bourke, L., et al. Exercise for Men with Prostate Cancer: A Systematic Review and Meta-analysis. Eur
Urol, 2016. 69: 693.
https://www.ncbi.nlm.nih.gov/pubmed/26632144
1502. Meng, F., et al. Stroke related to androgen deprivation therapy for prostate cancer: a meta-analysis
and systematic review. BMC Cancer, 2016. 16: 180.
https://www.ncbi.nlm.nih.gov/pubmed/26940836
1503. Nead, K.T., et al. Androgen Deprivation Therapy and Future Alzheimer’s Disease Risk. J Clin Oncol,
2016. 34: 566.
https://www.ncbi.nlm.nih.gov/pubmed/26644522

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 245

1504. Delmas, P.D. Clinical potential of RANKL inhibition for the management of postmenopausal
osteoporosis and other metabolic bone diseases. J Clin Densitom, 2008. 11: 325.
https://www.ncbi.nlm.nih.gov/pubmed/18375161
1505. Cummings, S.R., et al. Denosumab for prevention of fractures in postmenopausal women with
osteoporosis. N Engl J Med, 2009. 361: 756.
https://www.ncbi.nlm.nih.gov/pubmed/19671655
1506. Smith, M.R., et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N
Engl J Med, 2009. 361: 745.
https://www.ncbi.nlm.nih.gov/pubmed/19671656
1507. Gupta, M., et al., Bisphosphonate Related Jaw Osteonecrosis, in StatPearls. 2023, StatPearls
Publishing Copyright © 2023, StatPearls Publishing LLC.: Treasure Island (FL) ineligible companies.
Disclosure: Neha Gupta declares no relevant financial relationships with ineligible companies.
https://www.ncbi.nlm.nih.gov/pubmed/30521192
1508. Boquete-Castro, A., et al. Denosumab and osteonecrosis of the jaw. A systematic analysis of events
reported in clinical trials. Clin Oral Implants Res, 2016. 27: 367.
https://www.ncbi.nlm.nih.gov/pubmed/25639776
1509. Bennett, D., et al. Factors influencing job loss and early retirement in working men with prostate
cancer-findings from the population-based Life After Prostate Cancer Diagnosis (LAPCD) study. J
Cancer Surviv, 2018. 12: 669.
https://www.ncbi.nlm.nih.gov/pubmed/30058009
1510. Roberts, C., et al. The Experiences and Unmet Supportive Care Needs of Partners of Men Diagnosed
With Prostate Cancer: A Meta-aggregation Systematic Review. Clin Neuropharmacol, 2022.
https://www.ncbi.nlm.nih.gov/pubmed/36480350
1511. James, C., et al. Fear of cancer recurrence and PSA anxiety in patients with prostate cancer: a
systematic review. Support Care Cancer, 2022. 30: 5577.
https://www.ncbi.nlm.nih.gov/pubmed/35106656
