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EUROPEAN UROLOGY
Alberto Briganti, Editor-in-Chief
Vita-Salute San Raffaele University
Deputy Director of Urological Research Institute
Scientific Institute San Raffaele
Via Olgettina 60
20132 Milan, Italy
 EDITORIAL BOARD

Hashim Ahmed, UK Jack Elder, USA Benoit Peyronnet, France

Peter Albers, Germany Matthew Galsky, USA Tom Powles, UK
Peter Albertsen, USA John Gearhart, USA Benjamin Pradere, Austria
Andrea Apolo, USA Matthew Gettman, USA Ranjith Ramasamy, USA
Apostolos Apostolidos, Greece Inderbir Gill, USA Jens Rassweiler, Germany
Riccardo Autorino, Italy Francesco Greco, Germany Maria J. Ribal, Spain
Marko Babjuk, Czech Republic Jüergen Gschwend, Germany Jennifer R. Rider, USA
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Shin Egawa, Japan Nicolas Mottet, France Alex Zlotta, Canada
Scott Eggener, USA James N’dow, UK
Behfar Ehdaie, USA Valeria Panebianco, Italy

The Platinum Hall of Fame is online only at http://www.sciencedirect.com/science/journal/03022838/87/1

EUROPEAN UROLOGY
Alberto Briganti, Editor-in-Chief
Vita-Salute San Raffaele University
Deputy Director of Urological Research Institute
Scientific Institute San Raffaele
Via Olgettina 60
20132 Milan, Italy
 HONORARY BOARD OF EDITORS

Per Anders Abrahamsson, Marcus Graefen, Germany Francesco Pagano, Italy

Sweden Christian Gratzke, Germany Sava Petkovic, Serbia
Carl-Erich, Alken, Germany Willy Grégoir, Belgium António Pinto Carvalho, Portugal
Lars Erik Almgård, Sweden Indebir Gill, USA Antoni Puigvert, Soain
Karl-Erik Andersson, Sweden Francois Haab, France Giorgio Ravasini, Italy
Nicola, Atanassov, Bulgaria Fouad Habib, UK Vincent, Ravery, France
Jean Auvert, Paris Oliver Hakenberg, Germany Jack Schalken, Netherlands
Alec Williams Badenoch, UK Freddie Hamdy, UK Bernd Schmitz-Dräger, Germany
Ferenc Balogh, Hungary Peter Hammerer, Germany Roelof Scholtmeijer, Netherlands
George Bartsch, Austria Rudolf, Hohenfellner, Germany Fritz Schröder, Netherlands
Anders Bjartell Sweden Fernando Jimenez-Cruz, Spain Claude Schulman, Belgium
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Stephen Boorjian, USA Alexander Kutikov, USA Adolphe Steg, France
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Antony D’ Amico, USA W., Mathisen, Norway Henk van der Poel, Netherlands
Jean, De la Rosette, Netherlands Georg Mayor, Switzerland Christopher Wallis, Canada
Frans Debruyne, Netherlands Christine McKillop, UK Stefan Wesolowski, Poland
Constantine Dimopoulos, Greece Moritz Mebel, Germany Robert Whitaker, UK
Bob Djavan, Austria Francesco Montorsi, Italy Emily Zabor, USA
Stephen Freedland, USA Kurt Naber, Germany Alexandre Zlotta, Belgium
John Fitzpatrick, Ireland Donald Newling, Netherlands Vladimir Zvara, Slovakia
Karim Fizazi, France Kaarlo Oravisto, Finland
 e u r o p e a n u r o l o g y , v o l . 8 7 n o i , J A N UA RY 2 0 2 5

CONTENTS
The Platinum Hall of Fame e1
10.1016/j.eururo.2024.11.019

Platinium Opinions Tissue-based Biomarkers Steering Clinical Decisions in Patients with Urothelial Cancer 1
L. Afferi, A. Cimadamore, A. Gallioli, B. Pradere, L.S. Mertens, G. Marcq, G. Anguera, A. Necchi, A. Briganti,
F. Montorsi, M. Rouprêt, P. Gontero, A. Breda, M. Moschini, European Association of Urology Young
Academic Urologists Urothelial Carcinoma Working Group
The European Association of Urology (EAU), National Comprehensive Cancer Network, and
European Society for Medical Oncology guidelines recommend PD-L1 and FGFR testing for
patients with locally advanced bladder cancer or upper tract urothelial cancer (UTUC)
according to specific eligibility criteria; positive results indicate therapy with immune
checkpoint inhibitors or erdafitinib, respectively. The EAU guidelines recommend PD-L1
testing for subsequent adjuvant therapy in high-risk UC, and germline DNA sequencing in
patients with UTUC positive for DNA mismatch repair alterations.
Standard Repeat Biopsies During Active Surveillance for Prostate Cancer: Are They 5
Necessary in the Magnetic Resonance Imaging Era?
R.C.N. van den Bergh, I.G. Schoots, P.A. Cornford, European Association of Urology Prostate Cancer
Guidelines Panel
Active surveillance (AS) remains an important part of the efforts to decrease overtreatment
of prostate cancer. The increasing use of magnetic resonance imaging (MRI) can reduce the
need for repeat biopsy during AS. If MRI findings remain unchanged and clinical
characteristics such as prostate-specific antigen density are favourable, the relative risks
and benefits of repeat biopsy should be discussed with individual patients.

EAU Guidelines Clinical Implications of Basic Research: Exploring the Transformative Potential of 8
View Spatial ’Omics in Uro-oncology
S. Figiel, A. Bates, D.A. Braun, R. Eapen, M. Eckstein, B.J. Manley, M.I. Milowsky, T.J. Mitchell, R.J. Bryant,
J.P. Sfakianos, A.D. Lamb
This work explores the potential of spatial omics to improve our understanding of the
underlying biology of urological cancers, with the aim of improving prediction,
prognostication, and development of novel therapies. Despite challenges including cost,
expertise, and limited datasets, further use and streamlining of these techniques promise
dramatic improvements in personalised care.
Platinum Priority Prostate Cancer Therapy Cardiotoxicity Map (PROXMAP) for Advanced 15
Papers Disease States: A Systematic Review and Network Meta-analysis with
Bayesian Modeling of Treatment Histories
M.K. Aziz, D. Molony, D. Monlezun, T. Holder, O. Brunckhorst, N. Higgason, J. Roland, R. Magill,
M. Fatakdawala, A. Iacobucci, N. Mody-Bailey, C. Owen, A. Zarker, E. Thames, J. Swaby, D. Xiao, L. Choi,
S. Desai, J. Galan, B. Deng, T. Hartshorne, A. Nichols, A. Zhang, J. Imber, J. Song, W. Jones, A. Rivas,
D. Sanchez, M. Guhan, G. Gandaglia, S. Ranganath, J. Jacob, S. Howell, J. Plana, R. van den Bergh,
M. Roberts, S.G. Sommer, J. Oldenburg, G. Ploussard, D. Tilki, I. Schoots, E. Briers, J. Stranne, O. Rouviere,
I. van Oort, D. Oprea-Lager, M. De Santis, P. Cornford, E. Koutroumpakis, A. Ziaolhagh, A. Ali,
S. Wamique Yusuf, C. Iliescu, S. Canfield
Androgen deprivation therapy (ADT) plus docetaxel (DTX) plus darolutamide demonstrates
less cardiotoxicity than ADT + DTX plus abiraterone acetate with prednisone (AA + P) for
metastatic hormone-sensitive prostate cancer. Studied first-line nonmetastatic castrate-
resistant prostate cancer treatments did not demonstrate differences in cardiotoxicity.
Depending on treatment history, ADT + AA + P plus olaparib offers decreased
hypertension and ADT plus enzalutamide offers increased vascular toxicity when treating
first-line metastatic castrate-resistant prostate cancer.
 e u r o p e a n u r o l o g y , v o l . 8 7 n o i , J A N UA RY 2 0 2 5

Balancing Efficacy and Cardiotoxicity in Prostate Cancer Therapy: A Call for Precision 27
in Treatment Strategies
O. El-Taji, N.W. Clarke
Intensification Approaches and Treatment Sequencing in Metastatic 29
Castration-resistant Prostate Cancer: A Systematic Review
E. Francini, N. Agarwal, E. Castro, H.H. Cheng, K.N. Chi, N. Clarke, J. Mateo, D. Rathkopf, F. Saad,
B. Tombal
Treatment intensification strategies are reshaping the treatment landscape of metastatic
castration-resistant prostate cancer. Genomic, molecular, and clinical indicators should be
used to identify the optimal therapeutic pathway for each patient.
Management Decisions for Metastatic Castration-resistant Prostate Cancer in 2024 47
D.J. VanderWeele, M. Hussain
Testosterone Recovery Following Androgen Suppression and Prostate 49
Radiotherapy (TRANSPORT): A Pooled Analysis of Five Randomized Trials
from the Meta-Analysis of Randomized Trials in Cancer of the Prostate
(MARCAP) Consortium
W.L. Ong, T. Romero, S. Roy, J. Nikitas, D. Joseph, A. Zapatero, S. Malone, S.C. Morgan, M.L. Steinberg,
L.F. Valle, N.G. Zaorsky, T. Martin Ma, M.B. Rettig, N. Nickols, T. Jiang, R.E. Reiter, S.V. Eleswarapu,
X. Maldonado, Y. Sun, P.L. Nguyen, J.L. Millar, J.M. Martin, D.E. Spratt, A.U. Kishan and MARCAP
Consortium Investigators
For men receiving androgen deprivation therapy (ADT), time to testosterone recovery varies
according to baseline testosterone, age, and ADT duration. The relationship between
effective castration period and metastasis-free survival may be nonlinear, with a longer
effective castration period potentially helpful for men receiving 6 mo of ADT.
Transporting Testosterone Home: Navigating the Road to Recovery 58
V. Murthy, A. Dal Pra
Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of 60
the Phase 2 RAIDER Randomised Controlled Trial
R. Huddart, S. Hafeez, C. Griffin, A. Choudhury, F. Foroudi, I. Syndikus, B. Hindson, A. Webster, H. McNair,
A. Birtle, M. Varughese, A. Henry, D.B. McLaren, O. Parikh, A. Nikapota, C. Tang, E. Patel, E. Miles,
K. Warren-Oseni, T. Kron, C. Hill, L. Philipps, C. Vassallo-Bonner, K.C. Cheung, H. Gribble, R. Lewis, E. Hall
Image-guided adaptive radiotherapy allowed bladder tumour radiotherapy dose escalation
without a significant increase in toxicity. The use of multiple adaptive plans suggests an on-
going need for radiotherapy optimisation with adaptive therapy. Dose escalation achieves
promising tumour control with low salvage cystectomy rates.
From a Storm to Sunshine: The Future of Bladder-sparing Therapy is Bright 71
P. Sargos, E. Xylinas, J. Khalifa
Brief Report Long-term Outcomes and Patterns of Relapse Following High-dose Elective 73
Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes
in Prostate Cancer: OLIGOPELVIS (GETUG-P07)
L. Vaugier, C. Morvan, D. Pasquier, X. Buthaud, N. Magné, V. Beckendorf, P. Sargos, G. Crehange,
P. Pommier, G. Loos, A. Hasbini, I. Latorzeff, M. Silva, J. Paul, A. Blanc-Lapierre, S. Supiot
Pelvic radiotherapy offered prolonged tumor control for oligorecurrent prostate cancer in
pelvic lymph nodes, and grade 2+ toxicity remained below 15%. Approximately one-third of
patients were still in complete remission after 5 yr. Para-aortic lymph nodes were the main
sites of relapse.
OLIGOPELVIS and the ‘‘All You Can Eat’’ Strategy for Oligorecurrent Nodal Prostate 77
Cancer: Are We Already Full?
P. Ost, S. Siva, T. Zilli
Sample Site Impacts RNA Biomarkers for Renal Cell Carcinoma 79
L. Eismann, A.X. Xie, C. Tang, A. Knezevic, I. Ostrovnaya, F. Kuo, A. Ari Hakimi, E. Reznik,
R.R. Kotecha
The clinical relevance of gene expression profiles and their association with treatment
outcomes for patients with kidney cancer are significantly impacted by tumor site.
Consideration of tissue site as a variable is needed during RNA biomarker development for
renal cell carcinoma.
Refining the Tissue Source for Biomarker-based Approaches in Renal Cell Carcinoma 84
S.M. Haake, B.I. Rini
 e u r o p e a n u r o l o g y , v o l . 8 7 n o i , J A N UA RY 2 0 2 5

Cutting Edge Sensitive Detection of Urothelial Cancer via High-volume Urine DNA Analysis 86
Communication J. Nikkola, L. Ryyppö, J. Vuorinen, H. Kallio, H. Selin, P. Jämsä, J. Åkerla, T. Virtanen, T. Pekkarinen,
A. Kaipia, J. Pulkkinen, G. Vandekerkhove, D.C. Müller, A.W. Wyatt, P.C. Black, M. Nykter, T. Veitonmäki,
M. Annala

Words of Wisdom Re: International Survey on Urodynamic Investigations in Women Undergoing Stress 89
Urinary Incontinence Surgery
M. Serati, T. Tarcan, E. Finazzi Agrò

Re: Integrative Multi-Region Molecular Profiling of Primary Prostate Cancer in Men 90

with Synchronous Lymph Node Metastasis
R. Goradia, F. Abdollah, A. Sood

Re: Propensity-matched Analysis of Open Versus Robotic Primary Retroperitoneal 91

Lymph Node Dissection for Clinical Stage II Testicular Cancer
A. Ghoreifi, J. Porter, H. Djaladat

Re: Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced 92
Prostate Cancer: Results from the Phase 3 HERO Study
G. Di Lorenzo, C. Buonerba

Re: Long-term Prostate Cancer–specific Mortality After Prostatectomy, Brachyther- 93

apy, External Beam Radiation Therapy, Hormonal Therapy, or Monitoring for Localized
Prostate Cancer
F. Montorsi, M. Longoni, A. Briganti, G. Gandaglia

Re: Metastasis and Recurrence Patterns in the Molecular Subtypes of Urothelial 94

Bladder Cancer
E. Compérat, G. Wasinger, J. Kläger

Letters to the Editor Re: Pieter Vynckier, Lieven Annemans, Sarah Raes, et al. Systematic Review on the Cost e12
Effectiveness of Prostate Cancer Screening in Europe. Eur Urol. 2024;86:400–408
A. Gutiérrez, J.C. Boada, S. Peña

Reply to Andrés Gutiérrez, Julio Cesar Boada, and Sebastián PeñaÕs Letter to the Editor e14
re: Pieter Vynckier, Lieven Annemans, Sarah Raes, et al. Systematic Review on the
Cost-effectiveness of Prostate Cancer Screening in Europe. Eur Urol. 2024;86:400–408
P. Vynckier, L. Annemans, M. Roobol

Re: Niklas Klümper, Viktor Grünwald, Arndt Hartmann, et al. The Role of Microsatellite e15
Instability/DNA Mismatch Repair Deficiency and Tumor Mutational Burden as
Biomarkers in Predicting Response to Immunotherapy in Castration-resistant Prostate
Cancer. Eur Urol. 2025;87:388–390
F. Qi

Reply to Feng QiÕs Letter to the Editor re: Niklas Klümper, Viktor Grünwald, Arndt e17
Hartmann, et al. The Role of Microsatellite Instability/DNA Mismatch Repair Deficiency
and Tumor Mutational Burden as Biomarkers in Predicting Response to Immunother-
apy in Castration-resistant Prostate Cancer. Eur Urol. 2025;87:388–390
N. Klümper, M. Eckstein

Re: Frédéric Panthier, Vineet Gauhar, Eugenio Ventimiglia, Jia-Lun Kwok, Etienne e19
Xavier, Olivier Traxer. Rethinking Stone-free Rates and Surgical Outcomes in
Endourology: A Point of View from PEARLS Members. Eur Urol. 2024;86:198–199
R.L. Sur
 e u r o p e a n u r o l o g y , v o l . 8 7 n o i , J A N UA RY 2 0 2 5

Corrigendum Corrigendum to ‘‘Cabozantinib Plus Nivolumab in Patients with Non–Clear Cell Renal 96
Cell Carcinoma: Updated Results from a Phase II Trial’’ [Eur. Urol. 86(2) (2024) 90–94]
K.N. Fitzgerald, C.-H. Lee, M.H. Voss, M.I. Carlo, A. Knezevic, L. Peralta, Y. Chen, R.A. Lefkowitz, N.J. Shah,
C.N. Owens, D.J. McHugh, D.H. Aggen, A.L. Laccetti, R.R. Kotecha, D.R. Feldman, R.J. Motzer

Corrigendum to ‘‘Impact of Prostate-specific Membrane Antigen Positron Emission 97

Tomography/Computed Tomography on Prostate Cancer Salvage Radiotherapy
Management: Results from a Prospective Multicenter Randomized Phase 3 Trial (PSMA-
SRT NCT03582774)’’ [Eur Urol. 86(1) (2024) 52–60]
W.R. Armstrong, A.U. Kishan, K.M. Booker, T.R. Grogan, D. Elashoff, E.C. Lam, K.J. Clark, M.L. Steinberg,
W.P. Fendler, T.A. Hope, N.G. Nickols, J. Czernin, J. Calais

Congress Calendar Congress Calendar e20

 EUROPEAN UROLOGY 87 (2025) 1–4

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Opinion

Tissue-based Biomarkers Steering Clinical Decisions in Patients with

Urothelial Cancer

Luca Afferi a,b,y,*, Alessia Cimadamore c,y, Andrea Gallioli a, Benjamin Pradere d, Laura S. Mertens e,
Gautier Marcq f,g, Georgia Anguera h, Andrea Necchi i, Alberto Briganti j, Francesco Montorsi j,
Morgan Rouprêt k, Paolo Gontero l, Alberto Breda a, Marco Moschini j, on behalf of the European
Association of Urology Young Academic Urologists Urothelial Carcinoma Working Group
a
Department of Urology, Fundació Puigvert, Barcelona, Spain; b Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland; c Institute of Pathological
Anatomy, Department of Medicine, University of Udine, Udine, Italy; d Department of Urology, UROSUD, La Croix du Sud Hospital, Quint Fonsegrives, France;
e
Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands; f Urology Department, Claude Huriez Hospital, CHU Lille, Lille, France;
g
UMR9020-U1277-CANTHER, Institut Pasteur de Lille, Lille University, Lille, France; h Department of medical oncology, Hospital de la Santa Creu i Sant Pau,
Barcelona, Spain; i Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy; j Department of Urology, San Raffaele
Hospital and Scientific Institute, Milan, Italy; k GRC 5 Predictive Onco-Uro, Department of Urology, Pitie-Salpetriere Hospital, AP-HP, Sorbonne University, Paris,
France; l Department of Urology, Città della Salute e della Scienza, University of Torino School of Medicine, Torino, Italy

Several biomarkers have been investigated in patients with rized in Table 1. On the basis of the latest EAU, NCCN, and
urothelial cancer (UC) but only a few of them have demon- ESMO guidelines, we propose an algorithm indicating which
strated utility in guiding patient selection for specific treat- biomarkers to test for in different surgical and clinical
ments or diagnostic evaluations and are currently used in scenarios (Fig. 1).
clinical practice. Here we provide a practical overview of First, measurement of PD-L1 expression is helpful for
tissue biomarkers currently recommended by international both locally advanced and metastatic UC, as positivity
guidelines that influence the management of patients with may lead to eligibility for monoclonal antibodies to PD-L1
bladder cancer (BCa) and upper tract urothelial cancer (atezolizumab) or PD-1 (pembrolizumab and nivolumab).
(UTUC). The Checkmate 274 phase 3 trial evaluated nivolumab in
We reviewed current recommendations and methods patients with locally advanced UC and a high risk of recur-
endorsed by international guidelines released between Jan- rence after radical surgery [1]. The disease-free survival rate
uary 2022 and April 2024 for biomarker analysis of histo- at 6 mo was 74.9% with nivolumab versus 60.3% with pla-
logical specimens from patients with UC. The 2024 cebo, and 74.5% versus 55.7% in the group of patients with
European Association of Urology (EAU) Guidelines, the a PD-L1 expression level 1%. While the US Food and Drug
2024 National Comprehensive Cancer Network (NCCN) Administration (FDA) approved nivolumab regardless of
clinical practice guidelines, and the 2022 European Society PD-L1 expression, the European Medicines Agency approval
for Medical Oncology (ESMO) guidelines and its interim is only for cases with PD-L1 expression 1%. Thus, the EAU
2024 update met the search criteria. Two authors guidelines recommend PD-L1 measurement before consid-
(L.A. and A.C.) assessed the guidelines independently, with ering administration of nivolumab. Pembrolizumab was
disagreements resolved by a senior author (M.M.). After evaluated in the Keynote-052 phase 2 trial in patients with
full-text review, we identified three biomarkers with a locally advanced or metastatic UC ineligible for cisplatin-
direct impact on patient care: PD-L1, FGFR, and DNA based chemotherapy. Patients with a combined positive
mismatch repair (MMR) proteins. The results are summa- score (CPS) 10 had an objective response rate of 47.3%

* Corresponding author. Department of Urology, Fundació Puigvert, Calle Cartagena, Barcelona, Spain. Tel. +34 604 956523.
E-mail address: [email protected] (L. Afferi).
y
These authors share first authorship.

https://doi.org/10.1016/j.eururo.2024.08.033
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
 2
Table 1Recommendations on the use of molecular biomarkers from selected international oncological guidelines

Guideline and Condition Disease Consequence of Method Antibody Cutoff LoE/ GoR
biomarker positivity category
PD-L1
EAU 2024 High-risk LA UC (pT3–4a, pN+) BCa, Patients might be considered for aITx PD-L1 expression on tumor cells NR 1% expression on tumor cells NR Weak
after RC/NU ± neoadjuvant CTx UTUC with nivolumab on IHC
Advanced/mUC unfit for BCa, Patients are eligible for ATZ (platinum- PD-L1 expression on tumor and/ SP142 ATZ: 5% of tumor area IB Weak
platinum CTx UTUC unfit) or Pembro (cisplatin-unfit) or immune cells on IHC (Ventana) covered by PD-L1-stained
for ATZ TIICs b
Pembro: CPS 10 b
22C3 (Dako)
for Pembro
NCCN 2024 Cisplatin-ineligible treatment- BCa, Patients are eligible for ATZ or Pembro Pembro –

EUROPEAN UROLOGY 87 (2025) 1–4

naïve LA/mUC UTUC 2a
ATZ: 2b
ESMO 2022 Cisplatin-ineligible treatment- BCa, III C
naïve advanced UC UTUC
FGFR
EAU 2024 LA/mUC that progressed BCa, Patients are eligible for erdafitinib FGFR genomic alterations (FGFR3 - Actionable FGFR3 mutations IIA After EV/
following EV/P or PBC UTUC fusion or FGFR2/3 mutation) P: weak
After
PBC:
strong
NCCN 2024 LA/mUC that progressed during BCa, FGFR RGQ RT-PCR kit Susceptible FGFR3 genetic 2a –
or after PBC UTUC alterations c
a
ESMO 2022 Platinum-refractory BCa; BCa, FGFR analysis via PCR, NGS, or Susceptible FGFR3/2 gene III B
relapsed/advanced mUC UTUC gene panels alterations
DNA MMR proteins
EAU 2024 Sporadic UTUC with no suspicion UTUC Germline DNA sequencing for patient MMR positivity on PCR or IHC – – – –
of hereditary UTUC (MLH1, MSH2, MSH6, PSM2)
NCCN 2024 – – – – – – – –
a
ESMO 2022 – – – – – – – –
aITx = adjuvant immunotherapy; ATZ = atezolizumab ; CPS = combined positive score; CTx = chemotherapy; EAU = European Association of Urology; ESMO = European Society for Medical Oncology; EV/P = enfortumab vedotin
+ pembrolizumab; LA = locally advanced; NCCN = National Comprehensive Cancer Network; NGS = next-generation sequencing; PBC = platinum-based CTx; Pembro = pembrolizumab; RC/NU = radical cystectomy or
nephroureterectomy; TIICs = tumor-infiltrating immune cells; UC = urothelial cancer; BCa = bladder cancer; mUC = metastatic UC; UTUC = upper tract UC; MMR = mismatch repair; NR = not reported; IHC = immunohis-
tochemistry; CPS = combined positive score; GoR = grade of recommendation; LoE = level of evidence; RT-PCR = reverse transcription-polymerase chain reaction.
a
And interim 2024 update.
b
Recommendations on cutoffs and antibodies are from the European Medicines Agency.
c
Testing should only be performed in laboratories with Clinical Laboratory Improvement Amendments of 1988 certification.
 EUROPEAN UROLOGY 87 (2025) 1–4 3

Fig. 1 – Proposed algorithm for analysis of tissue-based biomarkers in patients with urothelial cancer according to the surgical and clinical scenario. TURBT =
transurethral resection of bladder tumor; MMR = mismatch repair. * According to the modified Amsterdam II criteria.