1512. Mundle, R., et al. The effectiveness of psychological intervention for depression, anxiety, and distress
in prostate cancer: a systematic review of literature. Prostate Cancer Prostatic Dis, 2021. 24: 674.
https://www.ncbi.nlm.nih.gov/pubmed/33750905
1513. Borji, M., et al. Positive Effects of Cognitive Behavioral Therapy on Depression, Anxiety and Stress of
Family Caregivers of Patients with Prostate Cancer: A Randomized Clinical Trial. Asian Pac J Cancer
Prev, 2017. 18: 3207.
https://www.ncbi.nlm.nih.gov/pubmed/29281868
1514. Bourke, L., et al. A qualitative study evaluating experiences of a lifestyle intervention in men with
prostate cancer undergoing androgen suppression therapy. Trials, 2012. 13: 208.
https://www.ncbi.nlm.nih.gov/pubmed/23151126
1515. Berruti, A., et al. Incidence of skeletal complications in patients with bone metastatic prostate cancer
and hormone refractory disease: predictive role of bone resorption and formation markers evaluated
at baseline. J Urol, 2000. 164: 1248.
https://www.ncbi.nlm.nih.gov/pubmed/10992374
1516. Carlin, B.I., et al. The natural history, skeletal complications, and management of bone metastases in
patients with prostate carcinoma. Cancer, 2000. 88: 2989.
https://www.ncbi.nlm.nih.gov/pubmed/10898342
1517. Smith, D.P., et al. Quality of life three years after diagnosis of localised prostate cancer: population
based cohort study. BMJ, 2009. 339: b4817.
https://www.ncbi.nlm.nih.gov/pubmed/19945997
1518. Taylor, K.L., et al. Long-term disease-specific functioning among prostate cancer survivors and
noncancer controls in the prostate, lung, colorectal, and ovarian cancer screening trial. J Clin Oncol,
2012. 30: 2768.
https://www.ncbi.nlm.nih.gov/pubmed/22734029
1519. Bhanvadia, S.K., et al. Financial Toxicity Among Patients with Prostate, Bladder, and Kidney Cancer: A
Systematic Review and Call to Action. Eur Urol Oncol, 2021. 4: 396.
https://www.ncbi.nlm.nih.gov/pubmed/33820747
1520. Ratti, M.M., et al. Standardising the Assessment of Patient-reported Outcome Measures in Localised
Prostate Cancer. A Systematic Review. Eur Urol Oncol, 2022. 5: 153.
https://www.ncbi.nlm.nih.gov/pubmed/34785188
1521. Groenvold, M., et al. Validation of the EORTC QLQ-C30 quality of life questionnaire through combined
qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol, 1997. 50:
441.
https://www.ncbi.nlm.nih.gov/pubmed/9179103

246 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1522. van Andel, G., et al. An international field study of the EORTC QLQ-PR25: a questionnaire for
assessing the health-related quality of life of patients with prostate cancer. Eur J Cancer, 2008. 44:
2418.
https://www.ncbi.nlm.nih.gov/pubmed/18774706
1523. Cella, D.F., et al. The Functional Assessment of Cancer Therapy scale: development and validation of
the general measure. J Clin Oncol, 1993. 11: 570.
https://www.ncbi.nlm.nih.gov/pubmed/8445433
1524. Esper, P., et al. Measuring quality of life in men with prostate cancer using the functional assessment
of cancer therapy-prostate instrument. Urology, 1997. 50: 920.
https://www.ncbi.nlm.nih.gov/pubmed/9426724
1525. Wei, J.T., et al. Development and validation of the expanded prostate cancer index composite (EPIC)
for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology,
2000. 56: 899.
https://www.ncbi.nlm.nih.gov/pubmed/11113727
1526. Szymanski, K.M., et al. Development and validation of an abbreviated version of the expanded
prostate cancer index composite instrument for measuring health-related quality of life among
prostate cancer survivors. Urology, 2010. 76: 1245.
https://www.ncbi.nlm.nih.gov/pubmed/20350762
1527. Litwin, M.S., et al. The UCLA Prostate Cancer Index: development, reliability, and validity of a health-
related quality of life measure. Med Care, 1998. 36: 1002.
https://www.ncbi.nlm.nih.gov/pubmed/9674618
1528. Giesler, R.B., et al. Assessing quality of life in men with clinically localized prostate cancer:
development of a new instrument for use in multiple settings. Qual Life Res, 2000. 9: 645.
https://www.ncbi.nlm.nih.gov/pubmed/11236855
1529. Lane, J.A., et al. Functional and quality of life outcomes of localised prostate cancer treatments
(Prostate Testing for Cancer and Treatment [ProtecT] study). BJU Int, 2022. 130: 370.
https://www.ncbi.nlm.nih.gov/pubmed/35373443
1530. van As, N., et al. Radical Prostatectomy Versus Stereotactic Radiotherapy for Clinically Localised
Prostate Cancer: Results of the PACE-A Randomised Trial. Eur Urol, 2024.
https://www.ncbi.nlm.nih.gov/pubmed/39266383
1531. Aksnessaether, B.Y., et al. Second Cancers in Patients With Locally Advanced Prostate Cancer
Randomized to Lifelong Endocrine Treatment With or Without Radical Radiation Therapy: Long-Term
Follow-up of the Scandinavian Prostate Cancer Group-7 Trial. Int J Radiat Oncol Biol Phys, 2020. 106:
706.
https://www.ncbi.nlm.nih.gov/pubmed/31786279
1532. Fransson, P., et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate
cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-
inferiority, phase 3 trial. Lancet Oncol, 2021. 22: 235.
https://www.ncbi.nlm.nih.gov/pubmed/33444529
1533. Hoffman, K.E., et al. Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery,
Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for
Localized Prostate Cancer. JAMA, 2020. 323: 149.
https://www.ncbi.nlm.nih.gov/pubmed/31935027
1534. Lantz, A., et al. Functional and Oncological Outcomes After Open Versus Robot-assisted
Laparoscopic Radical Prostatectomy for Localised Prostate Cancer: 8-Year Follow-up. Eur Urol, 2021.
80: 650.
https://www.ncbi.nlm.nih.gov/pubmed/34538508
1535. Hunt, A.A., et al. Risk of erectile dysfunction after modern radiotherapy for intact prostate cancer.
Prostate Cancer Prostatic Dis, 2021. 24: 128.
https://www.ncbi.nlm.nih.gov/pubmed/32647352
1536. Giesler, R.B., et al. Improving the quality of life of patients with prostate carcinoma: a randomized trial
testing the efficacy of a nurse-driven intervention. Cancer, 2005. 104: 752.
https://www.ncbi.nlm.nih.gov/pubmed/15986401
1537. Schumacher, O., et al. Effects of Exercise During Radiation Therapy on Physical Function and
Treatment-Related Side Effects in Men With Prostate Cancer: A Systematic Review and Meta-
Analysis. Int J Radiat Oncol Biol Phys, 2021. 111: 716.
https://www.ncbi.nlm.nih.gov/pubmed/34246737