(95% confidence interval 37.7–57%), in comparison to 20.3% zolizumab; CPS 10 for pembrolizumab) as an alternative
(95% confidence interval 15.5–25.8%) for those with a CPS to best supportive care. This restriction was issued in
<10. Thus, testing of formalin-fixed tumor samples for PD- 2018 on the basis of preliminary results from Keynote-361
L1 expression is recommended by the latest EAU, NCCN, and IMvigor130, two open-label phase 3 trials evaluating
and ESMO guidelines for patients with cisplatin-ineligible pembrolizumab and atezolizumab, respectively, in previ-
advanced or metastatic UC. Both pembrolizumab or ate- ously untreated patients with locally advanced or meta-
zolizumab are indicated only in platinum-ineligible patients static UC, as patients with low PD-L1 expression in the
with PD-L1 positivity (immune cell score 5% for ate- monotherapy arms had adverse outcomes [2,3].
4 EUROPEAN UROLOGY 87 (2025) 1–4

Second, testing for FGFR alterations is indicated in locally In conclusion, it is uniformly recommended that physi-
advanced and unresectable or metastatic UC previously cians request analysis of PD-L1 expression and FGFR alter-
treated with systemic chemotherapy or ineligible for cis- ations in tumor specimens from patients with advanced
platin. The BLC2001 phase 2 trial enrolled patients with UC, as the expression of these biomarkers dictates eligibility
FGFR2/3 alterations or fusions and found that overall sur- for systemic therapies. This analysis should be performed in
vival was independent of the type of genetic alteration; dis- selected patients using recommended platforms and tech-
ease control was achieved in 80% of patients [4]. In April niques. Analysis of tumor tissue for MMR alterations for
2019, the FDA granted accelerated approval to erdafitinib patients with UTUC remains a matter of debate, and the
for patients with locally advanced or metastatic UCs with presence of such alterations should prompt genetic screen-
FGFR3/2 alterations who had progressed on platinum- ing for Lynch syndrome.
based chemotherapy. The EAU, NCCN, and ESMO guidelines
recommend performing FGFR testing to determine eligibil- Conflicts of interest: The authors have nothing to disclose.
ity for erdafitinib; the NCCN and ESMO guidelines specify
that a companion FGFR reverse transcription-polymerase Acknowledgements: Luca Afferi is supported by the European Urological
chain reaction (RT-PCR) kit (Therascreen FGFR kit, Qiagen) Scholarship Programme.
should be used. Since none of the six patients harboring
an FGFR2 fusion in the trial showed an objective response, References
the EAU and NCCN guidelines recommend erdafitinib only
for patients with susceptible FGFR3 genetic alterations. [1] Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab
versus placebo in muscle-invasive urothelial carcinoma. N Engl J
Third, alterations in MMR proteins could be helpful in Med 2021;384:2102–14. https://doi.org/10.1056/NEJMoa2034442.
identifying patients with Lynch syndrome. Patients should [2] US Food and Drug Administration. FDA alerts health care
be selected for genetic analysis according to the modified professionals and oncology clinical investigators about an efficacy
Amsterdam II criteria and molecular testing. The EAU guide- issue identified in clinical trials for some patients taking Keytruda
(pembrolizumab) or Tecentriq (atezolizumab) as monotherapy to
lines propose germline DNA sequencing in patients with no treat urothelial cancer with low expression of PD-L1. https://www.
suspicion of hereditary UTUC if the tumor tissue exhibits fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-
loss of expression of any of four MMR proteins (MLH1, professionals-and-oncology-clinical-investigators-about-efficacy-
issue.
MSH2, MSH6, and PSM2), assessed via either immunohisto-
[3] European Society for Medical Oncology. EMA restricts use of
chemistry or PCR. Data supporting this approach are limited pembrolizumab and atezolizumab in bladder cancer. https://
and the EAU guidelines do not provide a level of evidence www.esmo.org/oncology-news/archive/ema-restricts-use-of-
for this recommendation. Therefore, it remains at the dis- pembrolizumab-and-atezolizumab-in-bladder-cancer.
[4] Siefker-Radtke AO, Necchi A, Park SH, et al. Efficacy and safety of
cretion of the clinician to determine which patients with erdafitinib in patients with locally advanced or metastatic
sporadic UTUC are eligible for this analysis. urothelial carcinoma: long-term follow-up of a phase 2 study.
There are new potential biomarkers in the pipeline. The Lancet Oncol 2022;23:248–58. https://doi.org/10.1016/S1470-2045
(21)00660-4.
DESTINY-PanTumor02 phase 2 trial demonstrated a durable
[5] Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of
clinical benefit with transtuzumab deruxtecan in patients trastuzumab deruxtecan in patients with her2-expressing solid
with locally advanced or advanced solid tumors, including tumors: primary results from the DESTINY-PanTumor02 phase II
BCa, and high expression of HER2 [5]. This finding led to trial. J Clin Oncol 2024;42:47–58. https://doi.org/10.1200/
JCO.23.02005.
accelerated FDA approval of transtuzumab deruxtecan for [6] US Food and Drug Administration. FDA grants accelerated approval
patients with unresesectable or metastatic HER2-positive to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic
solid tumors [6]. Moreover, two phase 2 trials evaluating HER2-positive solid tumors. FDA. Published online April 5, 2024.
disitamab vedotin, another HER2-targeted agent, reported Accessed June 27, 2024. https://www.fda.gov/drugs/resources-
information-approved-drugs/fda-grants-accelerated-approval-fam-
median overall survival of 14.2 mo for patients with locally trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2.
advanced or metastatic BCa [7]. Thus, expression of HER2 in [7] Sheng X, Wang L, He Z, et al. Efficacy and safety of disitamab
tumor tissue might become an important histological bio- vedotin in patients with human epidermal growth factor receptor
2-positive locally advanced or metastatic urothelial carcinoma: a
marker in the near future. Moreover, oral and intravesical
combined analysis of two phase II clinical trials. J Clin Oncol
FGFR inhibitors are being evaluated in patients with 2024;42:1391–402. https://doi.org/10.1200/JCO.22.02912.
intermediate- or high-risk non–muscle-invasive BCa and [8] Catto JWF, Tran B, Rouprêt M, et al. Erdafitinib in BCG-treated high-
susceptible FGFR alterations [8,9], potentially opening up risk non-muscle-invasive bladder cancer. Ann Oncol
2024;35:98–106. https://doi.org/10.1016/j.annonc.2023.09.3116.
alternative treatment options for a setting in which intrav- [9] Janssen Research & Development, LLC. A study to evaluate TAR-210
esical chemotherapy and immunotherapy have been the versus single agent intravesical cancer treatment in participants
mainstay of treatment for the past decades. Of note, enfor- with bladder cancer. https://clinicaltrials.gov/study/NCT06319820.
[10] Lopez-Beltran A, Cookson MS, Guercio BJ, Cheng L. Advances in
tumab vedotin and sacituzumab govitecan, targeting the
diagnosis and treatment of bladder cancer. BMJ 2024;384:e076743.
cell-surface proteins NECTIN4 and TROP2, respectively, do https://doi.org/10.1136/bmj-2023-076743.
not require assessment of NECTIN4 and TROP2 expression
for therapy selection [10].
 EUROPEAN UROLOGY 87 (2025) 5–7

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Opinion – EAU Guidelines View

Standard Repeat Biopsies During Active Surveillance for Prostate

Cancer: Are They Necessary in the Magnetic Resonance Imaging Era?

Roderick C.N. van den Bergh a,*, Ivo G. Schoots b,c, Philip A. Cornford d, on behalf of the European
Association of Urology Prostate Cancer Guidelines Panel
a
Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands; b Department of Radiology and Nuclear Medicine, Erasmus
University Medical Center, Rotterdam, The Netherlands; c Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands; d Department
of Urology, Liverpool University Hospitals NHS Trust, Liverpool, UK

1. Active surveillance in the magnetic resonance not require a confirmatory biopsy [5]. Considering the
imaging era improved concordance in GG assignment between targeted
biopsy and prostatectomy specimens, the indication for
When active surveillance (AS) for prostate cancer (PCa) was standard confirmatory biopsy before starting AS seems lim-
introduced as an alternative to active treatment, the diag- ited in comparison to diagnosis based on systematic biopsy.
nostic algorithm consisted of prostate-specific antigen However, repeat biopsy every 2–3 yr is still recom-
(PSA) measurement and/or digital rectal examination mended, as histopathological assessment is most closely
(DRE) followed by sextant systematic biopsies. Several associated with true tumour status and represents the most
prospective AS studies have shown favourable long-term objective criterion for AS (dis)continuation [6,7]. Therefore,
oncological outcomes using these classic eligibility criteria treatment decisions should predominantly be based on
[1]. histopathological progression rather than on rising PSA
Different novel diagnostic tools have become available levels or even progressive features on imaging [6]. However,
since then. Risk calculators and magnetic resonance imag- real-life data show underutilisation of repeat prostate biop-
ing (MRI) have reduced the number of unnecessary biop- sies in clinical practice [8].
sies. MRI also altered the biopsy core strategy by allowing The aim of protocol-directed repeat biopsy during AS is
targeting of the most abnormal areas. In men who undergo timely detection of pathological progression or compensa-
biopsy, this targeted-cores strategy optimises detection but tion for potential previous undersampling, but its value
also results in a grade shift [2]. Men with International Soci- may be variable and results can be difficult to interpret cor-
ety of Urological Pathology grade group (GG) 1 disease on rectly. A standard protocol for repeat biopsy does not con-
systematic biopsy are now being classified as having a sider the differences in risk and resulting ‘‘number needed
higher GG, while harbouring the exact same tumour previ- to biopsy’’ (NNB) to find one additional significant PCa. As
ously considered appropriate for AS [3]. This increases the a comparison, the EAU guidelines recommend no biopsy
risk of overtreatment, as urologists remain concerned that in the primary diagnostic setting for groups with a risk of
GG 2 disease with otherwise favourable characteristics is <10% for GG 2 cancer (3–8%) [6].
clinically significant on the basis of historical data [4]. The definition of upgrading has also changed, as the eli-
gibility criteria for AS have expanded in response to the
grade shift due to MRI targeted cores, and now also include
2. Standard repeat biopsy
GG 2 PCa with otherwise favourable characteristics. There-
fore, it seems counterintuitive to use GG 2 as a relevant end-
The DETECTIVE study led to consensus that men eligible for
point in AS studies. GG 3 may be a more appropriate
AS after combined systematic and MRI-targeted biopsy do

* Corresponding author. Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
E-mail address: [email protected] (R.C.N. van den Bergh).

https://doi.org/10.1016/j.eururo.2024.09.014
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
6 EUROPEAN UROLOGY 87 (2025) 5–7

endpoint. The number of previous biopsy sessions may owing to the altered recommendation on biopsy strategy
also be considered, as taking more biopsy cores from the in the primary diagnostic setting. However, there is no
prostate will by definition increase the risk of finding higher evidence showing that changes in imaging alone should
GG, but concurrently reduces the likeliness that this is a rel- direct active therapy without histopathological evidence
evant finding because of repeat testing bias. Tumours of progression.
upgraded during follow-up therefore have more favourable
outcomes than tumours with a similar GG detected at initial 4. Risk stratification for repeat biopsy
biopsy, as a higher cumulative number of cores was
required before this GG was detected [9]. During follow-up, repeat biopsy at least every 2–3 yr is still
Finally, the timing of finding higher-risk disease during recommended. Besides novel imaging-based predictors of
AS should be considered. A limited delay in detecting signif- upgrading, such as changes on MRI, classic baseline vari-
icant disease is unlikely to cause additional unfavourable ables remain important in predicting the course of the dis-
outcomes among men with such initial favourable disease ease. PSA density is one of the strongest predictors and
characteristics. Even a delay in definitive surgery of up to often has predictive value, particularly when used in combi-
>12 mo after upgrading to GG 2 was not associated with nation with imaging. Besides PSA density and MRI morpho-
recurrent disease [10]. logical kinetics, other factors associated with low
progression rates include slowly rising PSA and previous
3. MRI changes during AS negative repeat biopsy. The combination of favourable low
PSA density at baseline and stable or regressing disease
It is well accepted that high-quality MRI predicts the pres- (PRECISE score of 1–3) on MRI during follow-up therefore
ence of clinically significant PCa [2]. Although standard identifies a very favourable group [14]. Here, the NNB to
serial MRI is not yet recommended in the EAU guidelines, find one relevant case may not justify standard repeat
one could extrapolate that MRI would also allow early biopsy. The EAU guidelines therefore contain a weak recom-
detection of an aggressive cancer in men undergoing AS. mendation that serial MRI can be used to identify men for
The frequency of MRI may follow the elected repeat biopsy whom standard repeat biopsy may be omitted as they have
schedule, which should at least not be less than the mini- a very low risk of pathological upgrading at standard repeat
mum 2–3-yr interval used in protocols such as PRIAS, with biopsy (low-risk PCa, stable MRI PRECISE score of 1–3, and a
a higher frequency to be considered in cases with relative stable and low PSA density of <0.15 ng/ml/cm3).
risk factors. The higher the threshold for defining upgraded
disease, the better the ‘‘rule-out’’ performance of MRI 5. Future challenges
changes during AS. A review by Rajwa et al [11] showed that
use of MRI progression as an indication for repeat biopsy Additional challenges arise when moving towards a more
resulted in sensitivity of 0.587, specificity of 0.750, a posi- individualised and imaging-based AS strategy. Quality
tive predictive value (PPV) of 0.496, and a negative predic- issues as encountered in the diagnostic setting may be even
tive value (NPV) of 0.848 for upgrading (GG 2–5). MRI- more relevant for AS follow-up. The frequent repeat MRI
based AS would avoid repeat biopsy in up to 68% of patients, scans and comparison with previous scans during follow-
while missing 12% of PCa progression cases. Using the more up may have an important impact on imaging capacity.
relevant GG 3–5 as the endpoint, the sensitivity, specificity, Implementation of MRI-based repeat biopsy instead of stan-
PPV, and NPV were 0.695, 0.619, 0.134, and 0.954 respec- dard repeat biopsy may therefore differ by country and cen-
tively. The good NPV (considering low prevalence) may be tre. The definition of significant PCa and the point at which
particularly relevant for selected patients with a low risk to stop AS, especially given the grade shift caused by MRI-
of upgrading. targeted biopsy, have not been fully established. Dynamic
The information obtained via MRI during AS may be opti- surveillance may further optimise prediction of outcomes
mised using standardised PRECISE (Reporting Prostate Mag- [15]. Finally, with the lower risk of infectious complications
netic Resonance Imaging in Patients on Active Surveillance with transperineal biopsy in comparison to a transrectal
for PCa) scores. A consensus statement emphasised the biopsy approach, the incentive to avoid biopsy may have
importance of a quality standard for scans, that all previous decreased.
scans need to be taken into account, that the PRECISE score AS remains an important tool in efforts to decrease
is the highest score for any lesion, and that lesion visibility overtreatment of PCa. Eligibility for AS should be expanded,
is an important factor in a PRECISE score of 3 [12]. Gaps in while minimising the burden of follow-up at the same time,
knowledge on how to measure tumour size and on the def- exploiting the possibilities of modern diagnostics. In mod-
inition of a significant size increase were also identified. ern practice, prostate biopsy should be preceded by MRI,
There was also consensus that changes on repeat MRI dur- and if MRI findings remain unchanged in combination with
ing AS should not be used to change management strategy, favourable characteristics such as PSA density, discussion
but rather should trigger a confirmatory biopsy before con- with the patient regarding the relative risks and benefits
sidering active treatment [13]. It could make sense to use of repeat biopsy should be considered.
MRI lesion-diameter thresholds or the occurrence of addi-
tional lesions confirmed to harbour GG 2 PCa as surrogates Conflicts of interest: Roderick C.N. van den Bergh is a consultant for
for treatment indication, especially since the percentage of Astellas and Amgen; has received speaker honoraria from MSD and
positive systematic biopsy cores is no longer available Ipsen; has participated in trials for Janssen; and has received research
 EUROPEAN UROLOGY 87 (2025) 5–7 7

grants from Astellas and Janssen. Philip Cornford has received honoraria [7] Willemse PM, Davis NF, Grivas N, et al. Systematic review of active
or consultation fees from Accord Healthcare, Bayer UK, Bristol-Myers surveillance for clinically localised prostate cancer to develop
recommendations regarding inclusion of intermediate-risk
Squibb, and Janssen Cilag, and speaker honoraria from AstraZeneca
disease, biopsy characteristics at inclusion and monitoring, and
and Ipsen Biopharm. Ivo G. Schoots has nothing to disclose. surveillance repeat biopsy strategy. Eur Urol 2022;81:337–46.
[8] Olsson H, Nordström T, Clements M, Grönberg H, Lantz AW, Eklund
M. Intensity of active surveillance and transition to treatment in
Funding/Support and role of the sponsor: This work was supported by men with low-risk prostate cancer. Eur Urol Oncol 2020;3:640–7.
the European Association of Urology. The sponsor played a role in collec- [9] Perera M, Jibara G, Tin AL, et al. Outcomes of grade group 2 and 3
tion and management of the data, and preparation and review of the prostate cancer on initial versus confirmatory biopsy: implications
for active surveillance. Eur Urol Focus 2023;9:662–8.
manuscript.
[10] Shee K, Cowan JE, Washington SL, et al. The impact of delayed
radical prostatectomy on recurrence outcomes after initial active
References surveillance: results from a large institutional cohort. Eur Urol
Oncol 2024;7:838–43.
[1] Newcomb LF, Schenk JM, Zheng Y, et al. Long-term outcomes in [11] Rajwa P, Pradere B, Quhal F, et al. Reliability of serial prostate
patients using protocol-directed active surveillance for prostate magnetic resonance imaging to detect prostate cancer progression
cancer. JAMA 2024;331:2084–93. during active surveillance: a systematic review and meta-analysis.
[2] Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or Eur Urol 2021;80:549–63.
standard biopsy for prostate-cancer diagnosis. N Engl J Med [12] Englman C, Maffei D, Allen C, et al. PRECISE version 2: updated
2018;378:1767–77. recommendations for reporting prostate magnetic resonance
[3] Weinstein IC, Wu X, Hill A, et al. Impact of magnetic resonance imaging in patients on active surveillance for prostate cancer. Eur
imaging targeting on pathologic upgrading and downgrading at Urol, in press. https://doi.org/10.1016/j.eururo.2024.03.014.
prostatectomy: a systematic review and meta-analysis. Eur Urol [13] Moore CM, King LE, Withington J, et al. Best current practice and
Oncol 2023;6:355–65. research priorities in active surveillance for prostate cancer—a
[4] Ploussard G, Manceau C, Beauval JB, et al. Decreased accuracy of the report of a Movember international consensus meeting. Eur Urol
prostate cancer EAU risk group classification in the era of imaging- Oncol 2023;6:160–82.
guided diagnostic pathway: proposal for a new classification based [14] O’Connor LP, Wang AZ, Yerram NK, et al. Changes in magnetic
on MRI-targeted biopsies and early oncologic outcomes after resonance imaging using the Prostate Cancer Radiologic Estimation
surgery. World J Urol 2020;38:2493–500. of Change in Sequential Evaluation criteria to detect prostate cancer
[5] Lam TBL, MacLennan S, Willemse PM, et al. EAU-EANM-ESTRO- progression for men on active surveillance. Eur Urol Oncol
ESUR-SIOG Prostate Cancer Guideline Panel consensus statements 2021;4:227–34.
for deferred treatment with curative intent for localised prostate [15] Sushentsev N, Abrego L, Colarieti A, et al. Using a recurrent neural
cancer from an international collaborative study (DETECTIVE network to inform the use of prostate-specific antigen (PSA) and
study). Eur Urol 2019;76:790–813. PSA density for dynamic monitoring of the risk of prostate cancer
[6] Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO- progression on active surveillance. Eur Urol Open Sci
ESUR-ISUP-SIOG guidelines on prostate cancer—2024 update. Part I: 2023;52:36–9.
screening, diagnosis, and local treatment with curative intent. Eur
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 EUROPEAN UROLOGY 87 (2025) 8–14

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Opinion

Clinical Implications of Basic Research: Exploring the

Transformative Potential of Spatial ’Omics in Uro-oncology

Sandy Figiel a, Anthony Bates b, David A. Braun c, Renu Eapen d, Markus Eckstein e,
Brandon J. Manley f, Matthew I. Milowsky g, Tom J. Mitchell h, Richard J. Bryant a,b,
John P. Sfakianos i, Alastair D. Lamb a,b,*
a
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; b Department of Urology, Oxford University Hospitals NHS Foundation Trust,
Oxford, UK; c Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA; d Department of Genitourinary
Oncology & Division of Cancer Surgery, Peter MacCallum Cancer Centre, The University of Melbourne, Victoria, Australia; e Institute of Pathology, University
Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg & Bavarian Cancer Research Center (BZKF), Erlangen, Germany; f Department of
Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA; g Department of Medicine, University of North Carolina, Chapel Hill, NC, USA; h Early
Detection Centre, University of Cambridge, Cambridge, UK; i Department of Urology, Ichan School of Medicine at the Mount Sinai Hospital, New York, NY, USA

Article info Abstract

Article history: New spatial molecular technologies are poised to transform our understanding and
Accepted August 16, 2024 treatment of urological cancers. By mapping the spatial molecular architecture of
tumours, these platforms uncover the complex heterogeneity within and around indi-
Associate Editor: vidual malignancies, offering novel insights into disease development, progression, diag-
Laura Bukavina nosis, and treatment. They enable tracking of clonal phylogenetics in situ and immune-
cell interactions in the tumour microenvironment. A whole transcriptome/genome/pro
Keywords: teome-level spatial analysis is hypothesis generating, particularly in the areas of risk
Genomics stratification and precision medicine. Current challenges include reagent costs, harmon-
Transcriptomics isation of protocols, and computational demands. Nonetheless, the evolving landscape of
Proteomics the technology and evolving machine learning applications have the potential to over-
Urological cancer come these barriers, pushing towards a future of personalised cancer therapy, leveraging
detailed spatial cellular and molecular data.
Patient summary: Tumours are complex and contain many different components.
Although we have been able to observe some of these differences visually under the
microscope, until recently, we have not been able to observe the genetic changes that
underpin cancer development. Scientists are now able to explore molecular/genetic dif-
ferences using approaches such as ‘‘spatial transcriptomics’’ and ‘‘spatial proteomics’’,
which allow them to see genetic and cellular variation across a region of normal and
cancerous tissue without destroying the tissue architecture. Currently, these technolo-
gies are limited by high associated costs, and a need for powerful and complex compu-
tational analysis workflows. Future advancements and results through these new

* Corresponding author. Nuffield Department of Surgical Sciences, University of Oxford, Old Road
Campus Research Building, Oxford OX3 7DQ, UK. Tel. +44 7779 593099.
E-mail address: [email protected] (A.D. Lamb).

https://doi.org/10.1016/j.eururo.2024.08.025
0302-2838/Ó 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
 EUROPEAN UROLOGY 87 (2025) 8–14 9

technologies may assist patients and their doctors as they make decisions about treating
their cancer.
Ó 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association of
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).

1. Introduction tial proteomics, each offering unique advantages and

insights into tumour biology (Table 1).
Albert Einstein famously said: ‘‘Look deep into nature, and Spatial-omics technologies can be classified into two cat-
then you will understand everything better’’, and although egories: sequencing-based technologies (which includes
he wrote this 2 yr before Francis Crick and James Watson probe-based approaches) and imaging-based technologies
[1] discovered DNA, he may well have had genes in mind. (Fig. 1A). Sequencing-based technologies, such as spatial
While we have undoubtedly achieved ‘depth’ in under- transcriptomics, rely on capturing RNA transcripts and
standing the genetic composition of tumours, it has been using high-throughput sequencing to profile a select panel
difficult to actually ‘look’ at the genetic nature of tissue of genes or the whole transcriptome. Probe-based
because techniques have required tissue destruction to per- approaches are similar but employ oligonucleotide probes
mit a genetic analysis. The advent of spatial molecular tech- to target specific sequences within cells or tissues, which
nologies has changed this. are then ligated and sequenced. These sequencing
Spatial-omics refers to a set of methodologies aimed at approaches use spatially unique barcodes to reconstruct
providing spatially resolved molecular information within the precise spatial coordinates of each gene within the tis-
tissues [2,3]. It offers insights into the intricate heterogene- sue sample. Imaging-based technologies, including both
ity of tumours, where different regions exhibit distinct spatial proteomics and versions of spatial transcriptomics,
molecular profiles. Traditional bulk sequencing methods rely on fluorescence in situ hybridisation, where a fluo-
or laser-capture microdissection, while valuable, often fails rophore tagged molecule binds to either a short sequence
to capture the full complexity of tumours. These methods of RNA or an amino acid epitope. This enables simultaneous
provide an incomplete picture of the tumour landscape, detection of several biomolecules in tissue samples, elimi-
hindering our understanding of molecular complexity, pro- nating the need for sequencing while providing comprehen-
gression, and lethality. sive spatial information. Although fluorescence in situ
This is particularly relevant in the realm of urological hybridisation (FISH) permits spatial visualisation of single
cancer biomedical research, where tumour heterogeneity gene copies, as yet there are no multigene spatial DNA
alongside a poor understanding of the natural history of approaches. Nonetheless, spatial genomic status including
cancers has limited our ability to progress in the areas of copy number alternations (CNAs) can be inferred from spa-
screening, risk stratification, and the development of per- tial transcriptomics [8,24].
sonalised molecular therapies [4–6]. The use of spatial- Overall, each spatial-omics platform has its own
omics techniques presents an opportunity to delve deeper strengths and weaknesses, with variations in sensitivity,
into the intricate molecular architecture of urological can- resolution, throughput, and cost (Table 1). These platforms
cers, potentially revolutionising our understanding of dis- can also be combined into multi-omics approaches where
ease development, prognosis, and treatment selection. The the combined yield in information is greater than the sum
purpose of this article is to explore spatial-omics as an of the parts. Researchers should carefully consider these
investigative technique in urological cancers, highlight the factors when selecting the most suitable platform, or com-
key pieces of work in the field, and draw upon the conclu- bination of platforms, for their specific experimental needs.
sions of the growing literature in this area. From our over-
view of the ’omics landscape, we will suggest future 3. Clinical implications and opportunities provided by
directions for the uro-oncology fields of screening, diagnos- omics technologies
tics, and targeted treatment.
3.1. Enhancing screening and risk stratification

Current screening modalities for urological cancers often

2. Spatial-omics methodologies rely on serum biomarkers, imaging studies, and tissue biop-
sies, which may have limitations in terms of sensitivity and
Spatial-omics methodologies encompass a range of cutting- specificity [9–12]. The highly resolved characterisation of
edge techniques enabling the visualisation and analysis of tumours using spatial-omics data facilitates the spatial
molecular information within tissues at various spatial res- localisation of molecular alterations associated with disease
olutions. In contrast with traditional bulk tissue methods, progression. It enables translational researchers to identify
these approaches offer a comprehensive understanding of patterns of gene expression or protein signatures related
the spatial organisation of cellular components and their to tissue regions in early-stage disease with the potential
molecular profiles within a heterogeneous tumour microen- for lethality. Spatial-omics therefore offers novel screening
vironment such as urological tumours [7]. These techniques tools specifically focussed on survival, while also facilitating
include spatial transcriptomics, spatial genomics, and spa- risk stratification in the postdiagnostic space, minimising
10 EUROPEAN UROLOGY 87 (2025) 8–14