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 247

1538. Kang, D.W., et al. Effects of Exercise on Cardiorespiratory Fitness and Biochemical Progression in
Men With Localized Prostate Cancer Under Active Surveillance: The ERASE Randomized Clinical Trial.
JAMA Oncol, 2021. 7: 1487.
https://www.ncbi.nlm.nih.gov/pubmed/34410322
1539. Anderson, C.A., et al. Conservative management for postprostatectomy urinary incontinence.
Cochrane Database Syst Rev, 2015. 1: CD001843.
https://www.ncbi.nlm.nih.gov/pubmed/25602133
1540. Chen, Y.C., et al. Surgical treatment for urinary incontinence after prostatectomy: A meta-analysis and
systematic review. PLoS One, 2017. 12: e0130867.
https://www.ncbi.nlm.nih.gov/pubmed/28467435
1541. Crivellaro, S., et al. Systematic review of surgical treatment of post radical prostatectomy stress
urinary incontinence. Neurourol Urodyn, 2016. 35: 875.
https://www.ncbi.nlm.nih.gov/pubmed/26397171
1542. Cornu, J.-N., et al. , EAU Guidelines on Non-neurogenic Male LUTS, E.G. Office, Editor. 2023, EAU
Guidelines Office: EAU Guidelines published at the 38th EAU Annual Congress, Milan.
https://uroweb.org/guidelines/archive/management-of-non-neurogenic-male-luts
1543. Skolarus, T.A., et al. Androgen-deprivation-associated bone disease. Curr Opin Urol, 2014. 24: 601.
https://www.ncbi.nlm.nih.gov/pubmed/25144145
1544. Patel, H.R., et al. Effects of tadalafil treatment after bilateral nerve-sparing radical prostatectomy:
quality of life, psychosocial outcomes, and treatment satisfaction results from a randomized,
placebo-controlled phase IV study. BMC Urol, 2015. 15: 31.
https://www.ncbi.nlm.nih.gov/pubmed/25879460
1545. Philippou, Y.A., et al. Penile rehabilitation for postprostatectomy erectile dysfunction. Cochrane
Database Syst Rev, 2018. 10: CD012414.
https://www.ncbi.nlm.nih.gov/pubmed/30352488
1546. Salonia, A., et al., EAU Guidelines on Sexual and Reproductive Health. Edn. presented at the 40th EAU
Annual Congress, Madrid, Spain. 2025.
https://uroweb.org/guidelines/archive/sexual-and-reproductive-health
1547. Schubach, K., et al. Experiences of sexual well-being interventions in males affected by genitourinary
cancers and their partners: an integrative systematic review. Support Care Cancer, 2023. 31: 265.
https://www.ncbi.nlm.nih.gov/pubmed/37058163
1548. Dieperink, K.B., et al. The effects of multidisciplinary rehabilitation: RePCa-a randomised study
among primary prostate cancer patients. Br J Cancer, 2013. 109: 3005.
https://www.ncbi.nlm.nih.gov/pubmed/24169342
1549. Dieperink, K.B., et al. Long-term follow-up 3 years after a randomized rehabilitation study among
radiated prostate cancer survivors. J Cancer Surviv, 2021. 15: 668.
https://www.ncbi.nlm.nih.gov/pubmed/33079329
1550. Galvao, D.A., et al. Combined resistance and aerobic exercise program reverses muscle loss in
men undergoing androgen suppression therapy for prostate cancer without bone metastases: a
randomized controlled trial. J Clin Oncol, 2010. 28: 340.
https://www.ncbi.nlm.nih.gov/pubmed/19949016
1551. Bourke, L., et al. Lifestyle changes for improving disease-specific quality of life in sedentary men on
long-term androgen-deprivation therapy for advanced prostate cancer: a randomised controlled trial.
Eur Urol, 2014. 65: 865.
https://www.ncbi.nlm.nih.gov/pubmed/24119318
1552. Cella, D., et al. Estimating clinically meaningful changes for the Functional Assessment of Cancer
Therapy--Prostate: results from a clinical trial of patients with metastatic hormone-refractory
prostate cancer. Value Health, 2009. 12: 124.
https://www.ncbi.nlm.nih.gov/pubmed/18647260
1553. Galvao, D.A., et al. Psychological distress in men with prostate cancer undertaking androgen
deprivation therapy: modifying effects of exercise from a year-long randomized controlled trial.
Prostate Cancer Prostatic Dis, 2021. 24: 758.
https://www.ncbi.nlm.nih.gov/pubmed/33558661
1554. Lopez, P., et al. Resistance Exercise Dosage in Men with Prostate Cancer: Systematic Review, Meta-
analysis, and Meta-regression. Med Sci Sports Exerc, 2021. 53: 459.
https://www.ncbi.nlm.nih.gov/pubmed/32890199
1555. Shao, W., et al. The effects of exercise on body composition of prostate cancer patients receiving
androgen deprivation therapy: An update systematic review and meta-analysis. PLoS One, 2022. 17:
e0263918.
https://www.ncbi.nlm.nih.gov/pubmed/35167609