Table 1 – An overview of spatial-omics methods and platforms

Platform Omics Method Sample Resolution Coverage Cost# Pros Cons Ref
type
Visium, 10X genomics RNA Sequenced- FF, FFPE FF/FFPE: 18 000 + +++ + Whole - Requires careful [35]
based, 55 lm transcriptome sample preparation
probe- HD: 8 lm + Little specialised - Limited sensitivity
based equipment required for low-abundance
+ High number of transcripts
reads per ROI - Data storage &
bioinformatics needs
Slide-seq/Slide-seq V2 RNA Sequenced- FF, FFPE 10 lm 18 000 + + + Whole - Low RNA capture [36]
based transcriptome efficiency
- Low number of reads
per ROI
Xenium, 10X genomics RNA Image- FF, FFPE Subcellular 100 +++ + High sensitivity - Limited number of [37]
based + Lower false genes profiled
discovery rate (FDR) - Requires specialised
equipment
- Relatively low
throughput compared
to sequencing-only
approaches
GeoMx DSP, RNA, Probe- FF, FFPE 10 lm 18 000 + ++ + Whole - Need to select region [38,39]
NanoString protein based transcriptome of interest
Technologies + Protein co- - Requires specialised
detection equipment
- Low number of reads
per ROI
MERSCOPE, Vizgen RNA, Image- FF, FFPE Subcellular 1 000 ++ + High RNA capture - Limited number of [40]
protein based efficiency genes profiled
+ Protein co- - Requires specialised
detection equipment
- Low signal-to-
background ratio
CosMx SMI, NanoString RNA, Image- FF, FFPE Subcellular 600 / 6K +++ + Number of genes - Workflow requires [41]
Technologies protein based assayed compared multiple data
to others image- processing steps and a
based technology specialised equipment
+ Protein co- - Lack of field of view
detection stitching
- Bioinformatics needs
(CoxMx 6K)
Phenocycler, Akoya Protein Image- FF, FFPE Single cell 100 +++ + Faster imaging, - Custom modification [42]
Biosciences based shorter cycles of each antibody and
extensive
optimisation.
- Requires specialised
instrument
Cell DIVE, Leica Protein Image- FF, FFPE Single cell 21 + + Use of a - Slower cycles [43]
Microsystems based commercially - Requires specialised
available antibody instrument

IMC & MIBI Protein, Image- FF, FFPE 1 lm for 50 +++ + Metabolites -Heavy [44,45]
metabolites based, MCI IMC detection instrumentation
300 nm for + Higher resolution,
MIBI higher sensitivity
compared to MSI

MSI Protein, Image- FF, FFPE 10 lm 2 000 +++ + Quantitative - Decreased sensitivity [46]
metabolites based, MSI antibody-free for protein > 15 kDa
approach - Heavy
+ Metabolites instrumentation
detection - Non standardised
+ Greater coverage workflow
compared to MCI
DSP = digital spatial profiler; FF = freshly frozen; FFPE = formalin-fixed paraffin embedded; HD = high definition; IMC = imaging mass cytometry; MCI = mass
cytometry imaging; MIBI = multiplexed ion beam imaging; MSI = mass spectrometry imaging; Ref = reference; ROI = region of interest; SMI = spatial molecular
imager.
#
Cost range: + = < £100; ++ = £100-£1000 +++ = >£1000 per sample

overtreatment while ensuring timely management of high- oncology, with the potential to bridge the gap between
risk cases. imaging diagnostics and molecular medicine [13–16].
Radiogenomics, a burgeoning field within cancer While radiogenomics has predominantly relied on bulk
research, represents a paradigm-shifting approach in uro- genomics datasets [17–19], the advent of spatial-omics
 EUROPEAN UROLOGY 87 (2025) 8–14 11

A. Spatial technologies
Sequencing based Library preparation
Barcoded oligo-coated slides Data visualisation
& Next gen sequencing

A
Tissue RNA
T
AA TT
Slide barcodes

ST spot

25µM

Imaging based
Fluorophore-tagged probes Fluorescent imaging Data visualisation

Fluorescent
ISH
probes

Cycle

2.5µM

B. Applications
Local therapy Multimodal therapy Systemic / Chemotherapy

Detection of ‘lethal’ clone Neoantigen identification Companion diagnostic

to inform risk stratification to intensify multimodal local therapy to optimise selection of systemic therapy

Cancer marker A
Immune cells
Tumour Burden
(e.g. PSA level)

Cancer marker B
Immune cells

Cancer marker C
Immune cells

Lethal clone

Radical local therapy Salvage therapy Time (years)

Fig. 1 – (A) Spatial-omics technologies can broadly be divided into sequencing- and imaging-based approaches. Sequencing-based methods use slides coated
with barcoded oligonucleotides. These ‘‘oligos’’ have poly-T tails that capture the poly-A 30 end of RNA transcripts present across the tissue. The resulting
barcoded transcript is then profiled using next-generation sequencing. Probe-based techniques are similar but involve an extra step where oligonucleotide
probes, which bind to gene-specific sequences, are added before annealing to the barcoded slide. Imaging-based approaches use fluorescence in situ
hybridisation (ISH) to detect multiple biomolecules simultaneously. Multiple cycles are required in coordinated combinations to distinguish between many
transcripts. (B) Spatial-omics technologies could have transformative impact throughout the natural history of urological cancers. This includes optimisation
of diagnostic strategies, risk stratification, selection of local treatment options, approach to recurrence and salvage therapy, and identification of companion
diagnostic tests and therapeutic targets in advanced metastatic disease. Next gen sequencing = next-generation sequencing; PSA = prostate-specific antigen.

technology introduces the possibility to uncover unique with specific gene and protein expression patterns charac-
radiographic signatures associated with underlying molecu- teristic of aggressive disease phenotypes. This could be
lar alterations in urological cancers, which could then be the key to unlock efficacy in proposed international screen-
developed as noninvasive biomarkers. For instance, multi- ing mandates, providing meaningful alternatives to
parametric features such as lesion shape, signal intensity, prostate-specific antigen, imaging, and germline genetics
diffusion, vascularity, and metabolic activity may correlate [20,21].
12 EUROPEAN UROLOGY 87 (2025) 8–14

3.2. Unravelling intratumoral heterogeneity to focus on by inflammation macrophages, thus identifying a potential
lethality immune-therapeutic target to prevent cancer cell invasion
in renal cell cancer.
Intratumoral heterogeneity remains a confounding feature
There is a growing trend towards integrating an extra
of urological cancers [22]. This is particularly relevant for
layer of spatial-omics data by combining transcriptomics
primary prostate cancer. In 2023, the Oxford Prostate Biol-
with spatial proteomics. In bladder cancer, this integrated
ogy Group reanalysed spatial transcriptomic data to create
approach has unveiled a novel cell population, presenting
virtual prostate biopsies [23], highlighting the impact that
an exciting avenue for patient stratification and facilitating
disease heterogeneity could have on prognostic signatures
treatment decision-making [32–34]. As an example, ele-
applied to a bulk analysis of diagnostic prostate biopsies.
vated CDH12 expression levels are associated with a poorer
This work demonstrated how spatial transcriptomics pro-
outcome in patients undergoing surgery or chemotherapy,
vides information on intratumoral heterogeneity not visible
while also being associated with higher immunotherapy
through conventional histological profiling, raising ques-
response rates [32].
tions about the accuracy of applying transcript-based geno-
mic signatures to the bulk analysis of tumour biopsies. In
the future, this might include radiohistogenomic signatures
4. Challenges and future directions
or artificial intelligence–driven image interpretation, with
models derived from omics data integrated with conven-
tional histopathology and cross-sectional imaging. Spatial-omics technologies are labour intensive and expen-
Spatial-omics methodologies can facilitate the recon- sive, and there is no indication, currently, that these would
struction of evolutionary trajectories within tumours, shed- be cost effective or practical in the clinical setting. To over-
ding light on the dynamic nature of cancer progression and come hurdles in cost and big data handling, we will need
treatment response. Mapping these molecular changes ‘windows’ into the complex and highly resolved deductions
allows researchers to identify and track specific cell popula- from omics technologies. Such windows could include use
tions, and understand their development and spread of ‘liquid biopsies’ with identification of circulating tumour
[24,25]. These insights are invaluable for understanding cells or ctDNA indicative of potential lethality. Alternatively,
the evolution of cancers and emergence of drug-resistant we currently ignore a wealth of untapped molecular data in
cellular interactions or tumour clones, predicting disease cross-sectional imaging, and perhaps, magnetic resonance
recurrence and designing targeted therapeutic interven- imaging (MRI) correlates of spatial omics could improve
tions tailored to individual tumour subpopulations (Fig. 1B). the already excellent performance of multiparametric MRI
to predict higher-grade prostate cancer. A further window
into such technologies will come from machine learning,
3.3. Exploring tumour microenvironment dynamics to with computational power applied rigorously to large and
explain cancer phenotypes
highly annotated datasets. A key feature of spatial-omics
Urological cancers have variable immune activity, with con- is the number of tiles or regions of interest that can be gen-
sequent variable success of immune pathway modulators erated and linked to molecular features. Such data provide a
such as checkpoint inhibitors [26,27]. A new technique to rich training set to generate algorithms for pattern recogni-
study spatial immune cell distribution from SciLifeLab’s tion, for example, image-based detection of lethality fea-
Gene Technology group offers the potential to study cellular tures within a broader region of prostate cancer displaying
immunity clonally in a spatially resolved manner. Published a common Gleason Grade.
in Science [28], the so-called ‘‘Spatial VDJ’’ refers to T- and B-
lymphocyte receptors having unique ‘‘variable, diversity,
and joining’’ sequences reflecting antigen presentation and 5. Conclusion
activation of cellular immunity. In this pioneering method,
spatial transcriptomic mapping of full-length immunoglob- Spatial-omics technologies offer an opportunity to unravel
ulin transcripts within frozen human tissue sections per- previously hidden data available to translational research-
mits precise tracking of B- and T-cell clones across ers because of the ability to undertake broad-coverage
lymphoid and tumour tissues, refining our comprehension genomic molecular assays while retaining microscopic spa-
of the immune system and cancer. Application of this land- tial resolution. The opportunities are many, but the chal-
mark work to urological cancer may provide insights into lenges relate to the expense of reagents and data storage,
responses to immunotherapies [29–31] and the transition complexity of analysis, and lack of utility in a high-
from benign to malignant disease [24]. turnover clinical setting. We believe that the wealth of
In clear cell renal cell cancer, Li and colleagues [7] under- information available through spatial approaches will need
took single-cell sequencing from multiple tumour regions to be converted into scalable tests with the help of artificial
to explore diverse phenotypes and cellular network interac- intelligence for these technologies to be truly transforma-
tions. In recognition that cells do not exist in isolation, they tive to clinical care.
added a spatial-omics layer to their analysis, using Visium
spatial transcriptomics, to specifically examine the interface Author contributions: Alastair D. Lamb had full access to all the material
between tumour and normal tissue. This approach provided in the study and takes responsibility for the integrity and the accuracy of
evidence for epithelial-mesenchymal transition, mediated the presentation.
 EUROPEAN UROLOGY 87 (2025) 8–14 13

Study concept and design: Figiel, Bates, Lamb. [5] Erickson A, Hayes A, Rajakumar T, et al. a systematic review of
Acquisition of data: None. prostate cancer heterogeneity: understanding the clonal ancestry of
multifocal disease. Eur Urol Oncol 2021;4:358–69.
Analysis and interpretation of data: None.
[6] Meeks JJ, Al-Ahmadie H, Faltas BM, et al. Genomic heterogeneity in
Drafting of the manuscript: Figiel, Bates, Lamb. bladder cancer: challenges and possible solutions to improve
Critical revision of the manuscript for important intellectual content: Figiel, outcomes. Nat Rev Urol 2020;17:259–70.
Bates, Braun, Eapen, Eckstein, Manley, Milowsky, Mitchell, Bryant, Sfa- [7] Li R, Ferdinand JR, Loudon KW, et al. Mapping single-cell
kianos, Lamb. transcriptomes in the intra-tumoral and associated territories of
kidney cancer. Cancer Cell 2022;40:1583–1599.e10.
Statistical analysis: None.
[8] Erickson A, Sandy Figiel, Timothy Rajakumar, Srinivasa Rao,
Obtaining funding: None. Wencheng Yin, Dimitrios Doultsinos, Anette Magnussen, Reema
Administrative, technical, or material support: Figiel, Bates, Lamb. Singh, Ninu Poulose, Richard J Bryant, Olivier Cussenot, Freddie C
Supervision: Lamb. Hamdy, Dan Woodcock, Ian G Mills, Lamb AD. Clonal
phylogenies inferred from bulk, single cell, and spatial
Other: None.
transcriptomic analysis of cancer. bioRxiv 2023. doi: 10.1101/
2023.02.26.530145.
[9] Hamdy FC, Donovan JL, Lane JA, et al. Fifteen-year outcomes after
Financial disclosures: Alastair D. Lamb certifies that all conflicts of inter-
monitoring, surgery, or radiotherapy for prostate cancer. N Engl J
est, including specific financial interests and relationships and affiliations Med 2023;388:1547–58.
relevant to the subject matter or materials discussed in the manuscript [10] Loblaw A, Zhang L, Lam A, et al. Comparing prostate specific antigen
(eg, employment/affiliation, grants or funding, consultancies, honoraria, triggers for intervention in men with stable prostate cancer on
active surveillance. J Urol 2010;184:1942–6.
stock ownership or options, expert testimony, royalties, or patents filed,
[11] Waisbrod S, Natsos A, Wettstein MS, et al. Assessment of diagnostic
received, or pending), are the following: Alastair D. Lamb and Sandy Figiel yield of cystoscopy and computed tomographic urography for
use 10X Genomics products for their own spatial transcriptomic experi- urinary tract cancers in patients evaluated for microhematuria.
mental work and are dependent on on-going technical support. They do JAMA Netw Open 2021;4:e218409.
not have any commercial relationship with the company. Matthew I. [12] Posada Calderon L, Eismann L, Reese SW, Reznik E, Hakimi AA.
Advances in imaging-based biomarkers in renal cell carcinoma: a
Milowsky disclosure information can be found at https://coi.asco.org/
critical analysis of the current literature. Cancers (Basel)
share/7UQ-6ARQ/Matthew%20Milowsky. David A. Braun reports advisory 2023;15:354.
board fees from Exelixis, AVEO, Eisai, and Elephas; equity in Elephas, For- [13] Lambin P, Leijenaar RTH, Deist TM, et al. Radiomics: the bridge
tress Biotech (subsidiary), and CurIOS Therapeutics; consulting/personal between medical imaging and personalized medicine. Nat Rev Clin
Oncol 2017;14:749–62.
fees from Cancer Expert Now, Adnovate Strategies, MDedge, CancerNet-
[14] Ferro M, Musi G, Marchioni M, et al. Radiogenomics in renal cancer
work, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, management—current evidence and future prospects. Int J Mol Sci
Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, 2023;24:4615.
Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd.MD, DLA Piper, [15] Gopal N, Yazdian Anari P, Turkbey E, Jones EC, Malayeri AA. The
AbbVie, Compugen, Link Cell Therapies, and Scholar Rock; and research next paradigm shift in the management of clear cell renal cancer:
radiogenomics—definition, current advances, and future directions.
support from Exelixis and AstraZeneca, outside of the submitted work.
Cancers (Basel) 2022;14:793.
[16] Smith CP, Czarniecki M, Mehralivand S, et al. Radiomics and
radiogenomics of prostate cancer. Abdom Radiol 2019;44:2021–9.
Funding/Support and role of the sponsor: Alastair D. Lamb was sup- [17] Incoronato M, Aiello M, Infante T, et al. Radiogenomic analysis of
ported by a Cancer Research UK Clinician Scientist Fellowship award oncological data: a technical survey. Int J Mol Sci 2017;18:805.
(C57899/A25812). Sandy Figiel was funded by the Hanson Trust Research [18] Ye F, Hu Y, Gao J, et al. Radiogenomics map reveals the landscape of
(HJD00160). David A. Braun acknowledges support from the Department m6a methylation modification pattern in bladder cancer. Front
Immunol 2021;12:722642.
of Defense (KC190128/W81XWH-20-1-0882 and KC220016/HT9425-23-
[19] Dinis Fernandes C, Schaap A, Kant J, et al. Radiogenomics analysis
1-0735), the National Institutes of Health/National Cancer Institute linking multiparametric MRI and transcriptomics in prostate
(NIH/NCI; 1R37CA279822-01), the Louis Goodman and Alfred Gilman cancer. Cancers (Basel) 2023;15:3074.
Yale Scholar Fund, and the Yale Cancer Center (supported by NIH/NCI [20] Van Poppel H, Roobol MJ, Chandran A. Early detection of prostate
cancer in the European Union: combining forces with PRAISE-U. Eur
research grant P30CA016359).
Urol 2023;84:519–22.
[21] Prostate Cancer UK. TRANSFORM trial. https://prostatecanceruk.
org/research/transform-trial/.
Acknowledgements: We extend our acknowledgments to the Oxford
[22] Lee S, Kim G, Lee J, Lee AC, Kwon S. Mapping cancer biology in
Prostate Cancer Biology Group, led by Ian G. Mills, and the Nuffield space: applications and perspectives on spatial omics for oncology.
Department of Surgical Sciences, led by Freddie C. Hamdy. We acknowl- Mol Cancer 2024;23:26.
edge Thineskrishna Anbarasan for his critical review of the figure and [23] Figiel S, Yin W, Doultsinos D, et al. Spatial transcriptomic analysis of
virtual prostate biopsy reveals confounding effect of heterogeneity
table.
on genomic signature scoring. Mol Cancer 2023;22(1):162–367.
[24] Erickson A, He M, Berglund E, et al. Spatially resolved clonal copy
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available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Review – Prostate Cancer – Editor’s Choice

Editorial by Omar El-Taji, Noel W. Clarke on pp. 27–28 of this issue

Prostate Cancer Therapy Cardiotoxicity Map (PROXMAP) for

Advanced Disease States: A Systematic Review and Network
Meta-analysis with Bayesian Modeling of Treatment Histories

Moez Karim Aziz a,b,c, Donald Molony b, Dominique Monlezun a, Travis Holder a, Oliver Brunckhorst d,
Noel Higgason b, Jerry Roland b, Resa Magill b, Mariya Fatakdawala b, Alexander Iacobucci c,
Neal Mody-Bailey c, Chris Owen b, Andrew Zarker b, Emma Thames b, Justin Swaby e, Daniel Xiao b,
Lily Choi f, Shubh Desai c, Jacob Galan b, Brett Deng c, Taylor Hartshorne c, Alexis Nichols c,
Allan Zhang c, Jared Imber b, Jeffrey Song c, William Jones b, Alexis Rivas b, Darren Sanchez b,
Maya Guhan c, Giorgio Gandaglia g, Shreyas Ranganath b, Jerril Jacob b, Skyler Howell b, Juan Plana c,
Roderick van den Bergh h, Matthew Roberts h, Silke Gillessen Sommer h, Jan Oldenburg h,
Guillaume Ploussard h, Derya Tilki h, Ivo Schoots h, Erik Briers h, Johan Stranne h, Olivier Rouviere h,
Inge van Oort h, Daniela Oprea-Lager h, Maria De Santis h, Philip Cornford h, European Association
of Urology Prostate Cancer Guidelines Panel h, Efstratios Koutroumpakis a, Ali Ziaolhagh b,
Abdelrahman Ali a, Syed Wamique Yusuf a, Cezar Iliescu a, Steven Canfield b,*
a
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; b McGovern Medical School at The University of Texas
Health Science Center at Houston, Houston, TX, USA; c Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA; d MRC Centre for
Transplantation, Guy’s Hospital Campus, King’s College London, King’s Health Partners, London, UK; e Department of Internal Medicine, University of Georgia,
Augusta, GA, USA; f Department of Internal Medicine, University of the Incarnate Word, San Antonio, TX, USA; g Department of Urology, San Raffaele Hospital,
Milan, Italy; h Prostate Cancer Guidelines Panel, European Association of Urology, Arnhem, The Netherlands

Article info Abstract

Article history: Background and objective: Recommendations of first-line therapies for metastatic
Accepted August 23, 2024 hormone-sensitive (mHSPC), nonmetastatic castrate-resistant (M0CRPC), and metastatic
castrate-resistant (mCRPC) prostate cancer do not account for cardiotoxicity due to a
Associate Editor: lack of clear prior evidence. This manuscript assesses cardiotoxicity of these therapies.
Gianluca Giannarini Methods: We searched Ovid Medline, Elsevier Embase, and the Cochrane Library for ran-
domized clinical trials (RCTs) from database inception to January 14, 2024. Network
Keywords: meta-analyses of first-line mHSPC, M0CRPC, and mCRPC therapies were constructed
Cardiotoxicity for the five cardiotoxicity metrics defined by the International Cardio-Oncology

Please visit www.eu-acme.org/europeanurology

to answer questions on-line. The EU-ACME cred- * Corresponding author. Department of Urology, McGovern Medical School at the University of Texas
its will then be attributed automatically. Health Science Center at Houston, 7000 Fannin Street, Houston, TX 77030, USA. Tel. +1 713 500 7335.
E-mail address: [email protected] (S. Canfield).

https://doi.org/10.1016/j.eururo.2024.08.031
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
16 EUROPEAN UROLOGY 87 (2025) 15–26

Heart failure Society: heart failure, myocarditis, vascular toxicity, hypertension, and arrhythmias.
Myocarditis Additional Bayesian network meta-analyses also accounted for prior treatment history.
Vascular toxicity Key findings and limitations: Thirteen RCTs (16 292 patients) were included. For mHSPC,
Hypertension androgen deprivation therapy (ADT) plus docetaxel (DTX) plus abiraterone acetate (AA)
Arrhythmias with prednisone (P) demonstrated a significant increase in hypertension and arrhyth-
Docetaxel mias versus ADT + DTX (risk ratio [RR] 2.85, 95% confidence interval [CI] 1.67–4.89,
Abiraterone acetate and RR 2.01, 95% CI 1.17–3.44, respectively); however, no corresponding differences
Darolutamide were observed between ADT + DTX plus darolutamide (DAR) and ADT + DTX (RR 1.55,
Olaparib 95% CI 0.73–3.30, and RR 0.94, 95% CI 0.63–1.40, respectively). For mCRPC assuming a
history of mHSPC treatment, ADT + AA + P plus olaparib (OLA) demonstrated a statisti-
cally significant decrease in hypertension versus ADT + AA + P (RR 0.20, 95% CI 0.16–
0.26). M0CRPC results were unremarkable.
Conclusions and clinical implications: For mHSPC, ADT + DTX + DAR demonstrates less
cardiotoxicity than ADT + DTX + AA + P due to a lower risk of hypertension and arrhyth-
mias from decreased mineralocorticoid excess. In addition, OLA counterintuitively offers
decreased hypertension when superimposed on ADT + AA + P for mCRPC treatment after
prior androgen deprivation from mHSPC therapy.
Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are
reserved, including those for text and data mining, AI training, and similar technologies.

ADVANCING PRACTICE

What does this study add?

Androgen deprivation therapy (ADT) plus docetaxel (DTX) plus darolutamide offers less cardiotoxicity than ADT + DTX
plus abiraterone acetate with prednisone (AA + P) for metastatic hormone-sensitive prostate cancer due to less mineralo-
corticoid excess. Studied first-line nonmetastatic castrate-resistant prostate cancer treatments did not demonstrate dif-
ferences in cardiotoxicity. Depending on treatment history, ADT + AA + P plus olaparib offers decreased hypertension and
ADT plus enzalutamide offers greater vascular toxicity when treating first-line metastatic castrate-resistant prostate can-
cer due to alterations in autonomic and inflammatory pathways from prior treatments.

Clinical Relevance
Several large clinical trials have demonstrated survival benefits from various systemic therapies, mostly in combinations,
for patients with advanced prostate cancer. Several of these agents are known to cause, or worsen, cardiovascular disease,
which is the most common cause of non-cancer death among these patients. With growing interest in the field of cardio-
oncology, the Authors systematically reviewed data from randomized controlled trials to compare treatment combina-
tions for metastatic hormone sensitive, non-metastatic and metastatic castration-resistant prostate cancer in terms of five
well-defined cardiotoxicity domains. Despite some limitations inherent to quality of original data and lack of follow-up,
and considering that patients in these trials, mostly without pre-existing cardiovascular disease, may not reflect the real-
world practice, this work provides the highest-level reference for clinicians managing patients with advanced prostate
cancer while balancing the risks of cardiotoxicity. Associate Editor: Gianluca Giannarini MD.

Patient Summary
In this work, we looked at cardiotoxicities of first-line prostate cancer regimens for metastatic hormone-sensitive and
nonmetastatic castrate-resistant prostate cancer. Additionally, we analyzed cardiotoxicities of metastatic castrate-
resistant prostate cancer uniquely accounting for treatment histories from previous disease states. Among first-line ther-
apies for metastatic hormone-sensitive prostate cancer, ADT + DTX plus darolutamide offers less cardiac toxicity than
ADT + DTX + AA with P. Depending on treatment history, ADT + AA + P plus olaparib can have a lower risk of high blood
pressure and ADT plus enzalutamide can have a higher risk of vascular events for first-line metastatic castrate-resistant
prostate cancer treatment.