248 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1556. Ussing, A., et al. Supervised exercise therapy compared with no exercise therapy to reverse
debilitating effects of androgen deprivation therapy in patients with prostate cancer: a systematic
review and meta-analysis. Prostate Cancer Prostatic Dis, 2022. 25: 491.
https://www.ncbi.nlm.nih.gov/pubmed/34489536
1557. Toohey, K., et al. Exercise Adherence in Men with Prostate Cancer Undergoing Androgen Deprivation
Therapy: A Systematic Review and Meta-Analysis. Cancers (Basel), 2022. 14.
https://www.ncbi.nlm.nih.gov/pubmed/35626058
1558. Nair-Shalliker, V., et al. Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and
mortality in men with aggressive prostate cancer. Sci Rep, 2020. 10: 7736.
https://www.ncbi.nlm.nih.gov/pubmed/32385370
1559. Grant, W.B. Review of Recent Advances in Understanding the Role of Vitamin D in Reducing Cancer
Risk: Breast, Colorectal, Prostate, and Overall Cancer. Anticancer Res, 2020. 40: 491.
https://www.ncbi.nlm.nih.gov/pubmed/31892604
1560. Coleman, R., et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol, 2020. 31:
1650.
https://www.ncbi.nlm.nih.gov/pubmed/32801018
1561. Shapiro, C.L., et al. Management of Osteoporosis in Survivors of Adult Cancers With Nonmetastatic
Disease: ASCO Clinical Practice Guideline. J Clin Oncol, 2019. 37: 2916.
https://www.ncbi.nlm.nih.gov/pubmed/31532726
1562. Briot, K., et al. French recommendations for osteoporosis prevention and treatment in patients with
prostate cancer treated by androgen deprivation. Joint Bone Spine, 2019. 86: 21.
https://www.ncbi.nlm.nih.gov/pubmed/30287350
1563. Saylor, P.J., et al. Bone Health and Bone-Targeted Therapies for Prostate Cancer: ASCO Endorsement
of a Cancer Care Ontario Guideline. J Clin Oncol, 2020. 38: 1736.
https://www.ncbi.nlm.nih.gov/pubmed/31990618
1564. Brown, J.E., et al. Guidance for the assessment and management of prostate cancer treatment-
induced bone loss. A consensus position statement from an expert group. J Bone Oncol, 2020. 25:
100311.
https://www.ncbi.nlm.nih.gov/pubmed/32995252
1565. Smith, M.R., et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men
receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol, 2003. 169: 2008.
https://www.ncbi.nlm.nih.gov/pubmed/12771706
1566. Michaelson, M.D., et al. Randomized controlled trial of annual zoledronic acid to prevent
gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin
Oncol, 2007. 25: 1038.
https://www.ncbi.nlm.nih.gov/pubmed/17369566
1567. Migliorati, C.A., et al. Bisphosphonate-associated osteonecrosis: a long-term complication of
bisphosphonate treatment. Lancet Oncol, 2006. 7: 508.
https://www.ncbi.nlm.nih.gov/pubmed/16750501
1568. Wadhwa, V.K., et al. Frequency of zoledronic acid to prevent further bone loss in osteoporotic
patients undergoing androgen deprivation therapy for prostate cancer. BJU Int, 2010. 105: 1082.
https://www.ncbi.nlm.nih.gov/pubmed/19912210
1569. Clemons, M., et al. A randomised trial of 4- versus 12-weekly administration of bone-targeted agents
in patients with bone metastases from breast or castration-resistant prostate cancer. Eur J Cancer,
2021. 142: 132.
https://www.ncbi.nlm.nih.gov/pubmed/33023785
1570. Ohlmann C., et al. Second-line chemotherapy with docetaxel for prostate-specific antigen relapse in
men with hormone refractory prostate cancer previously treated with docetaxel based chemotherapy.
Eur Urol Suppl 2006. 5: abstract #289.
https://ascopubs.org/doi/10.1200/jco.2005.23.16_suppl.4682
1571. Chen, R.C., et al. Association Between Choice of Radical Prostatectomy, External Beam Radiotherapy,
Brachytherapy, or Active Surveillance and Patient-Reported Quality of Life Among Men With
Localized Prostate Cancer. JAMA, 2017. 317: 1141.
https://www.ncbi.nlm.nih.gov/pubmed/28324092
1572. Sanda, M.G., et al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part I: Risk
Stratification, Shared Decision Making, and Care Options. J Urol, 2018. 199: 683.
https://www.ncbi.nlm.nih.gov/pubmed/29203269
1573. Makarov, D.V., et al. AUA White Paper on Implementation of Shared Decision Making into Urological
Practice. Urol Pract, 2016. 3: 355.
https://www.ncbi.nlm.nih.gov/pubmed/37592546