1. Introduction (M0CRPC), and metastatic castrate-resistant (mCRPC) pros-

tate cancer. Some of these agents include androgen receptor
Multiple agents added to androgen deprivation therapy (ADT) targeted antagonists (enzalutamide [ENZ], apalutamide
have emerged as treatments for metastatic hormone- [APA], and darolutamide [DAR]), CYP17 inhibitors (abi-
sensitive (mHSPC), nonmetastatic castrate-resistant raterone acetate [AA] with prednisone [P]), docetaxel (DTX),
 EUROPEAN UROLOGY 87 (2025) 15–26 17

and poly-ADP ribose polymerase (PARP) inhibitors (olaparib ence abstracts were also searched in Elsevier Embase for the
[OLA]). While these agents have demonstrated efficacy in same time frame. Studies including patients with pre-
multiple clinical trials, cardiovascular adverse effects have existing cardiovascular disease were permitted. Additional
been reported [1]. information regarding inclusion/exclusion criteria and
Cardiovascular disease is the leading nononcological study eligibility is detailed in the Supplementary material.
cause of death in prostate cancer patients [2], even in
patients with metastatic disease [3]. In fact, a recent study
suggested that in metastatic prostate cancer patients, 2.2. Statistical analysis
between 28% and 46% of deaths occur due to cardiac disease A network meta-analysis was performed for each cardiotox-
[3]. Therefore, it is important to address treatment-related icity domain and each prostate cancer disease state
cardiotoxicity in patients with prostate cancer, even if (mHSPC, M0CRPC, and mCRPC) by combining direct and
metastatic, to prevent a key competing cause of morbidity indirect estimates across the network of interventions.
and mortality. Guidelines for first-line mHSPC, M0CRPC, The risk ratio (RR) and 95% confidence interval (CI) were
and mCRPC therapies focus on mortality benefit and have estimated for each intervention pairing. Given the low num-
not addressed potential cardiotoxicity defined most ber of studies, a frequentist fixed-effect model was used for
recently by the International Cardio-Oncology Society (IC- each analysis using the ‘‘netmeta’’ function in R version
OS) in 2021. To the best of our knowledge, no systematic 4.2.2 (R Foundation for Statistical Computing, Vienna, Aus-
reviews have yet applied this definition for cardiotoxicity tria). Heterogeneity, publication bias, consistency, and addi-
evaluation of mHSPC, M0CRPC, or mCRPC treatments. The tional meta-regressions could not be assessed due to the
IC-OS definition splits cardiotoxicity into five domains most low number of available studies. Transitivity within each
reported in the literature: heart failure, myocarditis, vascu- network was assessed qualitatively by examining clinical
lar toxicity, hypertension, and arrhythmias, with further and methodological characteristics of included trials. The
details provided in their consensus statement [1]. Vascular Confidence in Network Meta-analysis (CINeMA) algorithm
toxicity includes atherosclerosis (coronary, peripheral, or was used to provide confidence ratings for each compar-
carotid), arterial or venous thrombosis, abnormal vasoreac- ison, which is broadly based on the Grading of Recommen-
tivity, and any symptomatic vascular toxicity [1]. While we dations, Assessment, Development, and Evaluations criteria
acknowledge that multiple factors impact clinical decisions for assessment of quality of evidence [5]. Since two studies
related to the choice of therapy, cardiotoxicity is an impor- at early (<24 mo) and late (>24 mo) median follow-up times
tant consideration as it can decrease overall quality of life were published for each included M0CRPC randomized clin-
despite treatment-related increased survival. It may also ical trial (RCT), two sets of network meta-analyses were
represent a preventable cause of morbidity and mortality. performed for each cardiotoxicity outcome, one including
Additionally, it is possible that first-line treatments of early studies and the other including late studies.
prior disease states such as mHSPC and M0CRPC result in Included mCRPC studies permitted patients who had
residual cardiotoxicity even after a patient’s prostate cancer taken antiandrogens as previous treatments in addition to
progresses to mCRPC. To the best of our knowledge, no sys- ADT, but most did not include percentages. It is also unclear
tematic reviews have clearly accounted for this phe- which exact agents beyond ADT were used (only drug
nomenon either. We have performed a systematic review classes are provided for some studies). Additionally, it is
and network meta-analysis to determine the comparative unclear which patients progressed to mCRPC from mHSPC
cardiotoxicity of first-line agents for the mHSPC, M0CRPC, or from M0CRPC in each study. Therefore, Bayesian network
and mCRPC disease states. Additionally, we uniquely meta-analyses for the mCRPC treatments were performed
account for the possible residual cardiotoxicity imposed to address any preceding cardiotoxicity associated with
by prior first-line treatments of mHSPC and M0CRPC by per- studied first-line mHSPC and M0CRPC therapies before pro-
forming Bayesian network meta-analyses. gression to treatment for mCRPC [6]. This was done using
multilevel mixed-effect generalized linear models with a
2. Methods Markov chain Monte Carlo iterative process. The above
direct and indirect estimates from a frequentist network
Reporting of this systematic review and network meta- meta-analysis for each cardiotoxicity outcome by each
analysis is performed according to the Preferred Reporting treatment within each cancer stage prior to mCRPC were
Items for Systematic Reviews and Meta-analyses Network utilized to create distinct informative priors for the Baye-
Meta-analyses (PRISMA-NMA) reporting guidelines [4] with sian network meta-analysis models: the first set of models
an a priori protocol registered with the PROSPERO database assumed prior mHSPC treatments, the second assumed
(CRD42022314954). prior M0CRPC treatment with early progression to mCRPC,
and the third assumed prior M0CRPC treatment with late
progression to mCRPC. Each of the three Bayesian network
2.1. Search strategy
meta-analyses was then used to generate posterior proba-
A systematic search of the Ovid Medline (including bility distributions of the relative treatment effects (includ-
PubMed), Elsevier Embase, and Cochrane Library database ing quantification of parameter estimates’ uncertainty and
was performed from inception until January 14, 2024. The ranking of the treatments in the networks). Convergence
search strategy with search terms is presented in Supple- and goodness of fit were also assessed in addition to esti-
mentary Table 1. Urology, oncology, and cardiology confer- mates with Bayesian versus without network meta-
18 EUROPEAN UROLOGY 87 (2025) 15–26

analysis results. The above Bayesian network meta-analysis less hypertensive risk versus ADT + ENZ in early (RR 0.55,
was conducted in STATA (18.0 MP; StataCorp, College Sta- 95% CI 0.34–0.88 and RR 0.53, 95% CI 0.29–0.96, respec-
tion, TX, USA). tively) and late (RR 0.45, 95% CI 0.29–0.69 and RR 0.38,
95% CI 0.22–0.66, respectively) networks. Additionally,
ADT + DAR demonstrated less vascular toxicity risk than
3. Results
ADT + ENZ in the late network (RR 0.35, 95% CI 0.14–
0.87). For mCRPC, ADT + AA + P + OLA and ADT + AA + P
Our search identified 4846 manuscripts; of these, 16 studies demonstrated less hypertensive risk than ADT + ENZ (RR
involving 13 RCTs met all the inclusion criteria for the net- 0.40, 95% CI 0.19–0.84 and RR 0.51, 95% CI 0.31–0.85,
work meta-analysis (Supplementary Table 2) [7–22]. The respectively). Further details for all findings are provided
included interventions and the number of patients for each in the Supplementary material.
arm of each study are provided in Supplementary Table 2.
The primary outcomes were heart failure (six RCTs for
3.2. Bayesian analyses
mHSPC, three for M0CRPC, and three for mCRPC), myocardi-
tis (zero), vascular toxicity (seven for mHSPC, three for The Bayesian networks of heart failure, vascular toxicity,
M0CRPC, and three for mCRPC), hypertension (seven for hypertension, and arrhythmias assuming progression from
mHSPC, three for M0CRPC, and three for mCRPC), and mHSPC and the history of mHSPC treatments are provided
arrhythmias (six for mHSPC, three for M0CRPC, and three in Figure 3B. A second set of Bayesian network meta-
for mCRPC). For M0CRPC, three RCTs were found, each with analyses was performed assuming early and late progres-
two studies published (one for median follow-up times <24 sion from M0CRPC with M0CRPC treatment history, and
mo and the other for >24 mo). Therefore, two separate net- results are provided in Figure 4. When accounting for prior
works were constructed for M0CRPC, one for each group of mHSPC treatment, ADT + AA + P + OLA demonstrated less
studies with similar follow-up times to ensure fair compar- hypertensive risk than ADT + AA + P (RR 0.20, 95% CI
isons among event rates. The RCTs included in our analyses 0.16–0.26). ADT + AA + P also demonstrated less vascular
studied survival as their primary endpoint; data regarding toxicity risk than ADT + ENZ when accounting for prior
cardiotoxicity were harvested from the associated overall mHSPC (RR 0.21, 95% CI 0.13–0.57) or early progression
safety analyses. The exclusion criteria for all studies are pre- from prior M0CRPC (RR 0.40, 95% CI 0.27–0.75) treatment.
sented in Supplementary Table 3. Frequencies at which car- Further details regarding statistically significant differences
diotoxicity outcomes were assessed and event rates for each are provided in the Supplementary material.
RCT are described in Supplementary Tables 4 and 5, respec-
tively. Participants were still permitted to report adverse
events until the end of the study. No network meta- 4. Discussion
analyses of myocarditis could be performed since no studies
reported event rates. Risk of bias tables are provided in Sup- This study is the first to provide network meta-analyses
plementary Figure 2 and were generated using Cochrane’s based on a standardized definition of cardiotoxicity by the
RoB 2 tool [23]. Confidence ratings of comparisons using IC-OS comparing first-line therapies for advanced prostate
the CINeMA algorithm [5] are provided in Supplementary cancer states. This study also uniquely addresses the accu-
Tables 6, 7 and 8 for mHSPC, M0CRPC, and mCRPC studies, mulated cardiotoxicity risks of previously administered
respectively. Median follow-up times for included studies first-line treatments for prior disease states using Bayesian
are provided in the Supplementary material. Diagnostic cri- modeling.
teria for ascertaining cardiotoxicity outcomes were not sta-
ted explicitly in the included studies. 4.1. Part 1: mHSPC

In our mHSPC network, ADT + DTX + AA + P was associated

3.1. Network meta-analyses of mHSPC, M0CRPC, and mCRPC
with greater hypertension and arrhythmias than ADT + DTX,
therapies
but ADT + DTX + DAR was not. This observation is of partic-
The network meta-analyses for heart failure, vascular toxi- ular interest because current guidelines recommend that
city, hypertension, and arrhythmias for mHSPC, M0CRPC, ADT + DTX + AA + P and ADT + DTX + DAR are both first-
and mCRPC are presented in Figures 1, 2, and 3A, respec- line therapies for patients who can tolerate DTX [24]. Since
tively. Supplementary Table 9 shows the number of patients ADT + DTX + AA + P was associated with additional hyper-
and number of studies for each node of each prostate cancer tension and arrhythmias not demonstrated by ADT + DTX +
state. Most notable results for mHSPC therapies include sta- DAR, our review suggests a potential decision point
tistically significant differences between ADT + DTX + AA + P between these two options. The differential extent of min-
and ADT + DTX for hypertension and arrhythmias (RR 2.9, eralocorticoid excess provided by AA + P versus DAR may
95% CI 1.1–4.9 and RR 2.8, 95% CI 1.2–3.4, respectively). explain this observation. AA may contribute additional car-
Additionally, there were no corresponding statistically sig- diotoxicity worth consideration, especially for patients with
nificant differences between ADT + DTX + DAR and pre-existing cardiovascular disease. Studies of mCRPC
ADT + DTX (RR 1.6, 95% CI 0.73–3.3 and RR 0.94, 95% CI patients have shown that varying the dose of prednisone
0.63–1.4, respectively). We note that several 95% CIs could could further mitigate mineralocorticoid excess [25]; how-
not be computed for arrhythmias due to low event rates. ever, the possibility of a similar effect for mHSPC patients
For M0CRPC, both ADT + APA and ADT + DAR demonstrated has yet to be studied.
 EUROPEAN UROLOGY 87 (2025) 15–26 19

Fig. 1 – Forest plots of network meta-analyses of IC-OS cardiotoxicity domains for mHSPC with risk ratio and 95% confidence interval: (A) heart failure, (B)
vascular toxicity, (C) hypertension, and (D) arrhythmias. Comparisons containing direct estimates are provided in gray; statistically significant differences are
underlined and asterisked. Numbers of studies and patients for each node are provided in Supplementary Table 9. AA = abiraterone acetate; ADT = androgen
deprivation therapy; APA = apalutamide; DAR = darolutamide; DTX = docetaxel; ENZ = enzalutamide; IC-OS = International Cardio-Oncology Society;
P = prednisone. *p < 0.05.

Studies also suggest that mineralocorticoid excess con- cally significant differences in heart failure, and low num-
tributes to heart failure [26]; however, a mechanism linking bers of events were observed. Interestingly, all arms of
androgen deprivation to heart failure remains unclear [27]. included studies, including placebo arms with ADT alone,
It is therefore unclear whether our proposed hypothesis of had nonzero event rates, indicating an unavoidable baseline
mineralocorticoid excess should also suggest a difference level of heart failure risk with any treatment.
between these agents when evaluating heart failure. Both mineralocorticoid excess and androgen deprivation
Regardless, our studies were not powered to detect statisti- have been associated with increased vascular toxicity
20 EUROPEAN UROLOGY 87 (2025) 15–26

Fig. 1 (continued)

[28,29], which may explain the nonzero number of vascular component of the effect size estimates (Fig. 1); comparisons
toxicity events observed in all arms of included mHSPC with direct components are more certain when attempting
studies. As with heart failure, since all first-line mHSPC to draw conclusions.
therapies demonstrate efficacy through androgen depriva-
tion, a certain level of vascular toxicity must be accepted. 4.1.1. Key takeaways
Of note, while we do not see a statistically significant dif-
ference when directly comparing ADT + DTX + AA + P and 1. ADT + DTX + AA + P is associated with greater cardiotox-
ADT + DTX + DAR for hypertension, we note that this com- icity than ADT + DTX + DAR.
parison is based entirely on an indirect estimate. The com- 2. All studied first-line mHSPC therapies are associated
parisons of ADT + DTX + DAR versus ADT + DTX and ADT + with a certain amount of heart failure and vascular
DTX + AA + P versus ADT + DTX, by contrast, have a direct toxicity.
 EUROPEAN UROLOGY 87 (2025) 15–26 21

Fig. 2 – RCT median follow-up times and forest plots of IC-OS cardiotoxicity domains for M0CRPC studies with (A) early and (B) late median follow-up times,
with RR and 95% CI in the format RR (95% CI). Comparisons containing direct estimates are provided in gray; statistically significant differences are
underlined and asterisked. Median follow-up times are also provided. The numbers of studies and patients per node are provided in Supplementary Table 9.
ADT = androgen deprivation therapy; APA = apalutamide; CI = confidence interval; DAR = darolutamide; ENZ = enzalutamide; IC-OS = International Cardio-
Oncology Society; M0CRPC = nonmetastatic castrate-resistant prostate cancer; RCT = randomized clinical trial; RR = risk ratio. *p < 0.05.

3. There is insufficient evidence to profile the risk of similar in characteristics. These differences in placebo event
myocarditis among first-line mHSPC therapies. rates increase uncertainty in our indirect estimates and
could explain this statistically significant result. Therefore,
any clinically significant differences in hypertension among
4.2. Part 2: M0CRPC
first-line M0CRPC therapies remain uncertain.
For M0CRPC, ADT + ENZ was found to have an increased risk Our networks (early and late) for heart failure demon-
of hypertension compared with ADT alone and other first- strated equivalent event rates between ADT + DAR and
line therapies. Notably, at baseline, the placebo populations ADT + ENZ. There is no known molecular mechanism link-
treated with ADT alone had higher event rates of hyperten- ing DAR or ENZ to heart failure incidence. Additionally, data
sion in the SPARTAN trial than in the PROSPER trial. Indirect of appropriate quality on ADT + DAR and heart failure in
estimates of network meta-analyses assume that all placebo M0CRPC are limited to the already included ARAMIS trial.
populations of connected studies for distinct treatments are The currently available evidence suggests that heart failure
22 EUROPEAN UROLOGY 87 (2025) 15–26

Fig. 3 – Forest plots of IC-OS cardiotoxicity domains for mCRPC first-line therapies (A) without assuming any previous treatment and (B) assuming prior
mHSPC treatment. RR and 95% CIs are provided in the format RR (95% CI). Comparisons containing direct estimates are provided in gray; statistically
significant differences are underlined and asterisked. The numbers of studies and patients per node are provided in Supplementary Table 9. AA = abiraterone
acetate; ADT = androgen deprivation therapy; APA = apalutamide; CI = confidence interval; ENZ = enzalutamide; IC-OS = International Cardio-Oncology
Society; mCRPC = metastatic castrate-resistant prostate cancer; mHSPC = metastatic hormone-sensitive prostate cancer; OLA = olaparib; P = prednisone;
RR = risk ratio. *p < 0.05.

risk should not influence the choice between ADT + DAR and current [30]. An additional study from a phase 1b trial
ADT + ENZ in this disease stage. No studies that evaluated demonstrated that APA can produce modest QT prolonga-
ADT + APA were found. tion [31]. However, for DAR, we did not find studies describ-
For vascular toxicity, ADT + DAR demonstrated a lower ing a clear dose-dependent relationship with arrhythmia
risk than ADT + ENZ. There is no clear mechanism by which incidence. Since no arrhythmias occurred in either arm of
ADT + ENZ and ADT + DAR lead to distinct degrees of the PROSPER trial, our network could establish only an indi-
atherosclerosis. At baseline, we again notice that the pla- rect comparison between ADT + APA and ADT + DAR, with
cebo populations treated with ADT alone had a higher rate no statistically significant difference in arrhythmia risk
of vascular events in the ARAMIS trial than in the seen. No conclusions can be drawn regarding the arrhyth-
PROSPER trial; this observation may explain the statistically mia risk of ADT + ENZ.
significant difference observed in our indirect
estimate of vascular toxicity, which therefore remains 4.2.1. Key takeaways
uncertain.
For arrhythmias, ENZ has been shown to prolong the QT 1. Uncertain statistically significant differences in hyper-
interval by decreasing current through the delayed rectify- tension and vascular toxicity risk were noticed among
ing potassium channel while increasing delayed sodium first-line M0CRPC therapies.
 EUROPEAN UROLOGY 87 (2025) 15–26 23

Fig. 4 – Forest plots of IC-OS cardiotoxicity domains for mCRPC first-line therapies assuming previous M0CRPC treatment with (A) early and (B) late
progression to mCRPC. RR and 95% CIs are provided in the format RR (95% CI). Comparisons containing direct estimates are provided in gray; statistically
significant differences are underlined and asterisked. AA = abiraterone acetate; ADT = androgen deprivation therapy; APA = apalutamide; CI = confidence
interval; ENZ = enzalutamide; IC-OS = International Cardio-Oncology Society; M0CRPC = nonmetastatic castrate-resistant prostate cancer; mCRPC = metastatic
castrate-resistant prostate cancer; OLA = olaparib; P = prednisone; RR = risk ratio. *p < 0.05.

2. No statistically significant differences were noted in regarding treatment history were related to hypertension.
heart failure risk between ADT + ENZ and ADT + DAR, ADT + ENZ demonstrated greater hypertension than
but insufficient evidence is available for ADT + APA. ADT + AA + P and ADT + AA + P + OLA. Once again, the pla-
3. No statistically significant differences were noted in cebo populations were not balanced for hypertension in the
arrhythmia risk between ADT + APA and ADT + DAR, PREVAIL versus COU-AA-302 and PROpel trials, thereby ren-
but insufficient evidence is available for ADT + ENZ. dering our indirect comparisons less certain. No conclusions
4. Insufficient evidence is available to draw conclusions of can be drawn for heart failure risk of ADT + ENZ and for
myocarditis risk among M0CRPC first-line therapies. arrhythmia risk of ADT + AA + P + OLA since these items
were not reported.
Interestingly, ADT + AA + P and ADT + ENZ conferred
4.3. Part 3: mCRPC
increased vascular toxicity versus ADT alone. This finding
The only statistically significant differences among first-line could be explained by androgen deprivation raising vascular
therapies for mCRPC without additional assumptions inflammation; testosterone dampens the inflammatory cas-
24 EUROPEAN UROLOGY 87 (2025) 15–26

cade that may lead to atherosclerosis [32,33]. This increased circumvent these limitations would be a longitudinal plat-
risk to benefit balance may influence shared decision- form RCT that includes all treatment arms and follows the
making and inform close monitoring of patients with same individuals across all states of disease (mHSPC to
comorbid cardiovascular disease. mCRPC or M0CRPC to mCRPC). It is unknown whether such
a study will ever be conducted. Therefore, the Bayesian net-
4.3.1. Key takeaways work meta-analyses are our best approximation to account
for effects of previous treatments. Ultimately, all interpreta-
1. First-line mCRPC therapies increase vascular toxicity tion relying on the Bayesian network meta-analyses is
generally but without any observed significant differ- hypothesis generating.
ences among the studied options.
2. Uncertain statistically significant differences in hyper- 4.4.1. Key takeaways
tension were noticed among first-line mCRPC therapies.
3. No statistically significant differences were observed in 1. For patients with first-line mHSPC treatment history,
heart failure risk between ADT + AA + P + OLA and ADT + AA + P + OLA had decreased hypertension risk ver-
ADT + AA + P, but insufficient evidence is available for sus ADT + AA + P.
ADT + ENZ. 2. For patients with first-line mHSPC treatment history and
4. No statistically significant differences were observed in early progression from first-line M0CRPC treatment,
arrhythmia risk between ADT + ENZ and ADT + AA + P, ADT + ENZ had increased vascular toxicity relative to
but insufficient evidence is available for ADT + AA + P + ADT + AA + P. These findings should be interpreted in
OLA. light of Bayesian analysis limitations on certainty and
5. Insufficient evidence is available to draw conclusions of used to inform potential risk-benefit assessment.
myocarditis risk among mCRPC first-line therapies.
4.5. Part 5: additional study limitations
4.4. Part 4: Bayesian analyses
In addition to the limitations already discussed, there were
The Bayesian network meta-analyses in Figures 3 and 4 pro-
six other limitations: (1) the ENZAMET trial could not be
vided multiple results of statistical significance. We
included because it did not precisely stratify patients
observed that when patients are assumed to have a prior
receiving DTX [35]; (2) multiple studies had some concerns
history of any of our studied mHSPC treatments, ADT + A
for risk of bias due to their open-label nature and concerns
A + P + OLA demonstrated decreased hypertension versus
for a detection bias; (3) all evidence is at most of low quality
ADT + AA + P. Androgen deprivation can modulate
according to the CINeMA criteria; (4) studies that did not
dopaminergic transmission [34]; therefore, a previous his-
delineate the disease state of patients (mHSPC, M0CRPC,
tory of androgen deprivation may create a different set of
or mCRPC) clearly required exclusion; (5) patients with
conditions under which PARP inhibitors affect blood pres-
pre-existing cardiovascular disease were systematically
sure. This revised environment could, in principle, cause
excluded or poorly stratified across multiple trials; and (6)
OLA to dampen blood pressure. Therefore, it is plausible
frequencies at which outcomes were assessed were hetero-
that ADT + AA + P + OLA could cause less hypertension than
geneous among studies, and primary studies were vulnera-
ADT + AA + P. We note that unlike the PREVAIL trial, the
ble to a self-report bias.
COU-AA-302 and PROpel trials had more similar hyperten-
sion event rates in placebo populations (Supplementary
Table 5), thereby making associated comparisons more 5. Conclusions
certain.
Despite the statistically significant differences observed The key takeaways are provided at the end of each section
for heart failure, low event rates compounded with the of the discussion with findings for each cardiotoxicity
uncertainty of pooled risk from prior networks render these domain summarized in Table 1. Most importantly, ADT +
results highly uncertain. As for vascular toxicity, prior treat- DTX + DAR demonstrated less cardiotoxicity than ADT + D
ments with antiandrogens in preceding prostate cancer TX + AA + P for mHSPC likely due to less mineralocorticoid
states may impact the inflammatory environment under excess. Studied M0CRPC and mCRPC treatments without
which new mCRPC treatments are administered [32,33]. assessing prior first-line treatment history demonstrated
This may explain the increased vascular toxicity with either uncertain or no statistically significant differences
ADT + ENZ versus ADT + AA + P in patients with mHSPC in cardiotoxicity risk depending on the domain. However,
treatment history or with early progression after first-line when accounting for first-line mHSPC treatment history,
M0CRPC treatment. ADT + AA + P + OLA demonstrated a decreased hypertensive
Several limitations can affect this type of analysis: risk and ADT + ENZ demonstrated an increased risk of vas-
included studies for mCRPC have a proportion of patients cular toxicity for mCRPC treatment. When accounting for
with a variety of previous treatments that are not precisely first-line M0CRPC treatment history, ADT + ENZ demon-
delineated (Supplementary Table 2). Therefore, the Baye- strated an increased risk of vascular toxicity for early pro-
sian analysis may double count cardiotoxicity risk from pre- gression. Given the new definition of cardiotoxicity
vious treatments in these subsets. Additionally, there were proposed by the IC-OS, we hope that future studies will pro-
differences between placebo populations in baseline event file cardiotoxicity in a systematic way to allow for more
rates. The preferred study to optimize result validity and comprehensive and precise evaluation.
 EUROPEAN UROLOGY 87 (2025) 15–26 25

Table 1 – Summary table of key findings by cardiotoxicity domain

Prostate cancer Heart failure Myocarditis Vascular toxicity Hypertension Arrhythmias

state
mHSPC 1. No significant differences among Insufficient 1. No significant 1. ADT + DTX + AA + P 1. ADT + DTX + AA + P more
first-line therapies evidence differences among more associated with associated with arrhythmias
2. First-line therapies carry a first line therapies hypertension than than ADT + DTX + DAR
nonzero heart failure risk 2. First-line ADT + DTX + DAR 2. First-line therapies carry a
therapies carry a 2. First-line therapies nonzero arrhythmia risk
nonzero vascular carry a nonzero
toxicity risk hypertensive risk
M0CRPC No statistically significant Insufficient Uncertain Uncertain statistically No statistically significant
differences for ADT + DAR vs evidence statistically significant differences differences for ADT + DAR vs
ADT + ENZ; insufficient evidence to significant observed among first- ADT + APA; insufficient evidence
comment on ADT + APA differences observed line therapies to comment on ADT + ENZ
among first-line
therapies
mCRPC without No statistically significant Insufficient 1. First-line Uncertain statistically No statistically significant
assuming differences for ADT + AA + P + OLA evidence therapies carry a significant differences differences for ADT + ENZ vs
treatment vs ADT + AA + P; insufficient nonzero vascular observed among first- ADT + AA + P; insufficient
history evidence to comment on ADT + ENZ toxicity risk line therapies evidence to comment on
2. No statistically ADT + AA + P + OLA
significant
differences observed
among first-line
therapies
mCRPC assuming Uncertain statistically significant Insufficient ADT + ENZ had ADT + AA + P + OLA Uncertain statistically significant
mHSPC differences observed among first- evidence increased vascular had decreased differences observed among
treatment line therapies toxicity vs hypertension vs first-line therapies
history ADT + AA + P ADT + AA + P
mCRPC assuming Uncertain statistically significant Insufficient ADT + ENZ had Uncertain statistically Uncertain statistically significant
M0CRPC differences observed among first- evidence increased vascular significant differences differences observed among
treatment line therapies toxicity vs observed among first- first-line therapies
history with ADT + AA + P line therapies
early
progression
mCRPC assuming Uncertain statistically significant Insufficient Uncertain Uncertain statistically Uncertain statistically significant
M0CRPC differences observed among first- evidence statistically significant differences differences observed among
treatment line therapies significant observed among first- first-line therapies
history with differences observed line therapies
late progression among first-line
therapies

Author contributions: Moez Karim Aziz had full access to all the data in relevant to the subject matter or materials discussed in the manuscript
the study and takes responsibility for the integrity of the data and the (eg, employment/affiliation, grants or funding, consultancies, honoraria,
accuracy of the data analysis. stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.