PROSTATE CANCER - LIMITED UPDATE MARCH 2025 249

1574. Stiggelbout, A.M., et al. Shared decision making: Concepts, evidence, and practice. Patient Educ
Couns, 2015. 98: 1172.
https://www.ncbi.nlm.nih.gov/pubmed/26215573
1575. Violette, P.D., et al. Decision aids for localized prostate cancer treatment choice: Systematic review
and meta-analysis. CA Cancer J Clin, 2015. 65: 239.
https://www.ncbi.nlm.nih.gov/pubmed/25772796
1576. Ramsey, S.D., et al. Unanticipated and underappreciated outcomes during management of local
stage prostate cancer: a prospective survey. J Urol, 2010. 184: 120.
https://www.ncbi.nlm.nih.gov/pubmed/20478590
1577. Connolly, T., et al. Regret in Decision Making. Curr Direct Psy Sci, 2016. 11: 212.
https://journals.sagepub.com/doi/10.1111/1467-8721.00203
1578. Maguire, R., et al. Expecting the worst? The relationship between retrospective and prospective
appraisals of illness on quality of life in prostate cancer survivors. Psychooncology, 2018. 27: 1237.
https://www.ncbi.nlm.nih.gov/pubmed/29430755
1579. Schroeck, F.R., et al. Satisfaction and regret after open retropubic or robot-assisted laparoscopic
radical prostatectomy. Eur Urol, 2008. 54: 785.
https://www.ncbi.nlm.nih.gov/pubmed/18585849
1580. Steentjes, L., et al. Factors associated with current and severe physical side-effects after prostate
cancer treatment: What men report. Eur J Cancer Care (Engl), 2018. 27.
https://www.ncbi.nlm.nih.gov/pubmed/27726215
1581. Orom, H., et al. What Is a “Good” Treatment Decision? Decisional Control, Knowledge, Treatment
Decision Making, and Quality of Life in Men with Clinically Localized Prostate Cancer. Med Decis
Making, 2016. 36: 714.
https://www.ncbi.nlm.nih.gov/pubmed/26957566
1582. Davison, B.J., et al. Quality of life, sexual function and decisional regret at 1 year after surgical
treatment for localized prostate cancer. BJU Int, 2007. 100: 780.
https://www.ncbi.nlm.nih.gov/pubmed/17578466
1583. Wilding, S., et al. Decision regret in men living with and beyond nonmetastatic prostate cancer in the
United Kingdom: A population-based patient-reported outcome study. Psychooncology, 2020. 29:
886.
https://www.ncbi.nlm.nih.gov/pubmed/32065691
1584. Martinez-Gonzalez, N.A., et al. Shared decision making for men facing prostate cancer treatment: a
systematic review of randomized controlled trials. Patient Prefer Adherence, 2019. 13: 1153.
https://www.ncbi.nlm.nih.gov/pubmed/31413545
1585. Menichetti, J., et al. Quality of life in active surveillance and the associations with decision-making-a
literature review. Transl Androl Urol, 2018. 7: 160.
https://www.ncbi.nlm.nih.gov/pubmed/29594030
1586. Ivlev, I., et al. Prostate Cancer Screening Patient Decision Aids: A Systematic Review and Meta-
analysis. Am J Prev Med, 2018. 55: 896.
https://www.ncbi.nlm.nih.gov/pubmed/30337235
1587. Kinsella, N., et al. A Single Educational Seminar Increases Confidence and Decreases Dropout from
Active Surveillance by 5 Years After Diagnosis of Prostate Cancer. Eur Urol Oncol, 2019. 2: 464.
https://www.ncbi.nlm.nih.gov/pubmed/31277784
1588. Hoffman, R.M., et al. Selecting Active Surveillance: Decision Making Factors for Men with a Low-Risk
Prostate Cancer. Med Decis Making, 2019. 39: 962.
https://www.ncbi.nlm.nih.gov/pubmed/31631745
1589. Berry, D.L., et al. Decision Support with the Personal Patient Profile-Prostate: A Multicenter
Randomized Trial. J Urol, 2018. 199: 89.
https://www.ncbi.nlm.nih.gov/pubmed/28754540
1590. Campagna, J.P., et al. Prostate Cancer Survival Estimates by the General Public Using Unrestricted
Internet Searches and Online Nomograms. Eur Urol Focus, 2020. 6: 959.
https://www.ncbi.nlm.nih.gov/pubmed/30723050
1591. de Freitas, H.M., et al. Patient Preferences for Metastatic Hormone-Sensitive Prostate Cancer
Treatments: A Discrete Choice Experiment Among Men in Three European Countries. Adv Ther, 2019.
36: 318.
https://www.ncbi.nlm.nih.gov/pubmed/30617763
1592. Lorent, M., et al. Meta-analysis of predictive models to assess the clinical validity and utility
for patient-centered medical decision making: application to the CAncer of the Prostate Risk
Assessment (CAPRA). BMC Med Inform Decis Mak, 2019. 19: 2.
https://www.ncbi.nlm.nih.gov/pubmed/30616621