Study concept and design: Aziz, Molony, Yusuf, Iliescu, Canfield.

Acquisition of data: Aziz, Holder, Brunckhorst, Higgason, Roland, Magill, Funding/Support and role of the sponsor: This review was supported by
Fatakdawala, Iacobucci, Mody-Bailey, Owen, Zarker, Thames, Swaby, the European Association of Urology Guidelines Office.
Xiao, Choi, Desai, Galan, Deng, Hartshorne, Nichols, Zhang, Imber, Song,
Jones, Rivas, Sanchez, Guhan, Gandaglia, Ranganath, Jacob, Howell, Kou- Supplementary data
troumpakis, Ziaolhagh, Ali.
Analysis and interpretation of data: Aziz, Molony, Monlezun, Canfield.
Supplementary data to this article can be found online at
Drafting of the manuscript: Aziz, Molony, Monlezun, Canfield.
https://doi.org/10.1016/j.eururo.2024.08.031.
Critical revision of the manuscript for important intellectual content: Aziz,
Molony, Monlezun, Holder, Brunckhorst, Higgason, van den Bergh,
References
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[15] Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. 2019;140:1070–80.
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2020;382:2197–206. enzalutamide compared with abiraterone acetate/prednisone
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2017;71:151–4. 2019;381:121–31.
 EUROPEAN UROLOGY 87 (2025) 27–28

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Editorial

Referring to the article published on pp. 15–26 of this issue

Balancing Efficacy and Cardiotoxicity in Prostate Cancer Therapy:

A Call for Precision in Treatment Strategies

Omar El-Taji, Noel W. Clarke *

The Christie and Salford Royal Hospitals, Manchester, UK

High-risk, potentially lethal prostate cancer (PCa) requires by Aziz and colleagues [1] because of their exclusion of
systemic androgen deprivation therapy (ADT), with dou- other relevant published studies, the uncertainties inherent
blet therapy offering superior anticancer effects in compar- in this type of Bayesian analysis, and the key fact that this is
ison to monotherapy, and triplet therapy being more neither a head-to-head comparison nor a reanalysis of indi-
effective than doublet. However, nothing comes without vidual-patient data.
a cost. In the review of such combination therapies by Aziz The findings are particularly noteworthy for mHSPC, for
et al [1] in this issue of European Urology, the authors which differential effects of triplet therapy were observed.
endeavour to add granularity to the existing evidence, For instance, the combination of ADT + docetaxel (DTX)
showing that a significant cost on the final bill is a higher + abiraterone acetate/prednisone (AAP) was associated with
risk of cardiovascular toxicity. It is well established that higher risk of hypertension and arrhythmias in comparison
cardiovascular disease (CVD) is a leading cause of death to ADT + DTX alone, while the combination of ADT + DTX
among PCa patients [2], and men with pre-existing CVD + darolutamide (DAR) was not, although indirect estimates
fare worse: 18% of patients with baseline CVD in the HERO between the two did not reveal a statistically significant dif-
trial experienced a major adverse cardiac event within 1 yr ference. This potential differential risk profile may be attri-
of starting leuprolide [3]. The RADICAL-PC study demon- butable to the known mineralocorticoid excess caused by
strated that in the real world, 99% of men harbour at least AAP. Such findings may help clinical decision-making, par-
one, and 51% more than two, poorly controlled cardiovas- ticularly when selecting treatment for patients with high-
cular (CV) risk factors [4]. Should we be doing more to risk or high-volume disease, for which triplet therapy may
address this issue? Aziz et al [1] add weight to the evi- be under consideration, in the presence of specific cardiac
dence that we should, but there are caveats in interpreta- risk factors.
tion of the data presented. Analysis of doublet combinations also revealed differ-
Aziz et al [1] analysed the cardiotoxicity of various PCa ences in the M0CRPC setting: ADT + DAR and ADT + apalu-
therapies from 13 trials across different disease stages: tamide were associated with a lower risk of hypertension
metastatic hormone-sensitive prostate cancer (mHSPC), in comparison to ADT + enzalutamide (ENZ) in early trials,
nonmetastatic castration-resistant prostate cancer while ADT + DAR was also associated with a lower risk of
(M0CRPC), and metastatic castration-resistant prostate can- vascular toxicity in comparison to ADT + ENZ over longer
cer (mCRPC). This is the first study in PCa to use compre- follow-up. This may be a true effect, but the reliance on
hensive metrics from the International Cardio-Oncology indirect comparisons in varied patient populations and with
Society, which include heart failure, myocarditis, vascular differences in follow-up and outcome reporting may
toxicity, hypertension, and arrhythmias, within a meta-ana- explain the observation. These uncertainties underscore
lysis framework [5]. This approach provides greater struc- the need for more direct, head-to-head comparisons to bet-
tural rigour and clinical relevance to the results. However, ter elucidate the vascular risks associated with these combi-
caution is necessary in interpreting the results presented nation therapies.

*
Corresponding author. The Christie and Salford Royal Hospitals, Manchester, UK.
E-mail address: [email protected] (N.W. Clarke).

https://doi.org/10.1016/j.eururo.2024.10.005
0302-2838/[pdftagstart acctype=Ó 2024 Published by Elsevier B.V. on behalf of European Association of Urology.
28 EUROPEAN UROLOGY 87 (2025) 27–28

Importantly, Aziz et al [1] address cumulative CV risks uation 2 (SCORE2) and Systematic Coronary Risk Evaluation
associated with prior treatments, particularly during the for Older Persons (SCORE2-OP) to stratify CVD risk. The
transition from mHSPC to mCRPC. Their Bayesian analysis PROXMAP study by Aziz et al [1] may help to push clinicians
showed that prior mHSPC treatment influences cardiotoxic- a little further in this direction; its insights into the car-
ity from subsequent mCRPC therapies. Notably, addition of diotoxicity profiles of therapies for advanced PCa add to
olaparib (OLA) to ADT + AAP reduced the risk of hyperten- the body of evidence showing the need for careful CVD
sion in comparison to ADT + AAP, or ADT + ENZ. The analysis monitoring and personalised treatment planning. However,
also showed that in comparison to compared to ADT + ENZ, it is important to recognise the lack of comparative trials in
ADT + AAP with or without OLA was associated with a lower this area and the inherent weakness in methodology in
risk of vascular toxicity in patients with prior mHSPC treat- studies of this type, which combine the uncertainties of
ment and following early progression after M0CRPC treat- Bayesian analysis with limited individual-patient data and
ment. These findings align with previous work showing an lack of inclusion of the everyday patients in trials. This
increase in hard CV endpoints including myocardial infarc- necessitates caution to avoid overinterpretation of modest
tion and CV death with first-line mCRPC treatments versus differences between therapeutic agents and combinations.
ADT alone [6]. However, as the authors caution, their results With these caveats, this work will potentially help clini-
require careful interpretation because of the complex inter- cians, particularly urologists, to remember that they are
play and variability of prior treatments, uncertainties in not just surgeons: they must also be physicians if they are
Bayesian modelling, and the limited number of trials. These to provide better and potentially safer treatments for
limitations weaken the robustness of the conclusions and patients with advanced PCa.
add weight to the notion that these findings must be inter-
preted with a degree of caution. Conflicts of interest: The authors have nothing to disclose.
The study results align with previous research showing
that AAP causes higher rates of hypertension and other CV References
events due, at least in part, to glucocorticoid-induced min-
[1] Aziz MK, Molony D, Monlezun D, et al. Prostate cancer therapy
eralocorticoid excess [7]. The lower cardiotoxicity observed cardiotoxicity map (PROXMAP) for advanced disease states: a
with DAR, as reported by Aziz et al [1], suggests that DAR systematic review and network meta-analysis with Bayesian
may represent a safer therapeutic option for patients with modeling of treatment histories. Eur Urol 2025;87:15–26.
[2] Mani K, Deng D, Lin C, Wang M, Hsu ML, Zaorsky NG. Causes of death
high CV risk, although this is not a direct, head-to-head among people living with metastatic cancer. Nat Commun
comparison with AAP. Supporting this notion, prior studies 2024;15:1519.
revealed that the lowest CV toxicity among androgen recep- [3] Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-
deprivation therapy in advanced prostate cancer. N Engl J Med
tor–targeted agents (ARTAs) was in patients receiving DAR
2020;382:2187–96.
in addition to the standard of care [6]. [4] Leong DP, Fradet V, Shayegan B, et al. Cardiovascular risk in men
When applying these findings to clinical practice it is with prostate cancer: insights from the RADICAL PC study. J Urol
crucial to recognise that ADT combination treatments may 2020;203:1109–16.
[5] Herrmann J, Lenihan D, Armenian S, et al. Defining cardiovascular
affect patients with pre-existing CV conditions dispropor- toxicities of cancer therapies: an International Cardio-Oncology
tionately in comparison to those enrolled in clinical trials. Society (IC-OS) consensus statement. Eur Heart J 2022;43:280–99.
Real-world data reveal that up to 60% of patients receiving [6] El-Taji O, Taktak S, Jones C, et al. Cardiovascular events and androgen
an ARTA have at least one CV comorbidity [8]. Conse- receptor signaling inhibitors in advanced prostate cancer: a
systematic review and meta-analysis. JAMA Oncol 2024;10:874–84.
quently, the CV effects observed in this analysis are likely [7] Attard G, Merseburger AS, Arlt W, et al. Assessment of the safety of
to be more pronounced in the real-world population, where glucocorticoid regimens in combination with abiraterone acetate for
patients may not meet the strict eligibility criteria typical of metastatic castration-resistant prostate cancer: a randomized, open-
label phase 2 study. JAMA Oncol. 2019;5:1159–67.
clinical trials.
[8] Lu-Yao G, Nikita N, Keith SW, et al. Mortality and hospitalization risk
How should surgical and nonsurgical PCa clinicians following oral androgen signaling inhibitors among men with
address this important clinical issue in practice in general? advanced prostate cancer by pre-existing cardiovascular
The European Society of Cardiology Council of Cardio- comorbidities. Eur Urol 2020;77:158–66.
[9] European Society of Cardiology. European Society of Cardiology (ESC)
Oncology has highlighted the need for comprehensive cardio-oncology guidelines. Recommendations on cardiovascular
CVD risk assessment in patients undergoing treatment [9], risk assessment in prostate cancer patients. Eur Heart J. In press.
and recommends use of the Systematic Coronary Risk Eval-
 EUROPEAN UROLOGY 87 (2025) 29–46

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Review – Prostate Cancer – Editor’s Choice

Editorial by David J. VanderWeele, Maha Hussain on pp. 47–48 of this issue

Intensification Approaches and Treatment Sequencing in Metastatic

Castration-resistant Prostate Cancer: A Systematic Review

Edoardo Francini a, Neeraj Agarwal b, Elena Castro c, Heather H. Cheng d, Kim N. Chi e, Noel Clarke f,
Joaquin Mateo g, Dana Rathkopf h, Fred Saad i, Bertrand Tombal j,*
a
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; b Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt
Lake City, UT, USA; c Hospital Universitario 12 de octubre, Madrid, Spain; d University of Washington and the Fred Hutchinson Cancer Center, Seattle, WA, USA;
e
BC Cancer - Vancouver Center, University of British Columbia, Vancouver, BC, Canada; f The Christie and Salford Royal Hospital NHS Foundation Trusts and
University of Manchester, Manchester, UK; g Vall d’Hebron Institute of Oncology and Vall d’Hebron University Hospital, Barcelona, Spain; h Memorial Sloan
Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA; i Centre Hospitalier de l’Université de Montréal, Montreal, Canada; j Division of
Urology, Institut de Recherche Clinique, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium

Article info Abstract

Article history: Background and objective: Recently, research on treatment intensification has gathered
Accepted September 4, 2024 momentum, and three novel therapy combinations were approved for metastatic
castration-resistant prostate cancer (mCRPC). This systematic review summarizes the
Associate Editor: current and emerging evidence around intensified strategies for mCRPC and provides
Gianluca Giannarini guidance for an ideal therapeutic sequencing.
Methods: Preferred Reporting Items for Systematic Review and Meta-analysis Protocols
Keywords: (PRISMA-P) guidelines were followed to perform this review. PubMed, EMBASE, Web of
Metastatic castration-resistant Science, Cochrane Library, ClinicalTrials.gov, and major international societies’ online
prostate cancer proceedings were searched comprehensively until May 15, 2024, for terms related to
Combination therapy treatment intensification and sequencing for mCRPC.
Layering Key findings and limitations: Overall, 28 clinical trials and 24 ongoing studies of intensi-
Intensification fication treatments were included in this review. Algorithms of optimal sequencing of
Addition approved treatments for mCRPC were outlined according to the use of androgen receptor
Prostate cancer pathway inhibitors (ARPIs) with or without docetaxel for earlier disease states. In first
line, poly(ADP-ribose) polymerase inhibitor + ARPI combinations improve radiographical
progression-free survival (rPFS), particularly for those with BRCA1/2 alterations. The AKT
inhibitor combination of ipatasertib + abiraterone extends rPFS in those with PTEN loss
or PIK3CA/AKT1/PTEN alterations. In those with two or more risk factors for early pro-
Please visit www.eu-acme.org/europeanurology
gression on enzalutamide, radionuclide 177-Lu-PSMA-617 + enzalutamide prolongs
to answer questions on-line. The EU-ACME cred-
progression-free survival. Ongoing research of intensified approaches for mCRPC, and
its will then be attributed automatically.
available and potential predictive and prognostic biomarkers are discussed.
Conclusions and clinical implications: Recent approvals and ongoing investigations of
single agents and intensification approaches will keep transforming the mCRPC treat-
ment landscape. Improvement of patient profiling applying recognized genomic,

* Corresponding author. CHEX Avenue Hippocrate 55/B1.55.04, 1200 Woluwe-Saint-Lambert,

Belgium. Tel. +32 2 764 55 40; Fax: +32 2 764 55 80.
E-mail address: [email protected] (B. Tombal).

https://doi.org/10.1016/j.eururo.2024.09.008
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
30 EUROPEAN UROLOGY 87 (2025) 29–46

molecular, and clinical predictive and prognostic indicators is fundamental to optimize

sequential use of available therapies.
Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are
reserved, including those for text and data mining, AI training, and similar technologies.

ADVANCING PRACTICE

What does this study add?

This article reviews all current evidence and potential advances regarding the use of intensification approaches for meta-
static castration-resistant prostate cancer. Additionally, it offers potential algorithms of ideal therapeutic sequencing
according to the previous use of androgen receptor pathway inhibitors or docetaxel for earlier states of disease. Acknowl-
edged genomic, molecular, and clinical biomarkers should guide treatment decision-making.

Clinical Relevance
While combination therapies have prolonged survival in patients with metastatic castration-resistant prostate cancer,
determining the optimal sequencing of the rapidly expanding range of available treatments remains challenging. This sys-
tematic review of intensification strategies highlights the use of docetaxel, cabazitaxel, PARP/AKT inhibitors, and 177Lu-
PSMA-617, particularly in patients with specific genetic alterations, such as BRCA 1/2 or PIK3CA/AKT1/PTEN mutations.
Understanding treatment indications based on prior local and systemic therapies and prognostic and predictive biomark-
ers is crucial for personalizing care. Patient preferences, toxicity profiles, and local reimbursement considerations are also
key factors in selecting the optimal treatment options. The included figures covering the common scenarios of metastatic
castration-resistant disease effectively summarize the literature, and provide a very useful framework for individual clin-
ical decision-making. Associate Editor: Gianluca Giannarini MD.

Patient Summary
This systematic review summarizes what is currently known about combination treatments approved for metastatic
castration-resistant prostate cancer and potential new ones. It also provides a guide to a sequential use of these treat-
ments based on available biomarkers.

1. Introduction [4–15]. That adds to the conundrum of identifying the best

therapeutic sequence for patients with mCRPC. Despite a
In the past decade, emerging intensification strategies have rapidly growing portfolio of effective therapies, mCRPC
revolutionized the systemic treatment paradigm of prostate remains a lethal disease, and optimizing the sequence of
cancer. Combining an androgen receptor pathway inhibitor available drugs and improving patient selection are critical
(ARPI) with the traditional androgen deprivation therapy to extending survival [16,17]. This systematic review syn-
(ADT) is now the standard of care for the treatment of meta- thesizes the existing evidence regarding treatment intensi-
static hormone-naïve (mHNPC) and nonmetastatic fication for mCRPC and provides guidance for an optimal
castration-resistant (nmCRPC) prostate cancer, and more sequence of the approved therapies based on the use of
recently, high-risk localized prostate cancer [1–3]. Hence, ARPIs with or without docetaxel in earlier settings and
patients currently diagnosed with metastatic castration- available genomic, molecular, and clinical indicators.
resistant prostate cancer (mCRPC) have disease that has
progressed not only through ADT (ARPI-naïve mCRPC), but
also increasingly through a first-line ARPI (ARPI- 2. Methods
progressed mCRPC). Over the past 5 yr, seven new treat-
ments were shown to delay the progression or death of This systematic review was conducted in accordance with
men with mCRPC and have been approved in this late set- the Preferred Reporting Items for Systematic Review and
ting of disease [4–16]. Three of these are combinations of Meta-analysis Protocols (PRISMA-P) guidelines [18] and
a poly(ADP-ribose) polymerase inhibitor (PARPI) with an the protocol was registered in the International Prospective
ARPI and are indicated as first-line options for mCRPC with Registry of Systematic Reviews (PROSPERO; ID:
some provisions [8–13]. However, the vast majority of the CRD42024493318). The electronic registries PubMed, Web
patients recruited to the key phase 3 clinical trials of these of Science, EMBASE, Cochrane Library, and ClinicalTrials.-
novel combination therapies had disease progression on gov, and American Society of Clinical Oncology and Euro-
traditional ADT only, with or without docetaxel, and data pean Society of Medical Oncology annual proceedings
on those with ARPI-progressed mCRPC are very limited were systematically searched up to July 15, 2024, for the
 EUROPEAN UROLOGY 87 (2025) 29–46 31

following terms: ‘‘metastatic castration resistant prostate 3. Results

cancer,’’ ‘‘intensified approaches,’’ ‘‘intensification,’’ ‘‘combi-
nation,’’ ‘‘addition,’’ ‘‘layering,’’ ‘‘sequencing,’’ ‘‘first line,’’ 3.1. Study selection
‘‘second line,’’ ‘‘third line,’’ and ‘‘heavily pretreated.’’ Eligible
articles in English language, regarding treatment intensifi- The PRISMA diagram (Fig. 1) depicts the study selection
cation or sequencing for mCRPC and including prospective process. Overall, 798 investigations were originally identi-
clinical trials, meta-analyses, retrospective studies, fied through the electronic search. Of these, 743 were
abstracts, and ongoing clinical trials, were screened inde- excluded as duplicate records or after a critical review of
pendently by two reviewers (E.F. and N.A.), and the list titles/abstracts or full texts or as per the exclusion criteria.
was reviewed critically by the whole author roster. All Final screening resulted in 55 eligible studies.
authors further contributed to an accurate and complete
3.2. Study characteristics
article selection using their knowledge of the literature
related to the topics of the review. The aforementioned Of the selected studies, 29 were phase 2–4 trials of
two reviewers also independently assessed the quality and approved intensified treatments with registration or combi-
risk of bias (RoB) of the selected analyses (applying the nation/sequencing purposes. Their key demographic,
Cochrane RoB 2 tool for the randomized controlled trials methodological, and clinical data are presented in Table 1.
[19]) and performed extraction of data, including name of The RoB 2 analysis of such trials is described in Supplemen-
the first author, NCT number (if applicable), publication tary Table 1. The proposed treatment algorithms of the
year, study design, sample size, type and dose of drug used, drugs approved for mCRPC according to a prior failure of
baseline patient clinicopathological characteristics, geno- ARPIs and/or docetaxel are reported in Figure 2. The
mic and molecular determinants, relevant clinical out- remainder of the identified studies comprised 26 ongoing
comes, and adverse events. The study supervisor (B.T.) trials of investigational intensified approaches that can be
acted as a referee for any disagreement between the two considered promising based on preliminary translational
reviewers. or clinical data (Table 2).

Identification of studies via databases and registers

Records identified from:

Identification

PubMed (n = 183)
Web of Science (n = 143)
Records removed before screening:
EMBASE (n = 141)
Duplicate records removed (n = 375)
Cochrane library (n = 106)
ClinicalTrials.gov (n = 110)
ASCO/ESMO annual meetings (n = 115)

Records screened (n = 423) Records excluded after title/abstract review (n = 343)

Screening

Reports excluded as:

1. Reviews (n = 10)
2. Letters to the editor (n = 2)
Reports assessed for eligibility (n = 80)
3. Case reports (n = 7)
4. Editorials/commentaries/author replies (n = 2)
5. Ineligible after full-text review (n = 4)
Included

Studies included in this review (n = 55)

Fig. 1 – Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flowchart of study inclusion. ASCO = American Society of Clinical
Oncology; ESMO = European Society for Medical Oncology.
 32
Table 1 – Trials of intensified treatments approved for mCRPC

Trial name (identifier), year Population (patients) Design Period Patients with Patients Prespecified Primary Results of interest
(s) of publication of ARPI in earlier with Doc for subgroups endpoints
accrual settings (%) mHNPC (%) (patients)
PARPI + ARPI + ADT
BRCAAWAY (NCT03012321), mCRPC Phase 2 2017– 2 (3.3) 16 (26) NA PFS 8.4 (95% CI, 2.9–25) vs 14 (95%
2024 1st line R 1:1:1 NA CI, 8.4–20) vs 39 (95% CI, 16–NR)
BRCA1/2+ and/or ATM+ (N = 61) AAP (olaparib crossover) vs mo
olaparib (AAP crossover) vs
AAP + olaparib
TALAPRO-2 (NCT03395197), mCRPC Phase 3 2019– HRR+ 34 (8.5) 179 (22.2) HRR+ rPFS ITT
2023 1st line R 1:1 2020 (N = 399) NR vs 21.9 mo, HR = 0.63 (95% CI,
Asymptomatic or mildly symptomatic Enza + talazoparib vs Enza + 0.51–0.78), p < 0.0001
(N = 805) placebo HRR+
NR vs 13.8 mo, HR = 0.45 (95% CI,
0.33–0.61), p < 0.0001
PROpel (NCT03732820), mCRPC Phase 3 2018– 1 (0.1) 179 (22.5) NA rPFS rPFS
2022–2023 1st line R 1:1 2020 24.8 vs 16.6 mo, HR = 0.66 (95%

EUROPEAN UROLOGY 87 (2025) 29–46

(N = 796) AAP + olaparib vs AAP + CI, 0.54–0.81), p < 0.001;
placebo OS
42.1 vs 34.7 mo, HR = 0.81 (95%
CI, 0.67–1.00), p = 0.054
MAGNITUDE (NCT03748641), mCRPC Phase 3 2019– HRR+ HRR+ HRR+ rPFS rPFS (2nd IA)
2023 1st line R 1:1 2021 13 (3.1) 85 (20.1) (N = 423) BRCA+
AAP 4 mo allowed (N = 670) AAP + niraparib vs AAP + HRR– 19.5 vs 10.9 mo, HR = 0.55 (95%
placebo (N = 247) CI, 0.39–0.78), p = 0.0007
HRR+
16.7 vs 13.7 mo, HR = 0.76 (95%
CI, 0.60–0.97), p = 0.028;

OS (2nd IA)
BRCA+29.3 vs 28.6 mo,
HR = 0.88 (95% CI, 0.58–1.34),
p = 0.5505
PARPI + ADT
TRITON3 (NCT02975934), mCRPC Phase 3 2017– NA 91 (22.5) BRCA+ ibPFS ITT
2023 After 1 ARPI R 2:1 2022 (N = 302) 10.2 vs 6.4 mo, HR = 0.61 (95% CI,
BRCA+ and/or ATM+ (n = 405) Rucaparib vs Doc or AAP/Enza 0.47–0.80), p < 0.001
BRCA+
11.2 vs 6.4 mo, HR = 0.50 (95% CI,
0.36–0.69), p < 0.001
TRITON2 (NCT02952534), mCRPC Phase 2 2015– NA BRCA+ BRCA+ ORR BRCA+
2020–2023 After 1 taxane and 1 ARPI Rucaparib 2021 17 (14.8) (N = 172) 46%
HRR+ (95% CI, 35–57)
(N = 277)
PROfound (NCT02987543), mCRPC Phase 3 2017– 13 (3.4) NA BRCA+/ATM+ ibPFS ibPFS
2020 After AAP/Enza R 2:1 2018 (N = 245) BRCA+
HRR+ Olaparib vs alternative AAP/ Any other of 7.4 vs 3.6 mo, HR = 0.34 (95% CI,
(N = 387) Enza 12 HRR+ 0.25–0.47), p < 0.001;
(N = 142)
OS
BRCA+
19.1 vs 14.7 mo, HR = 0.69 (95%
CI, 0.50–0.97), p = 0.02
Table 1 (continued)

Trial name (identifier), year Population (patients) Design Period Patients with Patients Prespecified Primary Results of interest
(s) of publication of ARPI in earlier with Doc for subgroups endpoints
accrual settings (%) mHNPC (%) (patients)
Radionuclide + ARPI + ADT
ENZA-p (NCT04419402), 2024 mCRPC Phase 2 2020– 21 (13) 89 (54.9) NA PSA PFS 13.0 vs 7.8 mo,
1st line R 1:1 2022 HR = 0.43 (95% CI, 0.29–0.63), p <
2 risk factors for early Enza Enza + Lu177 vs Enza 0.0001
progression
(N = 162)
ERA223 (NCT02043678), mCRPC Phase 3 2014– NA NA NA Symptomatic 22.3 vs 26.0 mo HR = 1.122 (95%
2018 Doc-naïve asymptomatic or mildly R 1:1 2016 skeletal event– CI, 0.917–1.374), p = 0.2636
symptomatic with bone and no Radium-223 + AAP vs AAP + free survival
visceral metastases (N = 806) placebo
Radionuclide + ADT
PSMAfore (NCT04689828), mCRPC Phase 3 2021– 88 (18.8) NA NA rPFS 12.0 vs 5.6 mo,
2023 Doc-naïve R 1:1 2022 HR = 0.43 (95% CI, 0.33–0.54), p <
After 1 ARPI Lu177 vs alternative ARPI 0.0001
1 PSMA+ and no PSMA– lesions