250 PROSTATE CANCER - LIMITED UPDATE MARCH 2025

1593. Riikonen, J.M., et al. Decision Aids for Prostate Cancer Screening Choice: A Systematic Review and
Meta-analysis. JAMA Intern Med, 2019. 179: 1072.
https://www.ncbi.nlm.nih.gov/pubmed/31233091
1594. Vromans, R.D., et al. Communicative aspects of decision aids for localized prostate cancer treatment
- A systematic review. Urol Oncol, 2019. 37: 409.
https://www.ncbi.nlm.nih.gov/pubmed/31053529

10. CONFLICT OF INTEREST

All members of the EAU - EANM - ESTRO - ESUR - ISUP – SIOG Prostate Cancer Guidelines Working Group have
provided disclosure statements of all relationships that they have that might be perceived as a potential source
of a conflict of interest. This information is publicly accessible through the European Association of Urology
website: https://uroweb.org/guidelines/prostate-cancer/panel.

This guidelines document was developed with the financial support of the European Association of Urology. No
external sources of funding and support have been involved. The EAU is a non-profit organization and funding
is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements
have been provided.

11. CITATION INFORMATION

The compilation of the complete Guidelines should be referenced as:
EAU Guidelines. Edn. presented at the EAU Annual Congress Madrid 2025. ISBN 978-94-92671-29-5.

If a publisher and/or location is required, include:

EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/

References to individual guidelines should be structured in the following way:

Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

12. COPYRIGHT AND TERMS OF USE

The content of the EAU Guidelines and all products derived from them is made available for personal and
educational use only. No commercial usage is authorised. No part of the EAU Guidelines or any related products
may be translated or reproduced in any form without written permission from the EAU. Furthermore, the EAU
prohibits the usage or upload of its Guidelines, and any material derived from these texts (whether in full or
in part) on external websites, bots, pages, portals, servers, software, or external applications, including those
employing artificial intelligence technologies and infrastructure, such as large language models and generative
AI, deep learning and machine learning, unless written permission has been granted for such by the EAU.

The EAU accepts no responsibility for the content, quality, or performance of materials, applications and
products derived from the EAU Guidelines and does not endorse or warrant their use. In the event of any
discrepancies the original language version shall be considered authoritative.

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