EUROPEAN UROLOGY 87 (2025) 29–46

(N = 468)
TheraP (NCT03392428), mCRPC Phase 3 2018– NA NA NA PSA response PSA response
2021–2024 After Doc R 1:1 2019 (50%); OS 66% vs 37%
Cab next appropriate treatment Lu177 vs Cab (95% CI, 16–42), p < 0.0001;
1 PSMA+ and no PSMA– lesions and OS
no discordant FDG sites 16.4 vs 19.4 mo, HR = 0.97 (95%
(N = 200) CI, 0.70–1.35), p = 0.99
VISION (NCT03511664), 2021 mCRPC Phase 3 2018– NA NA NA ibPFS; ibPFS
After 1 taxane and 1 ARPI R 2:1 2019 OS 8.7 vs 3.4 mo, HR = 0.40 (99.2%
1 PSMA+ and no PSMA– lesions Lu177 + SoC vs SoC CI, 0.29–0.57), p < 0.001;
(N = 831) OS
15.3 vs 11.3 mo, HR = 0.62 (95%
CI, 0.52–0.74), p < 0.001
ALSYMPCA mCRPC Phase 3 2008– NA NA NA OS 14.9 vs 11.3 mo, HR = 0.70 (95%
(NCT00699751), 2013 After Doc R 2:1 2011 CI, 0.58–0.83), p < 0.001
Symptomatic with bone and no Radium-223+ SoC vs placebo
visceral metastases + SoC
(N = 921)
ARPI + taxane + ADT
CHAARTED2 mCRPC Phase 2 2018– 0 (0) 223 (100) NA PFS 14.9 vs 9.9 mo,
(NCT03419234), 2024 After ADT + Doc for mHNPC R 1:1 2023 HR = 0.73
AAP + Cabv (80% CI, 0.59–0.90)
s p = 0.049
AAP

a
PRESIDE mCRPC Phase 3b 2014– NA NA NA PFS 9.5 vs 8.3 mo, HR = 0.72 (95% CI,
(NCT02288247), 2023 1st line Period 1: 2016 0.53–0.96), p = 0.027
Asymptomatic or mildly symptomatic Enza with no PSA or
(N = 688) radiographic progression at
week 13 until progression
Period 2:
R 1:1
Enza + Doc vs placebo + Doc

(continued on next page)

33
 34
Table 1 (continued)

Trial name (identifier), year Population (patients) Design Period Patients with Patients Prespecified Primary Results of interest
(s) of publication of ARPI in earlier with Doc for subgroups endpoints
accrual settings (%) mHNPC (%) (patients)
ABIDO mCRPC Phase 2 2014– NA NA NA 12-mo rPFS 34.9% (95% CI, 20.7–49.2) vs
(NCT02036060), 2022 1st line Period 1: 2019 rate a 33.9% (95% CI, 19.5–48.3),
Asymptomatic or mildly symptomatic AAP until progression p = 0.527
(N = 148) Period 2:
R 1:1
AAP + Doc vs P + Doc
CHEIRON mCRPC Phase 2 2014– NA NA NA 6-mo 12.5% (95% CI, 8.1–20.6) vs 27.8%
(NCT02453009), 2021 1st line R 1:1 2017 progression (95% CI, 22.8–39.4), p = 0.002
(N = 246) Doc + Enza vs Enza rate
ARPI + ARPI + ADT
a
PLATO mCRPC Phase 4 NA NA NA NA PFS 5.7 vs 5.6 mo, HR = 0.83 (95% CI,
(NCT01995513), 2018 1st line Period 1: 0.61–1.12), p = 0.22
Doc-naïve (N = 509) Enza with no PSA increase at
weeks 13 and 21 until PSA
progression

EUROPEAN UROLOGY 87 (2025) 29–46

Period 2:
R 1:1
Enza + AAP vs placebo + AAP
ARPI + ADT
A randomized phase 2 study mCRPC Phase 2 2014– NA 11 (5.5) NA Time to second Time to second PSA progression
of sequencing AAP and 1st line R 1:1 2016 PSA 19.3 vs 15.2 mo, HR = 0.66 (95%
Enza in mCRPC (N = 202) AAP until PSA progression, progression; CI, 0.45–0.97), p = 0.036;
(NCT02125357), 2019 then Enza vs Enza until PSA PSA response PSA response
progression, then AAP (30%) 26% vs 4%, p < 0.0001
PREVAIL mCRPC Phase 3 2010– NA NA NA rPFS; rPFS
(NCT01212991), 2014– Doc-naïve R 1:1 2012 OS 20.0 vs 5.4 mo, HR = 0.32 (95% CI,
2018 Asymptomatic or mildly symptomatic Enza vs placebo 0.28–0.37), p < 0.0001;
(N = 1717) OS
35.3 vs 31.3 mo, HR = 0.77 (95%
CI 0.67–0.88), p = 0.0002
AFFIRM mCRPC Phase 3 2009– NA NA NA OS 18.4 vs 13.6 mo, HR = 0.63 (95%
(NCT00974311), 2012 After Doc R 2:1 2010 CI, 0.53–0.75), p < 0.001
(N = 1199) Enza vs placebo
COU-AA-302 mCRPC Phase 3 2009– NA NA NA rPFS; rPFS
(NCT00887198), 2013– Doc-naïve R 1:1 2010 OS 16.5 vs 8.3 mo, HR = 0.53 (95% CI,
2015 Asymptomatic or mildly symptomatic AAP vs placebo + P 0.45–0.62), p < 0.001
(N = 1088) OS
34.7 vs 30.3 mo, HR = 0.81 (95%
CI, 070–0.93), p = 0.0033
COU-AA-301 (NCT00091442), mCRPC Phase 3 2008– NA NA NA OS 15.8 vs 11.2 mo, HR = 0.74 (95%
2011–2012 After Doc R 2:1 2009 CI, 0.64–0.86), p < 0.0001
(N = 1195) AAP vs placebo + P
Taxane + ADT
CARD mCRPC Phase 4 2015– 1 32 (12.5%) NA ibPFS ibPFS
(NCT02485691), 2019 After ARPI (AAP/Enza, rPFS 12 mo) R 1:1 2018 (0.4%) 8.0 vs 3.7 mo, HR = 0.54 (95% CI,
and After Doc/Cab (N = 255) Cab (25 mg/m2) vs alternative 0.40–0.73), p < 0.001;
ARPI (Enza/AAP) OS
13.6 vs 11.0 mo, HR = 0.64 (95%
CI, 0.46–0.89), p = 0.008
Table 1 (continued)

Trial name (identifier), year Population (patients) Design Period Patients with Patients Prespecified Primary Results of interest
(s) of publication of ARPI in earlier with Doc for subgroups endpoints
accrual settings (%) mHNPC (%) (patients)
FIRSTANA mCRPC Phase 3 2011– NA NA NA OS Cab (25 mg/m2) 25.2 vs Doc (75
(NCT01308567), 2017 Doc-naïve R 1:1:1 2013 mg/m2) 24.3 mo,
(N = 1168) Cab (25 mg/m2) vs Cab (20 HR = 0.97 (95% CI, 0.82–1.16),
mg/m2) vs Doc (75 mg/m2) p = 0.757
Cab (20 mg/m2)
24.5 vs Doc (75 mg/m2) 24.3 mo,
HR = 0.97 (95% CI, 0.82–1.16),
p = 0.757
TROPIC mCRPC Phase 3 2007– NA NA NA OS 15.1 vs 12.7 mo, HR = 0.70 (95%
(NCT00417079), 2010 After Doc R 1:1 2008 CI, 0.59–0
83), p < 0.0001
(N = 755) Cab (25 mg/m2) vs
mitoxantrone
SWOG 9916, 2004 mCRPC Phase 3 1999– NA NA NA OS 17.5 vs 15.6 mo, HR = 0.80 (95%
Doc-naïve R 1:1 2003 CI, 0.67–0.97), p = 0.02
(N = 674) Doc (60 mg/m2) vs

EUROPEAN UROLOGY 87 (2025) 29–46

estramustine
TAX-327, 2004–2008 mCRPC Phase 3 2000– NA NA NA OS Doc (75 mg/m2)
Doc-naïve R 1:1:1 2002 19.2 vs mitoxantrone
(N = 1006) Doc (75 mg/m2) vs Doc (30 16.3 mo,
mg/m2) vs mitoxantrone HR = 0.79 (95% CI, 0.67–0.93),
p = 0.004
Doc (30 mg/m2)
17.8 vs mitoxantrone
16.3 mo,
HR = 0.87 (95% CI, 0.74–1.08),
p = 0.86
Sipuleucel-T b + ADT
IMPACT mCRPC Phase 3 2003– NA NA NA OS 25.8 vs 21.7 mo,
(NCT00065442), 2010 Before/after Doc R 2:1 2007 HR = 0.77 (95% CI, 0.61–0.97),
Asymptomatic or minimally Sipuleucel-T vs Placebo p = 0.02
symptomatic
(N = 512)
AAP = abiraterone acetate plus prednisone; ADT = androgen deprivation therapy; ARPI = androgen receptor pathway inhibitor; ATM+ = ATM mutated; BRCA+ = mutations in BRCA1/2 genes; Cab = cabazitaxel; CI = confidence
interval; Doc = docetaxel; Enza = enzalutamide; FDG = 2-flourine-18 [18F] fluoro-2-deoxy-D-gluycose; HR = hazard ratio; HRR+ = mutations in homologous recombination repair genes; HRR– = no mutations in homologous
recombination repair genes; IA = interim analysis; ibPFS = imagine-based progression-free survival; ITT = intention to treat; Lu177 = [177Lu]Lu-PSMA-617; mCRPC = metastatic castration-resistant prostate cancer; mHNPC =
metastatic hormone-naïve prostate cancer; NA = not available or applicable; NR = not reached; ORR = objective response rate; OS = median overall survival; P = prednisone or prednisolone; PARPI = poly(ADP-ribose)
polymerase inhibitor; PET-CT = positron emission tomography computed tomography; PFS = median progression-free survival; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; PSMA– = negative
lesions at a gallium-68 [68Ga]Ga-PSMA-11 PET-CT scan; PSMA+ = positive lesions at a gallium-68 [68Ga]Ga-PSMA-11 PET-CT scan; R = randomized; rPFS = median radiographic progression-free survival; SoC = standard of care.
a
Period 2.
b
Not authorized in Europe.

35
36 EUROPEAN UROLOGY 87 (2025) 29–46

3.3. General considerations parib + abiraterone, whereas the olaparib + abiraterone

combination is approved for all patients provided that
Although research on treatment intensification has been
chemotherapy is not indicated. Based on the rPFS subgroup
gaining momentum in recent years, it should be noted that
analyses of the RCT TALAPRO-2 exploring the talazoparib
all available therapies for mCRPC are de facto already inten-
plus enzalutamide combination, this intensified strategy
sification approaches, in that these are layering of an anti-
grants greater benefit to those with HRR+ [12,13]. In the
cancer agent to the ADT started in an earlier setting and
USA, talazoparib + enzalutamide is restricted to HRR+
continued beyond progression to castration resistance
patients, whereas in Europe this combination is approved
(Table 1). Since ADT was used in all registration trial designs
for all patients provided that chemotherapy is
as the treatment foundation, it should be maintained in the
contraindicated.
course of mCRPC (Fig. 2).

3.4.1.2. Second line. Upon progression on first-line abi-

3.4. ARPI-naı̈ve mCRPC
raterone/enzalutamide, docetaxel could be used, particu-
The updated international guidelines recommend the addi- larly in patients without BRCA+, with poor prognostic
tion of an ARPI to traditional ADT as the standard of care for factors and rPFS on a previous ARPI for 12 mo [27,28]. In
the treatment of mHNPC or nmCRPC [20,21]. However, contrast, a switch of ARPI is discouraged by the interna-
despite an ever-growing use of ARPI-intensified strategies tional guidelines owing to recognized cross-resistance
in these and earlier states of disease [1–3], currently, almost mechanisms [20,21]. Recently, the phase 2 randomized
two-thirds of newly diagnosed mCRPC cases have pro- BRCAAWAY trial suggested a superior progression-free sur-
gressed following ADT monotherapy [22]. A lack of prior vival (PFS) benefit (crossover included) for the olaparib +
exposure to ARPIs may depend on local access issues or abiraterone combination (39 mo, 95% CI 16–not reached)
the physician’s choice to use ADT alone. versus olaparib-abiraterone sequence (14 mo, 95% CI 8.4–
20) or the opposite sequence (8.4 mo, 95% CI 2.9–25) in
3.4.1. ARPI naïve, docetaxel naïve those with BRCA+ or ATM mutations (ATM+) [29]. There-
3.4.1.1. First line. For ARPI- and docetaxel-naïve patients, fore, for BRCA+ disease, olaparib should be considered with
particularly those without visceral metastases and with abiraterone in first line. If that did not occur, second-line
mild or no symptoms, abiraterone acetate plus pred- olaparib monotherapy should be considered based on the
nisone/prednisolone (hereafter termed abiraterone) or rPFS advantage achieved with this PARPI versus abi-
enzalutamide are a standard of care first-line therapy raterone/enzalutamide after the failure of an alternative
[23,24]. In asymptomatic or minimally symptomatic dis- ARPI in the phase 3 PROfound study (HR = 0.34, 95% CI
ease without visceral metastases, an alternative is the autol- 0.25–0.47; p < 0.001) [6]. The phase 3 TRITON3 trial showed
ogous dendritic cell vaccine sipuleucel-T (authorized only in improved rPFS for those with BRCA+ (or ATM+) treated with
the USA) [25]. In contrast, docetaxel chemotherapy should PARPI rucaparib versus a control arm including docetaxel or
preferably be contemplated for those with symptomatic ARPI after previous alternative ARPI (HR = 0.61, 95% CI 0.47–
disease, poor prognostic features that could portend resis- 0.80; p < 0.001), and hence a stronger control arm than that
tance to ARPIs (ie, visceral metastases particularly of the of PROfound (which included abiraterone/enzalutamide
liver, prior ADT failure 12 mo, and rapidly increasing only). However, mature OS data are not available yet and
prostate-specific antigen [PSA]), and no predictive biomark- rucaparib is currently not indicated in this setting [5]. In
ers such as alterations of homologous recombination repair PROfound, extended OS was observed with olaparib com-
genes (HRR+), particularly BRCA1 or BRCA2 (hereafter ter- pared with the control (HR = 0.69, 95% CI 0.50–0.97;
med BRCA+) [26,27]. Recent approvals of PARPI plus ARPI p = 0.02) [7]. Following first-line docetaxel, abiraterone/en-
combinations for mCRPC led to more available options in zalutamide is an efficient therapy supported by level 1 evi-
this setting [20,21]. The phase 3 randomized controlled tri- dence [30,31]. For those with poor prognostic features and
als (RCTs) PROPEL and TALAPRO2 reported prolonged radio- still fit for chemotherapy, cabazitaxel is the favored treat-
graphic progression-free survival (rPFS; primary endpoint) ment [28,32]. For those with HRR+/BRCA+ whose disease
for the experimental regimens abiraterone + olaparib (haz- progressed on a PARPI + ARPI combination, prospective data
ard ratio [HR] = 0.66, 95% confidence interval [CI] 0.54–0.81; guiding the choice of following treatments are lacking. As
p < 0.001) and enzalutamide + talazoparib (HR = 0.63, 95% CI taxane was the subsequent treatment most commonly used
0.51–0.78; p < 0.0001), respectively, compared with the in the TALAPRO2 (cohort 1, 23%) and PROPEL (68.9%) trials
ARPI control [10,12]. The phase 3 RCT MAGNITUDE showed (MAGNITUDE trial data are not available), despite these
extended rPFS (primary endpoint) for the combination nira- being indirect data, docetaxel appears a logical choice
parib + abiraterone compared with abiraterone + placebo in [8,10,12].
a preselected HRR+ cohort (HR = 0.76, 95% CI 0.60–0.97;
p = 0.028) [8]. The gene-stratified subanalyses of rPFS and 3.4.1.3. Third line. In cases of mCRPC progressed after one
overall survival (OS; mature OS currently available solely ARPI and one taxane, different strategies may be applied. If
for the PROPEL trial) of PROPEL and MAGNITUDE showed rPFS on prior ARPI was 12 mo, cabazitaxel is a valid option
that BRCA+ derived the most significant benefit from these in light of the survival advantage achieved with cabazitaxel
intensified approaches [8–11]. In the USA, olaparib or nira- compared with an alternative ARPI after the docetaxel-ARPI
parib and abiraterone combinations are indicated for BRCA+ or opposite sequence in the phase 4 randomized CARD trial
patients only. In Europe, this restriction applies only to nira- [33]. In case of prostate-specific membrane antigen (PSMA)-
 EUROPEAN UROLOGY 87 (2025) 29–46 37

A ARPI- and Doc-naïve mCRPC

1st PARPI +
Doc AAP/Enza a
line AAP/Enza

A b
2nd Cab AAP/Enza Doc Olaparib Doc
D
line T

Olaparib b/ e d
AAP/Enza Cab Lu-177 d Ra-223 Doc Cab Lu-177 Ra-223 e
3rd rucaparib c
line

B ARPI-naïve and Doc-progressed mCRPC

1st Olaparib + AAP/

Cab AAP/Enza
line talazoparib + Enza a

A Olaparib b/ d e
2nd AAP/Enza Cab Lu-177 Ra-223 Doc
D rucaparib c
line T

d e Olaparib b/
3rd Lu-177 Ra-223 Cab Cab Lu-177 d
Ra-223 e
rucaparib c
line

C ARPI-progressed and Doc-naïve mCRPC D ARPI- and Doc-progressed mCRPC

Talazoparib + d Olaparib b/
1st Doc 1st Cab Lu-177
Enza a rucaparib c
line line

A Olaparib b A Ra-223 Olaparib b

Cab Ra-223 e Lu-177d Lu-177 d Cab
2nd D Doc 2nd D
Rucaparib c e Rucaparib c
line T line T

Lu- Ra- Olaparib b Lu- Ra- Lu-177 d Ra-223 e

3rd Cab Cab 3rd
177 d 223 e Rucaparib c 177 d 223 e
line line

Figure 2 – Proposed treatment algorithms in mCRPC according to prior progression on ARPIs and/or Doc: (A) ARPI- and Doc-naïve, (B) ARPI-naïve and Doc-
progressed, (C) ARPI-progressed and Doc-naïve, and (D) ARPI- and Doc-progressed mCRPC. AAP = abiraterone acetate plus prednisone; ADT = androgen
deprivation therapy; ARPI = androgen receptor pathway inhibitor; Cab = cabazitaxel; Doc = docetaxel; Enza = enzalutamide; HRR = homologous recombination
repair; Lu-177 = [177Lu]Lu-PSMA-617; mCRPC = metastatic castration-resistant prostate cancer; PARPI = poly(ADP-ribose) polymerase inhibitor; PET-CT =
positron emission tomography computed tomography; PSMA = prostate-specific membrane antigen; Ra-223 = radium-223. a In the USA, niraparib or olaparib
combinations with abiraterone acetate plus prednisone are approved only for men with BRCA1/2 mutations, and talazoparib plus enzalutamide for men with
HRR defects; in Europe, both olaparib and talazoparib combinations are approved for all patients if chemotherapy is not clinically indicated, and niraparib
plus abiraterone is only for men with BRCA1/2 mutations. b Only for patients with BRCA1/2 mutations. c Not approved in Europe. d Only for patients with
positive lesions at a gallium-68 [68Ga]Ga-PSMA-11 PET-CT scan. e Only for patients with symptomatic bone metastases and no visceral metastases.
Table 2 – Ongoing trials of intensified treatments for mCRPC

38
Trial identifier Population Design Prespecified Primary endpoints Status/preliminary
(name) (patients) subgroups results
AKTI + ARPI + ADT
NCT03072238 mCRPC Phase 3 PTEN loss by IHC rPFS Active, not
(IPATential150) 1st line R 1:1 recruiting/ rPFS
(N = 1101) AAP + ipatasertib vs AAP + placebo ITT
19.2 vs 16.6 mo,
HR = 0.84 (95% CI,
0.71–0.99), p = 0.043
PTEN loss
18.5 vs 16.5 mo,
HR = 0.77 (95% CI,
0.61–0.98), p = 0.034
AKTI + chemotherapy + ADT
NCT05348577 mCRPC Phase 3 NA OS Recruiting
(CAPItello280) Progressed on/after 1 ARPI used for mCRPC, mHNPC, R 1:1
or nmCRPC Doc + capivasertib vs Doc + placebo
IO + TKI + ADT

EUROPEAN UROLOGY 87 (2025) 29–46

NCT04446117 mCRPC Phase 3 Liver metastatic PFS; Active, not
(CONTACT-02) Progressed on/after 1 ARPI used for mCRPC, mHNPC, R 1:1 Prior Doc for mHNPC OS recruiting/ PFS
or nmCRPC and with soft-tissue lesions Atezolizumab + cabozantinib vs alternative ITT
(N = 507) AAP/Enza 6.3 vs 4.2 mo,
HR = 0.65 (95% CI,
0.50–0.84),
p = 0.0007
Liver metastatic
6.0 vs 2.1 mo,
HR = 0.47 (95% CI
0.30–0.74)
Prior Doc for mHNPC
8.8 vs 4.1 mo,
HR = 0.55 (95% CI,
0.32–0.96);

OS
ITT
16.7 vs 14.6 mo,
HR = 0.79 (95% CI,
0.58–1.07), p = 0.13
NCT05168618 mCRPC Phase 2 NA 24-wk disease control rate Recruiting
(AtezoCab) Progressed on/after 1 ARPI used for mCRPC, mHNPC, Atezolizumab + cabozantinib
or nmCRPC
IO + ARPI + ADT
NCT03834493 mCRPC Phase 3 NA OS: Active, not recruiting
(MK-3475-641/KEYNOTE- R 1:1 rPFS
641) Enza + pembrolizumab vs Enza + placebo
PARPI + ARPI + ADT
NCT04691804 mCRPC Phase 3 NA rPFS Recruiting
1st line R 1:1
AAP + fuzulaparib vs AAP + placebo
PARPI + chemotherapy + ADT
NCT03442556 mCRPC Phase 2 NA rPFS Active, not recruiting
(PLATI-PARP) After any therapy excluding carboplatin HRR+ Induction phase
Doc + carboplatin (4 cycles)
Maintenance phase
Rucaparib camsylate
Table 2 (continued)

Trial identifier Population Design Prespecified Primary endpoints Status/preliminary

(name) (patients) subgroups results
PARPI + VEGF RTK inhibitor + ADT
NCT02893917 mCRPC Phase 2 NA rPFS Active, not recruiting
After 2 therapies R 1:1
Cediranib + olaparib vs olaparib
Radionuclides + IO + ADT
NCT05150236 mCRPC Phase 2 NA 1-yr PSA-PFS Active, not recruiting
(EVOLUTION/ANZUP2001) After 1 ARPI R 2:1
1 PSMA+ Lu177 + ipilimumab + nivolumab vs Lu177
NCT05766371 mCRPC Phase 2 NA 12-mo rPFS Recruiting
Progressed on/after 1 taxane and 1 ARPI used for Lu177+
mCRPC, mHNPC, or nmCRPC Pembrolizumab
1 PSMA+
NCT04946370 mCRPC Phase 1 NA DLT Recruiting
Progressed on/after 1 AAP/Enza used for mCRPC, Dose escalation 225Ac-J591+ RP2D
mHNPC, or nmCRPC Pembrolizumab + ARPI Composite response rate

EUROPEAN UROLOGY 87 (2025) 29–46

Phase 2
R 1:1
Dose expansion at recommended dose 225Ac-
J591+
Pembrolizumab + ARPI vs pembrolizumab +
ARPI
NCT03093428 mCRPC Phase 2 NA Number of participants with Active, not recruiting
After any therapy excluding radium-223 and anti– R 1:1 increased immune cell
PD-1/PD-L1/2 IO with bone metastases Radium-223 + pembrolizumab vs radium-223 infiltration
NCT04071236 mCRPC Phase 1 NA MTD; Recruiting
After any therapy with bone metastases Dose escalation and dose expansion DLT;
Radium-223 + peposertib (arm B) rPFS
Radium-223 + peposertib + avelumab (arm C)

Phase 2
R 1:1:1
Radium-223 (arm A) vs arm B vs arm C
Radionuclides + PARPI + ADT
NCT03874884 mCRPC Phase 1 NA DLT; Recruiting
(LUPARP) After 1 taxane and 1 ARPI Dose escalation (3 + 3 design) and dose RP2D
1 PSMA+ and no PSMA– lesions expansion at recommended dose in second
phase
Lu177 + olaparib
Radionuclides + chemotherapy + ADT
NCT05340374 (LuCAB) mCRPC Phase 1 NA MTD; Recruiting
After 1 taxane and 1 ARPI Dose escalation and dose expansion at DLT;
1 PSMA+ recommended dose in second phase RP2D
Lu177 + Cab
NCT06303713 mCRPC Phase 1 NA MTD; Not yet recruiting
(LuCarbo) Progressed on/after 1 taxane and 1 ARPI used for Dose escalation (3 + 3 design) and dose RP2D
mCRPC, mHNPC, or nmCRPC expansion at recommended dose in second
1 PSMA+ phase
Lu177 + carboplatin
Radionuclides + ARPI + ADT
NCT02194842 mCRPC Phase 3 NA rPFS Active, not recruiting
(PEACE III) 1st line R 1:1

39
(continued on next page)
 40
Table 2 (continued)

Trial identifier Population Design Prespecified Primary endpoints Status/preliminary

(name) (patients) subgroups results
With bone and no visceral metastases Enza + radium-223 vs Enza + placebo
Asymptomatic or mildly symptomatic
Radionuclides + ADT
NCT05383079 mCRPC Phase 1/2 NA MTD; Recruiting
(AlphaBet) Progressed on/after 1 ARPI used for mCRPC, mHNPC, Lu-177 + radium-223 DLT;
or nmCRPC with bone metastases RP2D
1 PSMA+
Radionuclides + TKI + ADT
NCT05613894 mCRPC Phase 1b NA MTD; Recruiting
(CaboLu) Progressed on/after 1 taxane and 1 ARPI used for Dose escalation (3 + 3 design) and dose DLT;
mCRPC, mHNPC, or nmCRPC expansion at recommended dose in second 24-wk PFS
1 PSMA+ phase
Lu177 + cabozantinib
AR degraders + ARPI + ADT
NCT05067140 mCRPC Phase 1/2 NA DLT; Recruiting
After 2 therapies including 1 ARPI ARV-766 ± AAP Toxicity;

EUROPEAN UROLOGY 87 (2025) 29–46

Safety;
PSA response
NCT05177042 mCRPC Phase 1b NA DLT; Active, not recruiting
With PSA progression on ongoing AAP for mHNPC or ARV-110 + AAP RP2D;
mCRPC Toxicity;
Safety
CDK4/6 inhibitor + IO + ADT
NCT04751929 mCRPC Phase 2 CDK12+ 6-mo PFS rate; Active, not recruiting
Progressed on/after 1 ARPI used for mCRPC, mHNPC, (R 1:1 in CDK12–) CDK12– Overall response rate;
or nmCRPC, and not candidate for chemotherapy Abemaciclib + atezolizumab vs abemaciclib DLT;
Safety
ARPI + chemotherapy + ADT
NCT05762536 mCRPC Phase 2 NA PFS Recruiting
(DAROTAXEL) After 1 ARPI used for mCRPC or mHNPC R 1:1
Darolutamide + Doc/Cab vs Doc/Cab
NCT02913196 mCRPC Phase 1 NA DLT Active, not recruiting
Dose escalation and dose expansion at
recommended dose in second phase
Apalutamide + AAP + Doc
CYP11A1 inhibitors + ADT
NCT06136624 mCRPC Phase 3 AR ligand-binding OS; Recruiting
(OMAHA1) Progressed on/after 2 taxanes and 1 ARPI used for R 1:1 domain mutation rPFS
mCRPC, mHNPC, or nmCRPC MK-5684 vs alternative AAP/Enza status
NCT06136650 mCRPC Phase 3 AR ligand-binding OS; Recruiting
(OMAHA2a) Progressed on/after 1 ARPI used for mCRPC, mHNPC, R 1:1 domain mutation rPFS
or nmCRPC MK-5684 vs alternative AAP/Enza status
AAP = abiraterone acetate plus prednisone; ADT = androgen deprivation therapy; AKTI = AKT inhibitor; AR = androgen receptor; ARPI = androgen receptor pathway inhibitor; Cab = cabazitaxel; CDK12+ = mutations in CDK12;
CI = confidence interval; DLT = dose limiting toxicity; Doc = docetaxel; Enza = enzalutamide; HR = hazard ratio; HRR+ = mutations in homologous recombination repair genes; IHC = immunohistochemistry; IO =
immunotherapy; ITT = intention to treat; Lu177 = [177Lu]Lu-PSMA-617; mCRPC = metastatic castration-resistant prostate cancer; MTD = maximum tolerated dose; mHNPC = metastatic hormone-naïve prostate cancer; NA =
not available or applicable; nmCRPC = nonmetastatic castration-resistant prostate cancer; OS = overall survival; PARPI = poly(ADP-ribose) polymerase inhibitor; PET-CT = positron emission tomography computed
tomography; PFS = progression-free survival; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen; PSMA– = negative lesions at a gallium-68 [68Ga]Ga-PSMA-11 PET-CT scan; PSMA+ = positive lesions
at a gallium-68 [68Ga]Ga-PSMA-11 PET-CT scan; R = randomized; rPFS = median radiographic progression-free survival; RP2D = recommended phase 2 dose; RTK = receptor tyrosine kinase; TKI = tyrosine kinase inhibitor;
VEGF = vascular endothelial growth factor.
 EUROPEAN UROLOGY 87 (2025) 29–46 41

positive (PSMA+) disease at a [68Ga]Ga-PSMA-11 positron etaxel for mHNPC; hence, this is not high-level evidence.
emission tomography computed tomography (PET-CT) scan Alternatively, in case of PSMA+ disease and no discordance
(and no discordant sites, ie, 2-[18F]FDG PET-CT–positive or at the 2-[18F]FDG PET-CT, [177Lu]Lu-PSMA-617 may be
PSMA-negative lesions), the radioligand [177Lu]Lu-PSMA- considered. However, evidence is not strong as the propor-
617 is also an efficient therapy according to the positive tions of patients receiving upfront docetaxel in the VISION
results of the VISION and TheraP trials (Table 1) [14,34]. and TheraP trials are not available [14,34]. Radium-223 is
Of note, because nearly 53% (n = 278) of patients in the an option with painful and bone-only disease [35,36]. For
experimental cohort of the VISION trial received an ARPI BRCA+, either olaparib (if not used previously in first line)
(chiefly enzalutamide/abiraterone) as the standard of care or rucaparib (not authorized in Europe) could be valid alter-
in addition to [177Lu]Lu-PSMA-617 + ARPI, a combination natives. However, despite olaparib showing prolonged OS
of these two agents in eligible patients is reasonable. In than the control (HR = 0.64, 95% CI 0.39–1.08) in BRCA+
symptomatic disease with bone and no visceral metastases, men treated previously with taxane chemotherapy in PRO-
the radionuclide radium-223 could be administered [35,36]. found [41], the rate of those treated with docetaxel for
For those with BRCA+, either olaparib (provided that it was mHNPC is unclear (and only 14.8% [n = 17] in the BRCA+
not used previously in first line) or rucaparib is indicated subgroup of TRITON2 trial) [5–7].
[4–7]. The latter was granted accelerated approval in the
USA based on the positive findings in the BRCA+ subgroup 3.4.2.3. Third line. If abiraterone/enzalutamide or cabazi-
from the single-arm phase 2 TRITON2 trial but is still not taxel was second-line therapy, [177Lu]Lu-PSMA-617 and
approved in Europe [4]. The immune checkpoint inhibitor radium-223, with their respective indications, or PARPI
(ICI) pembrolizumab was approved with a tumor agnostic monotherapy, if BRCA+, can be third-line strategies
indication including prostate cancer and is available in [6,14,35,36]. After the failure of olaparib or [177Lu]Lu-
some countries for men with microsatellite instability- PSMA-617, taxanes were the most used subsequent thera-
high (MSI-H) or mismatch repair deficiency (dMMR) muta- pies in the respective registration trials (21.1% and 16.6%,
tions or a high tumor mutational burden who progressed on respectively); hence, cabazitaxel is eligible [6,14].
available standard treatments [15].
3.5. ARPI-progressed mCRPC

3.4.2. ARPI naïve, docetaxel progressed A prior ARPI with or without docetaxel for earlier settings is
The doublet ADT + docetaxel, without an ARPI, is no longer still underutilized in real-world clinical practice [22], and
recommended for mHNPC except for unavailability or con- high-level evidence to guide treatment is currently scarce.
traindications to any ARPI [20,21]. However, upfront use of ARPIs and/or docetaxel was per-
mitted in some recent trials (Table 1). In the randomized
3.4.2.1. First line. Upon failure of ADT + docetaxel, despite phase 2 ENZA-p study exploring first-line enzalutamide +
the lack of prospective data for this specific setting, abi- [177Lu]Lu-PSMA-617 (two or four doses, if the PSMA-PET-
raterone or enzalutamide seems to retain its activity as CT scan performed after the first two doses shows persis-
first-line therapy for mCRPC [37]. For those with unfavor- tent PSMA+ disease) versus enzalutamide alone in patients
able prognostic factors, docetaxel rechallenge seems to have with two or more risk factors for early progression on enza-
limited activity and cabazitaxel should be used [38,39]. In lutamide (metastatic disease at diagnosis, <3 yr from diag-
this regard, the phase 2 RCT CHAARTED2 recently showed nosis, more than five bone or visceral metastases, prior
that cabazitaxel for up to six cycles added to abiraterone use of abiraterone for mHNPC, PSA doubling time <84 d,
versus abiraterone alone prolonged PFS (primary endpoint) opioid use for >14 d, serum levels of lactate dehydrogenase
of men pretreated with ADT + docetaxel for high-volume or alkaline phosphatase upper limit of normal, and albu-
mHNPC (HR = 0.73, 80% CI 0.59–0.90; p = 0.049) [40]. min <35 g/l), those who received either abiraterone or doc-
Although the secondary endpoint of OS was not met etaxel for mHNPC accounted for 13% (n = 21) and 54.9%
(p = 0.67), this combination might be considered in this set- (n = 89) of the population, respectively. The study reported
ting. In case of HRR+, especially BRCA+, prespecified sub- improved PSA PFS (primary endpoint) for the combination
analyses of rPFS in PROPEL (HR = 0.61, 95% CI 0.40–0.92) compared with the comparator (HR = 0.43, 95% CI 0.29–
and TALAPRO2 (cohort HRR+; HR = 0.39, 95% CI 0.22–0.69) 0.63; p < 0.0001). However, OS data are immature, and this
showed that olaparib + abiraterone or talazoparib + enzalu- intensification strategy is still investigational [42]. The
tamide are more effective than the respective ARPI counter- phase 3 RCT PSMAfore demonstrated longer rPFS (primary
part regardless of the previous use of docetaxel for mHNPC endpoint) for [177Lu]Lu-PSMA-617 versus a switch of ARPI
[10,12]. In contrast, rPFS data from the MAGNITUDE trial (abiraterone/enzalutamide) for taxane-naïve mCRPC pro-
(cohort HRR+; HR = 0.89, 95% CI 0.48–1.66) did not highlight gressing on one ARPI, including apalutamide, darolutamide,
any benefit for the niraparib + abiraterone regimen com- abiraterone, or enzalutamide, and with one or more PSMA+
pared with the control in this specific population [8]. and no PSMA– lesions (HR = 0.43, 95% CI 0.33–0.54;
p < 0.0001). Of note, the rPFS benefit is also seemingly main-
3.4.2.2. Second line. If abiraterone/enzalutamide was used tained (HR = 0.57, 95% CI 0.33–0.98) in those who had an
in first line, cabazitaxel might be a valid option [32], espe- ARPI for mHNPC (18.8%, n = 88) [43]. However, no OS differ-
cially if rPFS on first-line ARPI was 12 mo according to ence was found at the third interim analysis (HR = 0.98, 95%
the CARD trial criteria [33]. It should be noted, however, CI 0.75–1.28), and [177Lu]Lu-PSMA-617 is still not indi-
that only 12.5% (n = 32) of patients in this trial received doc- cated in this setting [44].
42 EUROPEAN UROLOGY 87 (2025) 29–46

3.5.1. ARPI progressed, docetaxel naïve ADT + docetaxel therapy for mHNPC may be a candidate
3.5.1.1. First line. Docetaxel was the subsequent systemic for cabazitaxel, [177Lu]Lu-PSMA-617 if PSMA+, or PARPI
therapy administered most commonly in all registration tri- monotherapy if BRCA+.
als of ARPI + ADT for mHNPC [45–48]. Indirectly, these data
suggest that docetaxel may be a viable first-line strategy. 3.5.2.2. Second line. After the failure of cabazitaxel,
For those with BRCA+, provided that enzalutamide was radium-223, [177Lu]Lu-PSMA-617, and a PARPI with their
not used previously (as per the TALAPRO2 protocol criteria), respective indications are possible alternatives
only talazoparib + enzalutamide may be reasonable [12]. [4,6,14,35,36]. After progression on [177Lu]Lu-PSMA-617
Indeed, while the portion of patients treated with ARPIs or PARPI monotherapy, cabazitaxel may be used.
for earlier disease states in TALAPRO2 (cohort HRR+;
n = 34, 8.5%) was limited, those of PROPEL (n = 1, 0.1%)
3.5.2.3. Third line. Following second-line cabazitaxel,
and MAGNITUDE (cohort HRR+; n = 13, 3.1%) were minimal.
either radionuclide may be applied [14,35,36]. Finally, par-
The corresponding rPFS was available only in TALAPRO 2
ticipation in a clinical trial whenever available should be
and found to be consistent with the treatment effect shown
considered the best option in any scenario or setting of
in the general population (HRR+ cohort; HR = 0.53, 95% CI
disease.
0.20–1.42). Abiraterone/enzalutamide should be avoided
in first line owing to the well-known cross-resistance mech-
anisms between sequential ARPIs [49]. However, the 3.6. Future directions
increasing use of ARPIs in earlier spaces of disease leads to
Ongoing research is trending toward intensification of
the question whether, similarly to ADT, their continuation
treatment by layering or combining standard or investiga-
beyond progression to castration resistance in combination
tional therapeutics (Table 2). In this regard, several ongoing
with other therapies may turn into an effective approach. In
studies are evaluating combinations including radionu-
this regard, the phase 3b RCT PRESIDE explored the addition
clides, in particular [177Lu]Lu-PSMA-617, owing to its
of docetaxel to enzalutamide used as first-line therapy for
property of selectively delivering radiation to cancer cells
mCRPC and continued after progression compared with
and inducing DNA strand breakage that may enhance the
enzalutamide + placebo. Despite this trial showing an rPFS
efficacy of additional anticancer agents. In this respect, the
benefit for the experimental arm (HR = 0.72, 95% CI 0.53–
ongoing trial LUPARP (NCT03874884) is a phase 1 trial, with
0.96; p = 0.027), OS was not assessed [50]. Further, the
a dose escalation design, investigating the dose-limiting
phase 2 ABIDO-SOGUG trial investigated the addition of
toxicity and recommended dose of olaparib + [177Lu]Lu-
docetaxel to abiraterone used in first line and continued
PSMA-617 for ARPI– and taxane-pretreated PSMA+ mCRPC.
beyond progression versus docetaxel alone. However, this
The two phase 1 ongoing studies LuCAB (NCT05340374)
study failed to meet the primary endpoint of 12-mo rPFS
and LuCarbo (NCT06303713) are assessing the recom-
improvement for the combination arm (p = 0.527) [51].
mended dose of cabazitaxel and carboplatin chemotherapy,
The contrasting results may depend on discrepancies in trial
respectively, combined with [177Lu]Lu-PSMA-617 for
design. However, neither of these studies explored continu-
PSMA+ mCRPC progressed on one or more taxanes and
ing an ARPI beyond progression to the mCRPC state.
one or more ARPIs. Lastly, the intensified strategy of
radium-223 + enzalutamide is being assessed versus enza-
3.5.1.2. Second line. After docetaxel progression, cabazi- lutamide alone as first-line treatment for mCRPC with bone
taxel, [177Lu]Lu-PSMA-617, or radium-223 with their and no visceral metastases in the randomized phase 3 study
respective provisions may be used [6,7,14,34–36]. For PEACE III (NCT02194842), which was recently reported to
BRCA+, olaparib or rucaparib (the latter not in Europe) have reached its primary endpoint of rPFS and key sec-
may be considered. However, the rate of those pretreated ondary endpoint OS.
with ARPIs prior to mCRPC is 3.4% (n = 13) in PROfound There is increasing interest in combining standard ther-
and unknown in TRITON2 [4,6]. After progression on tala- apies with agents that bypass specific tumor pathways.
zoparib + enzalutamide, docetaxel was the most adminis- The ongoing phase 3 RCT IPATential150 (NCT03072238) is
tered therapy in TALAPRO2 and may be used [12]. assessing the investigational combination of the AKT inhibi-
tors ipatasertib and abiraterone versus abiraterone + pla-
3.5.1.3. Third line. After the failure of a PARPI or [177Lu] cebo in first line [52]. As opposed to what was found in
Lu-PSMA-617, cabazitaxel may be administered [6,14]. the intention-to-treat population (HR = 0.84, 95% CI 0.71–
After progression on second-line docetaxel, cabazitaxel, 0.99; p = 0.043; not significant at a = 0.01), the primary end-
[177Lu]Lu-PSMA-617, or radium-223 may be used point rPFS was extended significantly with the experimen-
[14,35,36]. If cabazitaxel was applied as second line, the tal strategy in those with PTEN loss (HR = 0.77, 95% CI
radionuclides with their respective indications or PARPI 0.61–0.98; p = 0.034; significant at a = 0.04) and those with
monotherapy for BRCA+ are available options [4,6,14,35,36]. PIK3CA/AKT1/PTEN alterations (HR = 0.63, 95% CI 0.44–
0.88). Survival data are immature. The cyclin-dependent
3.5.2. ARPI progressed, docetaxel progressed kinase 4/6 inhibitor abemaciclib was being investigated in
3.5.2.1. First line. Owing to the lack of published guiding combination with abiraterone versus abiraterone + placebo
evidence in this setting, expert opinions from the 2022 as first-line treatment in the phase 2/3 RCT CYCLONE 2
Advanced Prostate Cancer Consensus Conference may be (NCT03706365). However, this trial did not meet its pri-
considered [16]. Those who underwent a triplet ARPI + mary endpoint of rPFS and was terminated recently [53].
 EUROPEAN UROLOGY 87 (2025) 29–46 43

Despite the historical failures of immunotherapy for (HR = 0.81 and HR = 0.66, respectively), and the least in
mCRPC (sipuleucel-T aside), much attention is currently HRR– patients (HR = 0.89 and HR = 0.76, respectively)
devoted to intensified approaches of ICIs plus tyrosine- [8,9]. These results are in line with the rPFS data reported
kinase inhibitors (TKIs) or radiopharmaceuticals hypothe- in TALAPRO2 and, for those with HRR+ or BRCA+, also in
sizing a synergistic effect. The ongoing phase 3 RCT MAGNITUDE [10,12]. In a recent US Food and Drug Admin-
CONTACT-02 (NCT04446117) is evaluating the ICI ate- istration pooled HRR+ analysis of patient-level data from
zolizumab plus the TKI cabozantinib versus a second ARPI PROPEL, MAGNITUDE, and TALAPRO2, the benefit of PARPI
(abiraterone/enzalutamide) for mCRPC progressed on/after + ARPI combinations was observed not only for BRCA+,
one ARPI used for mCRPC or earlier settings and with soft- but also for CDK12 and PALB2 mutations, whereas no
tissue metastases. At a first-interim analysis, the combina- apparent advantage was found for ATM+ and CHEK2 muta-
tion achieved longer PFS than the control (HR 0.65, 95% CI tions [57]. This underscores that HRR is a heterogeneous
0.50–0.84; p = 0.0007) [54]. Awaiting the OS analysis, this subgroup including also genes the mutation of which may
combination has not been authorized yet. be detrimental for the activity of PARPI + ARPI and warrants
Current focus is also on novel molecules suppressing the better characterization through gene-selected prospective
synthesis of steroid hormones and thus the androgen- data. While final OS analyses from MAGNITUDE and TALA-
receptor (AR) signaling pathway. The two ongoing phase 3 PRO2 may shed more light on the matter, current evidence
RCTs OMAHA2a (NCT06136650) and OMAHA1 indicates that these intensification strategies may prefer-
(NCT06136624) are assessing the CYP11A1 selective inhibi- ably be used in those with BRCA+, considering also the rel-
tor MK-5684 versus a change of ARPI (abiraterone/enzalu- evant toxicities these may cause. In this respect, a careful
tamide) after the failure of one ARPI used for mCRPC or evaluation of the fitness state of these patients should be
prior settings and the failure of one ARPI and two or fewer performed prior to deciding whether to use PARPIs in a
taxanes, respectively. The primary endpoints in both studies combination as opposed to monotherapy.
are rPFS and OS according to AR ligand-binding domain As research is striving to introduce novel agents and
mutation status. intensification treatments and/or shifting the approved
Finally, there is growing interest in AR degraders, agents ones earlier in the disease course, the conundrum of finding
able to target and destroy wild-type and mutant ARs, which the ideal sequence of therapies is destined to become more
may be used in combination with ARPIs in hopes to over- intricate. In addition, real-world data showed that less than
come cancer mechanisms of resistance to ARPIs. In this half of patients will receive two or more life-prolonging
sense, the ongoing phase 1/2 trial NCT05067140 investi- therapies [58,59]. Therefore, the choice of the first two lines
gated the dose limiting toxicity of the AR degrader ARV- is fundamental, and the application of known genomic,
766 with or without abiraterone for mCRPC progressed on molecular, and clinical predictive and prognostic indicators
two or more therapies, including one or more ARPI. The is essential to improve patient profiling. In this regard, BRCA
phase 2 expansion cohort is exploring the activity and toler- +, present in 10–15% of men with prostate cancer, is a
ability of two doses of ARV-766 for those who received strong predictor of an aggressive cancer phenotype and
three or fewer ARPIs and two or fewer taxanes, and prelim- poor prognosis and is associated with worse clinical out-
inary data seem promising in those harboring mutant ARs comes compared with non-BRCA+ when ARPIs or taxanes
(43% rate of PSA decline 50%) [55]. are used in first line [41,60,61]. However, BRCA+ is associ-
ated with the highest sensitivity to PARPIs and PARPI-
4. Discussion based approaches [8–13]. In particular, those with BRCA2
homozygous deletions may be exceptional responders to
In this article, we synthesized the available data regarding olaparib after first-line abiraterone/enzalutamide, as shown
intensification treatments and utilized the current best evi- in a recent post hoc analysis of the PROfound trial [41]. As
dence to outline the optimal therapeutic pathways through above, also CDK12 and PALB2 may be predictive of the effi-
four possible mCRPC scenarios according to prior progres- cacy of PARPI-based combinations [55]. Further, CRISPR-
sion on ARPIs and/or docetaxel (Fig. 2). Cas9 (clustered regularly interspersed short palindromic
Three intensified approaches of a PARPI plus abiraterone/ repeat-CRISPR associated nuclease 9) screen analyses
enzalutamide are currently approved in first line based on demonstrated that MMS22L and RNASEH2B deletions, not
rPFS benefits [8,10,12]. However, while rPFS is a paramount included within HRR+ and frequently found in prostate can-
clinical endpoint, it is not a valid surrogate of OS [56]. cer, are able to hypersensitize cancer cells to PARPIs and are
Therefore, the rPFS results need to be supported by survival potential predictive biomarkers of PARPI-based therapy
data. PROPEL is currently the only trial that presented final [62,63]. Amplifications and mutations of the AR are
OS results. In the biomarker-unselected overall population, observed commonly in mCRPC and are implicated in cancer
although a 7.4-mo OS numerical advantage for the combi- resistance to abiraterone/enzalutamide. In particular, muta-
nation was found, there was no statistically significant dif- tions of L702H and T878A, resulting in AR activation by glu-
ference between olaparib + abiraterone and the control cocorticoids or progesterone, respectively, may be potential
(p = 0.054). However, clear gradients of OS and rPFS were indicators of resistance to abiraterone [64]. Additionally,
found aligned with biology; thereby, the combination regi- growing evidence indicates that splicing of AR mRNA, espe-
men was most effective in BRCA+ (HR = 0.29 and HR = 0.23, cially AR splice variant 7, is a potential determinant of resis-
respectively), followed by HRR+ (HR = 0.66 and HR = 0.50, tance to abiraterone/enzalutamide [64]. As indicated in the
respectively), less effective in biomarker-unselected IPATential150 trial, PIK3CA/AKT1/PTEN alterations and
44 EUROPEAN UROLOGY 87 (2025) 29–46

immunohistochemistry-assessed PTEN loss, found in 40– Administrative, technical, or material support: None.
50% of prostate cancer cases, are promising predictive Supervision: Tombal.
biomarkers for AKT inhibitors [52]. Furthermore, while the Other: None.
MSI-H/dMMR molecular phenotype is relatively uncommon
in prostate cancer (3.1%), it elicited durable responses to Financial disclosures: Edoardo Francini certifies that all conflicts of inter-
anti–PD-1/PD-L1 therapies such as pembrolizumab in a case est, including specific financial interests and relationships and affiliations
series [15,65]. In particular, a 50% PSA decrease was relevant to the subject matter or materials discussed in the manuscript
observed in 54.5% (n = 6) of MSI-H/dMMR patients, four of (eg, employment/affiliation, grants or funding, consultancies, honoraria,
whom had a radiographic response. Most responsive stock ownership or options, expert testimony, royalties, or patents filed,
patients (five of the six) remained on therapy for at least received, or pending), are the following: Dana Rathkopf: uncompensated
20.5 mo. High PSMA expression (mean standardized uptake advisor—Janssen, Astra Zeneca, Bayer, Myovant, Genentech, Promontory,
value 10) at [68Ga]Ga-PSMA-11 PET-CT and high meta- BMS/Celgene, Novartis, and Astellas; research support (PI of study)—Jans-
bolic tumor volume at 2-[18F]FDG PET-CT were independent sen, AstraZeneca, Bayer, Genentech, Promontory, and BMS/Celgene. Joa-
poor prognostic factors in the VISION trial [14]. Moreover, quin Mateo: advisory boards: AstraZeneca, Amunix/Sanofi, Daichii-
the former was associated with better PSA responses with Sankyo, Janssen, MSD, Pfizer, and Roche; member of the scientific
[177Lu]Lu-PSMA-617, while the latter was correlated with board—Nuage Therapeutics; research funding—AstraZeneca and Pfizer

a worse biochemical response and survival outcome in the to VHIO (institution) investigating optimal use of PARPiin prostate cancer.
Fred Saad: consultant or advisory fees—AbbVie, Novartis, Astellas Pharma,
TheraP trial [34]. As reported above, unfavorable clinical
AstraZeneca, Bayer, Janssen Oncology, Merck, Pfizer, and Tolmar; research
features (ie, rapid PSA progression on ADT or a first-line
funding (to institution): Astellas Pharma, AstraZeneca, Bayer, Bristol
ARPI, high PSA serum levels, low hemoglobin, high levels
Myers Squibb, Janssen Oncology, Merck, Novartis, Pfizer, and Sanofi. Noel
of alkaline phosphatase or lactose dehydrogenase, liver
Clarke: advisory boards and lectures—Janssen, Astellas, Bayer, Merck,
metastases, poor performance status, and pain) are associ-
AstraZeneca, Pfizer, Ipsen, and Novartis; research funding via the STAM-
ated with a better response to taxane therapy [27,33,39].
PEDE trial—Janssen, Astellas, and Novartis; academic conflicts—PI/Co-PI
of Stampede, Radicals, Propel, and Patch Trials. Neeraj Agarwal (lifetime
5. Conclusions COI): consultant or advisory fees—Astellas, AstraZeneca, Aveo, Bayer, Bris-
tol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis,
Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma,
The recent introduction of novel agents and intensification
Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; research
strategies has changed the therapeutic armamentarium in
funding—Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol
mCRPC profoundly as well as posed new challenges in find-
Meyers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli
ing an optimal sequence for the available treatments. The
Lilly, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immu-
increasing use of ARPIs with or without docetaxel in prior
nomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link
disease spaces rendered this task even more complex. Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle
While data from prospective trials assessing head-to-head Genetics, Takeda, and Tracon.
comparisons, combinations, or sequences are useful, these
are not sufficient to identify the ideal sequence of therapies.
In an era of precision oncology, the genomic, molecular, and Funding/Support and role of the sponsor: None.

clinical profiling of patients provides irreplaceable guidance

in the sequential selection of therapeutics and must be Supplementary material
implemented regularly in clinical practice. Finally, every
effort should be made to identify and validate new predic-
Supplementary data to this article can be found online at
tive and prognostic biomarkers, the application of which
https://doi.org/10.1016/j.eururo.2024.09.008.
would allow for maximizing the efficacy of available drugs
and intensified approaches while avoiding the toxicity of
futile ones. References

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 EUROPEAN UROLOGY 87 (2025) 47–48

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Editorial

Referring to the article published on pp. 29–46 of this issue

Management Decisions for Metastatic Castration-resistant Prostate

Cancer in 2024

David J. VanderWeele, Maha Hussain *

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

1. Introduction The first step is testing for specific biomarkers. In partic-

ular, if genomic testing is not performed, it is not known if
Over the past 20 years there has been significant evolution the patient is a candidate for a PARP inhibitor or for
of management strategies for metastatic castration-resis- immunotherapy. We recommend early genomic testing,
tant prostate cancer (mCRPC) that has led to improvements preferably in the hormone-sensitive prostate cancer (HSPC)
in patient outcomes and survival. By 2012, docetaxel, abi- stage if feasible. This means that information is available to
raterone, enzalutamide, and cabazitaxel were approved for make management decisions when needed, and reduces the
treatment of mCRPC, all of which led to overall survival likelihood of tissue age affecting the feasibility and quality
(OS) benefits. Historically, the strategies were ‘‘one drug of sequencing. If archival tissue is negative, then a fresh
and one size fit all’’. Since 2017 we have entered the era biopsy should be considered. If tissue testing is not feasible
of precision and personalized therapy and intensification and liquid biopsy is being considered, this is best performed
with combination strategies. In this issue of European Urol- in cases with a higher disease burden [4]. It should be noted
ogy, Francini et al [1] provide a comprehensive summary of that a negative liquid biopsy result does not necessarily rule
phase 2 and 3 trials that inform management decisions for out potential actionable genetic alterations, and a fresh tis-
patients with mCRPC. sue biopsy can be considered.
It is also important to know the value of a specific bio-
2. One size does not fit all: the importance of biomarkers marker and for the research community to refine current
biomarkers. In the PROFOUND study, patients with alter-
One of the themes from the review by Francini et al [1] that ations in ATM, BRCA1, and BRCA2 were all included in cohort
should be highlighted is the importance of biomarkers. Sev- A [5]. As Francini et al [1] highlight, it now seems clear that
eral new therapies are approved for biomarker-selected patients with ATM alterations receive little benefit from
patients. When the right biomarker is present, patients have PARP inhibition.
a better chance of deriving greater benefit from biomarker- In the IPATential150 trial, no OS benefit was observed
directed therapy. In PROPEL, the hazard ratio (HR) for OS with the AKT1 inhibitor ipatasertib in patients with PTEN
with addition of olaparib versus abiraterone alone for loss according to immunohistochemistry, which was a key
patients with a BRCA1 or BRCA2 alteration was 0.29 [2]. secondary endpoint. There was an apparent greater ipata-
Many patients with tumors with high microsatellite insta- sertib benefit in patients with PIK3CA, AKT1, or PTEN alter-
bility or mismatch repair deficiency continue to respond ations using a DNA-based biomarker rather than protein-
to immunotherapy past 30 wk [3]. For cases with an action- based biomarker [6].
able biomarker, biomarker-directed therapy should be Biomarker test results are not always binary (positive or
prioritized. negative) but may instead inform prioritization of therapy.

*
Corresponding author. Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Superior Street,
Chicago, IL 60611, USA. Tel. +1 312 9085487; Fax: +1 312 9081372.
E-mail address: [email protected] (M. Hussain).

https://doi.org/10.1016/j.eururo.2024.10.003
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
48 EUROPEAN UROLOGY 87 (2025) 47–48

For PARP inhibitors, BRCA1 and BRCA2 appear to be the best molecular and clinical biomarkers can inform estimates of
predictive biomarkers. PALB2 and CDK12 have also been benefit from future therapies. Ultimately, a shared decision
predictive across trials, with fewer data available for other between the treating physician and the patient helps
genes [7]. While PARP inhibitors should be prioritized for patients best accomplish their goals.
patients with a BRCA1 or BRCA2 alteration, a PARP inhibitor
might be considered, but deprioritized, for a patient with a Conflicts of interest: David J. VanderWeele reports advisory board fees,
RAD54L alteration [5]. For Lu-labeled prostate-specific travel support, and fees for educational talks from Exelixis, Janssen,
membrane antigen (PSMA)-targeted radioligand therapy, Bayer, Astellas, and Myovant; and institutional research support from
patients are selected on the basis of radiotracer uptake on AstraZeneca, Pfizer, Genentech, Bayer, and Nikang Therapeutics. Maha
PSMA positron emission tomography imaging. The TheraP Hussain reports institutional contracts for clinical trials with APCCC

trial demonstrated radiographic progression-free survival (AstraZeneca), Bayer, and Arvinas; advisory board fees from Bayer,
Tango, Novartis, Convergent, and AstraZeneca; and honoraria for lec-
(PFS) benefit for all patients, but a greater benefit was
tures/talks from AstraZeneca, Bayer, MJH Life Sciences, MedScape, and
observed for patients with higher mean standardized
RTP; and travel and accommodation expenses from Bayer.
uptake value [8].
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ARPIs are relatively well tolerated and are thus ideal candi- (ipat) in metastatic castration-resistant prostate cancer (mCRPC):
Next-generation sequencing (NGS) data from the phase III
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IPATential150 trial. J Clin Oncol 2022;40(16 Suppl):5056. https://
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[9] de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus
response, with an odds ratio of 5.34 favoring the experi- abiraterone or enzalutamide in metastatic prostate cancer. N Engl J
mental arm. There was also an improvement in PFS (17 Med 2019;381:2506–18. https://doi.org/10.1056/NEJMoa1911206.
mo vs not reached; HR 0.35) [11]. [10] Emmett L, Subramaniam S, Crumbaker M, et al. [177Lu]Lu-PSMA-
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5. Patients’ wishes and shared decision-making randomised, phase 2 trial. Lancet Oncol 2024;25:563–71. https://
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 EUROPEAN UROLOGY 87 (2025) 49–57

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Original Article

Editorial by Vedang Murthy, Alan Dal Pra on pp. 58–59 of this issue

Testosterone Recovery Following Androgen Suppression and

Prostate Radiotherapy (TRANSPORT): A Pooled Analysis of Five
Randomized Trials from the Meta-Analysis of Randomized Trials in
Cancer of the Prostate (MARCAP) Consortium

Wee Loon Ong a,y, Tahmineh Romero b,y, Soumyajit Roy c, John Nikitas d, David Joseph e,
Almudena Zapatero f, Shawn Malone g, Scott C. Morgan h, Michael L. Steinberg d, Luca F. Valle d,
Nicholas G. Zaorsky h, Ting Martin Ma i, Matthew B. Rettig j, Nicholas Nickols d, Tommy Jiang k,
Robert E. Reiter k, Sriram V. Eleswarapu k, Xavier Maldonado l, Yilun Sun h,m, Paul L. Nguyen n,
Jeremy L. Millar a, Jarad M. Martin o, Daniel E. Spratt h, Amar U. Kishan d,*, on behalf of the MARCAP
Consortium Investigators
a
Alfred Health Radiation Oncology, Monash University, Melbourne, Australia; b Division of General Internal Medicine and Health Services Research, University of
California-Los Angeles, Los Angeles, CA, USA; c Department of Radiation Oncology, Rush University Medical Centre, Chicago, IL, USA; d Department of Radiation
Oncology, University of California-Los Angeles, Los Angeles, CA, USA; e Department of Medicine and Surgery, University of Western Australia, Perth, Australia;
f
Department of Radiation Oncology, Health Research Institute, Hospital Universitario de la Princesa, Madrid, Spain; g Department of Radiology, Radiation Oncology
and Medical Physics, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Canada; h Department of Radiation Oncology, University Hospitals Seidman
Cancer Centre, Case Western Reserve University School of Medicine, Cleveland, OH, USA; i Department of Radiation Oncology, University of Washington, Seattle,
WA, USA; j Department of Medical Oncology, University of California-Los Angeles, Los Angeles, CA, USA; k Department of Urology, University of California-Los
Angeles, Los Angeles, CA, USA; l Hospital Universitari Vall d’Hebron, Barcelona, Spain; m Department of Population Quantitative Health Sciences, Case Western
Reserve University, Cleveland, OH, USA; n Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA; o Department of Radiation Oncology, Calvary Mater Newcastle Hospital, University of Newcastle, Newcastle, Australia

Article info Abstract

Article history: Background and objective: Time to testosterone recovery (TR) following androgen depri-
Accepted September 5, 2024 vation therapy (ADT) with gonadotropin-releasing hormone agonists varies widely. We
evaluate TR kinetics and the oncological impact of an effective castration period in
Associate Editor: patients receiving definitive radiotherapy and ADT for prostate cancer.
Gianluca Giannarini Methods: We obtained individual patient data from randomized controlled trials of
radiotherapy with ADT and prospectively collected serial testosterone data from the
Keywords: MARCAP Consortium. We estimated the times to noncastrate TR (>1.7 nmol/l) and non-
Prostate cancer hypogonadal TR (>8.0 nmol/l) were estimated for each prescribed ADT duration, and
developed corresponding nomograms. The association between effective castration

y
These authors contributed equally to this work.
* Corresponding author. Department of Radiation Oncology, University of California-Los Angeles,
200 Medical Plaza, Los Angeles, CA 90095, USA.
E-mail address: [email protected] (A.U. Kishan).

https://doi.org/10.1016/j.eururo.2024.09.009
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
50 EUROPEAN UROLOGY 87 (2025) 49–57

Radiotherapy period and metastasis-free survival (MFS) for any given ADT duration was evaluated via
Androgen deprivation therapy multivariable Cox regression. We conducted cubic spline analyses to assess nonlinear
Testosterone recovery associations.
Key findings and limitations: We included 1444 men from five trials in the analysis, of
whom 115 received 4 mo, 880 received 6 mo, 353 received 18 mo, 36 received 28 mo,
and 60 received 36 mo of ADT. Times to noncastrate TR and to nonhypogonadal TR var-
ied considerably by ADT duration. Higher baseline testosterone and lower age were asso-
ciated with a higher likelihood of TR (p < 0.001 for both). Effective castration period was
not linearly associated with MFS for any ADT duration on Cox regression. Cubic spline
analysis revealed that the optimal effective castration period for an MFS benefit was
10.6 mo for men who received 6 mo of ADT and 18 mo for men who received 18 mo
of ADT.
Conclusions and clinical implications: Time to TR varies according to the ADT duration,
baseline testosterone, and age. The relationship between effective castration period
and MFS may be nonlinear, with a longer effective castration period being helpful for
men receiving 6 mo of ADT.
Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are
reserved, including those for text and data mining, AI training, and similar technologies.

ADVANCING PRACTICE

What does this study add?

Our comprehensive analyses using individual patient data from prospective trials confirm prior, largely retrospective,
data that testosterone recovery after definitive prostate radiotherapy and androgen deprivation therapy (ADT) varies sig-
nificantly according to ADT duration, baseline testosterone, and age. We developed a nomogram to estimate the proba-
bility of testosterone recovery. Our findings suggest that the effective castration period has a nonlinear association with
metastasis-free survival, and that for patients receiving 6 mo of ADT, castrate testosterone levels for 11 mo may be
optimal.

Clinical Relevance
Androgen deprivation therapy improves oncological outcomes when combined with primary radiation therapy for clin-
ically localized prostate cancer. Optimally counselling patients undergoing therapy with gonadotropin-releasing hormone
agonists requires estimating time from finishing therapy to recovery of normal testosterone and relief from the side
effects of having castrate levels. In this study, the authors performed an individual patient data meta-analysis of five ran-
domized trials and showed how older age, lower baseline testosterone, and long-term androgen deprivation therapy (28
and 36 months) were associated with longer time to testosterone recovery. The authors also evaluated the relationship
between actual time with castrate level testosterone and oncological outcomes, and found that only with shorter dura-
tions of therapy (i.e., 6 months), a longer effective castration period may be associated with optimal outcomes. These find-
ings have major implications for clinical decision-making and optimal usage of gonadotropin-releasing hormone
antagonists, which have significantly shorter times to testosterone recovery. Associate Editor: Gianluca Giannarini MD.

Patient Summary
We looked at testosterone recovery for men who had radiotherapy and androgen deprivation therapy (ADT) for prostate
cancer. We found that testosterone recovery depends on baseline testosterone, age, and the length of the ADT treatment
period. For patients who received ADT for 6 months, a testosterone level close to zero for a period of 11 months seemed to
have the best effect in improving survival free from metastasis of their cancer.

1. Introduction that older age, longer ADT duration, and lower baseline
testosterone are associated with longer time to TR [5–10],
The combination of androgen deprivation therapy (ADT) although confirmation in prospectively followed patients
with definitive radiotherapy is a well-established standard is lacking and the kinetics of TR remains largely understud-
of care for treatment of intermediate- to high-risk prostate ied [3,4]. Moreover, it is unclear whether the time to TR to
cancer [1]. However, ADT is associated with side effects that noncastrate levels impacts overall oncological outcomes
adversely impact quality of life [2]. Testosterone recovery [11]. All the randomized clinical trials showing that longer
(TR) can vary widely and unpredictably among patients fol- ADT durations improve oncological outcomes [1] involved
lowing ADT [3–7]. Several retrospective studies have shown ADT delivery via a depot gonadotropin-releasing hormone
 EUROPEAN UROLOGY 87 (2025) 49–57 51

(GnRH) agonist ± an oral antiandrogen. Given the aforemen- restricted inclusion to men with nonhypogonadal testos-
tioned variability in TR, it is thus unclear whether a longer terone at baseline. We used multivariable Cox
effective castration period for a specified ADT duration has proportional-hazards regression to evaluate the effect of
an impact on outcomes. An understanding of TR after ADT baseline testosterone and age on the time to TR. To assess
is important in the context of newly available novel GnRH the model assumptions when modeling age and baseline
antagonists that have been associated with more rapid TR testosterone as continuous variables, we adopted two
[12–14]. approaches: investigation of the p value for the interaction
We hypothesized that longer prescribed ADT duration is between baseline testosterone and age with log(time); and
associated with longer time to TR, and that for any pre- the use of natural splines with four degrees of freedom.
scribed ADT duration, older age and lower baseline testos- The age effect was assessed per 5-yr increment. Men who
terone are associated with longer time to TR. We also developed biochemical failure before TR were censored on
hypothesized that for any prescribed ADT duration, effec- the date of biochemical failure or the date of last docu-
tive castration period would be associated with mented testosterone level, whichever occurred first. The pre-
metastasis-free survival (MFS), a surrogate endpoint for scribed ADT duration, age, and ECOG performance status
overall survival (OS) in prostate cancer [15]. were included as covariables in all the multivariable models
evaluating time to TR. Sensitivity analyses were conducted to
2. Patients and methods assess the robustness of the results for both time to TR and
nonhypogonadal TR. These analyses included clinically rele-
vant cut points for age (<65 vs 65 yr) and the three baseline
2.1. Study cohorts
testosterone strata (>1.7–8.0, >8.0–10.5, and >10.5 nmol/l).
We identified prospective randomized trials in the Meta- Nomograms were built for both TR to noncastrate and non-
Analysis of Randomized Trials in Cancer of the Prostate hypogonadal levels using these parameters, with sixfold
(MARCAP) Consortium [1] that included men receiving a cross-validation used to determine C index values.
combination of definitive radiotherapy and ADT for prostate For analyses of the impact of effective castration period
cancer, had prospectively collected data on serial testos- on oncological outcomes, multivariable Cox regression
terone available, and included patient-level compliance models were developed to estimate the hazard ratio (HR)
data for prescribed ADT regimens. Five randomized trials and 95% confidence interval (CI) for MFS and OS. Men
that met these criteria were included: TROG9601 [16], who never experienced the event in question were censored
TROG0304/RADAR [17], OTT0101 [18], OTT0502, and on the date of last known follow-up. All analyses were strat-
GICOR0105 [19]. Details of the ADT start date and different ified by the prescribed ADT duration, and adjusted for age,
ADT formulations used in each trials are summarized in clinical T stage, Gleason score, PSA at diagnosis, radiother-
Supplementary Table 1. Overall, these five trials provided apy dose, ECOG performance status, and midpoint year of
distinct cohorts of men who received 4, 6, 18, 28, or 36 trial enrolment. We did not include baseline testosterone;
mo of ADT. We included only men who had a noncastrate although it has been shown that baseline testosterone is
testosterone level (>1.7 nmol/l) at baseline. associated with time to TR, there is not yet any evidence
that it is associated with oncological outcomes. We first
2.2. Endpoints explored the association between baseline testosterone
and MFS, and OS, adjusted for age. We found no statistically
The co-primary endpoints for TR analyses were time of TR significant association between baseline testosterone and
to a noncastrate level (>1.7 nmol/l) and to a nonhypogo- MFS (p = 0.8) or OS (p = 0.3). Therefore, baseline testos-
nadal level (>8.0 nmol/l). Time of TR to baseline testos- terone was not included as a confounder in our models for
terone level was also evaluated. The time to TR for each evaluation of oncological outcomes.
threshold was estimated from the end date of the pre- In a prespecified analysis, natural cubic splines with four
scribed ADT duration to the date of TR. For analysis of the degrees of freedom were used to evaluate a continuous
impact of effective castration period, the primary endpoint nonlinear relationship between effective castration period
was MFS, defined as the time from random assignment until and MFS. This analysis was prespecified only for men
metastasis or death from any cause. effective castration per- receiving 6 mo or 18 mo of ADT, as these durations are com-
iod was defined from the ADT start date to the date of first monly used for men with intermediate- to high-risk pros-
documented noncastrate testosterone level (>1.7 nmol/l). tate cancer and they represented the two largest ADT
duration cohorts in the study [20]. Given the highly variable
2.3. Statistical analyses TR kinetics, we also prespecified that we would exclude the
For all analyses, the following variables were included: age at top 10% patients in either cohort with the longest effective
treatment, natural logarithm of baseline testosterone, East- castration period so that the splines would be more repre-
ern Cooperative Oncology Group (ECOG) performance status sentative. Thus, the maximum effective castration period
(dichotomized as 1–2 vs 0), clinical T stage (dichotomized as was 16.4 mo with 6 mo of ADT, and 26 mo with 18 mo of
T1–2 vs T3–4), Gleason score (categorical), natural logarithm ADT. Splines were adjusted for age, clinical T stage, Gleason
of initial prostate-specific antigen (PSA) at diagnosis (contin- score, PSA at diagnosis, radiotherapy dose, ECOG perfor-
uous), radiotherapy dose (dichotomized as <74 Gy vs mance status, and midpoint year of trial enrolment. The
74Gy), and midpoint year of treatment (categorical). When ‘‘optimal’’ effective castration period was defined as the
estimating time to nonhypogonadal TR (>8.0 nmol/l), we point on the spline at which all other values would have a
52 EUROPEAN UROLOGY 87 (2025) 49–57

greater ln(HR) for MFS, which was determined mathemati- nonhypogonadal levels for men receiving 4 mo of ADT were
cally. The 95% CI for the optimal effective castration period longer than anticipated, and were longer than the times for
was calculated using 10 000 bootstraps. Analyses were per- men receiving 6–18 mo of ADT. This highlights differences
formed using SAS v15.2 (SAS Institute, Cary, NC, USA) and R between cohorts in important baseline factors, including base-
v4.3.1 (R Foundation for Statistical Computing, Vienna, line testosterone and specifically the proportion of patients
Austria). with clinical hypogonadism or low testosterone at the time
of ADT initiation (Table 1).
3. Results The multivariable analysis results for TR are shown in
Table 2, and the splines describing associations of TR with
baseline testosterone and age are shown in Figure 2. Base-
3.1. Testosterone recovery
line testosterone exhibited a log-linear relationship in these
Testosterone data were recorded for 1650 men who models and was modeled as log-transformed baseline
received radiotherapy with ADT in the five trials. Of these, testosterone. After adjusting for ADT duration and ECOG
108 were excluded because baseline testosterone was miss- performance status, men with higher baseline testosterone
ing or <1.7 ng/dl, and 102 were excluded because their were more likely to have TR to noncastrate and nonhypog-
baseline testosterone was measured 30 d after ADT initia- onadal levels. The modeling was repeated using dichoto-
tion. The remaining 1444 men were included in our analy- mized age (<65 vs 65 yr) and three clinically relevant
ses (Table 1). The median survival time was 14.8 yr thresholds for baseline testosterone. Although the relation-
(interquartile range [IQR] 9.3–18). The median follow-up ship between baseline testosterone and time to TR did not
for survivors was 11 yr (IQR 10–12). Overall, 72% of men exhibit a clear threshold effect, the clinically relevant cut
across the prescribed AST durations had a normal testos- points were still evaluated for their potential impact on
terone level (>10.5 nmol/l) at baseline. the outcomes and for nomogram development (Supplemen-
Testosterone levels over time are shown in Figure 1. The tary Table 2).
median time to TR to a noncastrate level was 8.3 mo (IQR Nomograms for predicting the probability of TR to non-
6.7–10.0), 5.9 mo (IQR 5.8–5.9), 5.8 mo (IQR 5.8–5.9), 14.1 castrate or nonhypogonadal levels at 6, 12, 18, 24, and 36
mo (IQR 12.6–15.6), and 11.7 mo (IQR 9.6–13.6) for the groups mo after ADT cessation are shown in Figure 3.
that received 4-mo, 6-mo, 18-mo, 28-mo, and 36-mo ADT,
respectively (Fig. 1A and Supplementary Figs. 1 and 2). The
3.2. Effective castration period and oncological outcomes
median time to TR to a nonhypogonadal level was 20.3 mo
(IQR 11.5–23.8), 8.1 mo (IQR 6.5–9.4), 11.8 mo (IQR 11.4– The unadjusted median effective castration period was 12.8
12.0), 27.0 mo (IQR 22.6–62.4), and 44.3 mo (IQR 23.1–not mo (IQR, 11.1–13.9), 11.9 mo (IQR 11.8–11.9), 23.8 mo (IQR
applicable) for the groups that received 4-mo, 6-mo, 18-mo, 23.8–23.9), 42.2 mo (IQR 40.6–43.6), and 47.9 mo (IQR
28-mo, and 36-mo ADT, respectively (Fig. 1B and Supplemen- 45.6–49.6) for ADT durations of 4 mo, 6 mo, 18 mo, 28
tary Figs 3 and 4). Of note, the times to TR to noncastrate and mo, and 36 mo, respectively.

Table 1 – Baseline characteristics of the study cohort stratified by the ADT duration prescribed
a
Parameter ADT duration p value
4 mo 6 mo 18 mo 28 mo 36 mo
Patients, n (%) 115 (8) 880 (61) 353 (24) 36 (2) 60 (4)
Median age, yr (IQR) 71.7 69.8 68.6 70.8 71 0.001
(66.3–74.1) (64.9–73.6) (63.3–72.7) (68.8–74.5) (67–74.2)
Stage T3/4, n (%) 18 (16) 207 (24) 126 (36) 7 (19) 22 (37) <0.001
Gleason score, n (%) <0.001
6 20 (17) 174 (20) 32 (9.1) 3 (8.3) 4 (6.7)
7 67 (58) 536 (61) 190 (54) 27 (75) 14 (23)
8 23 (20) 95 (11) 60 (17) 6 (17) 18 (30)
9 5 (4.3) 75 (8.5) 71 (20) 0 24 (40)
Median PSA, ng/ml (IQR) 11.2 12 14 9.6 19.9 <0.001
(7.7–20.4) (7.9–18.7) (9.2–24) (5.8–16.1) (9.5–33.2)
Radiotherapy dose, n (%) <0.001
<74 Gy 0 353 (40) 181 (51) 0 0
>74 Gy 115 (100) 527 (60) 171 (49) 36 (100) 60 (100)
Median FU, mo (IQR) 119 123 131 122 126 <0.001
(91–125) (89.8–143) (114–143) (114.8–125) (90.5–156.5)
NCCN high risk, n (%) 61 (53) 401 (46) 238 (67) 16 (44) 60 (100) <0.001
Baseline testosterone, n (%) <0.001
>1.7–8.0 nmol/l 32 (28) 96 (11) 16 (4) 5 (14) 12 (20)
>8.0–10.5 nmol/l 25 (22) 151 (17) 44 (13) 14 (39) 13 (22)
>10.5 nmol/l 58 (50) 633 (72) 293 (83) 17 (47) 35 (58)
Recovered to ncT, n (%) 110 (96) 871 (99) 342 (97) 32 (89) 45 (75) <0.001
Recovered to nhgT, n (%) 82 (71) 759 (86) 269 (76) 21 (58) 24 (40) <0.001
Recovered to nT, n (%) 58 (50) 662 (75) 226 (64) 18 (50) 21 (35) <0.001
ADT = androgen deprivation therapy; FU = follow-up; IQR = interquartile range; NCCN = National Comprehensive Cancer Network; ncT = noncastrate testos-
terone (>1.7 nmol/l); nhgT = nonhypogonadal testosterone (>8.0 nmol/l); nT = normal testosterone (>10.5 nmol/l); PSA = prostate-specific antigen.
a
Calculated using Fisher’s exact test for categorical variables and the Kruskal-Wallis test for continuous variables.
 EUROPEAN UROLOGY 87 (2025) 49–57 53

Fig. 1 – Testosterone recovery over time. Unadjusted Kaplan-Meier curves showing the time to recovery to (A) noncastrate and (B) nonhypogonadal
testosterone levels for the entire cohort according to androgen deprivation therapy (ADT) duration. Median times to noncastrate testosterone after ADT
cessation were 8.3 mo for4-mo ADT, 5.9 mo for 6-mo ADT, 5.9 mo for 18-mo ADT, 14.1 mo for 28-mo ADT, and 11.7 mo for 36-mo ADT. The median time to
nonhypogonadal testosterone after ADT cessation was 20.3 mo for 4-mo ADT, 8.1 mo for 6-mo ADT, 11.4 mo for 18-mo ADT, 27.0 mo for 28-mo ADT, and 44.3
mo for 36-mo ADT.

a
Table 2 – Multivariable Cox regression results for the effect of baseline testosterone level and age on testosterone recovery

Parameter Recovery to ncT Recovery to nhgT Recovery to bT

HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value
ln(bT) 1.86 (1.63–2.13) <0.001 3.00 (2.52–3.70) <0.001 0.38 (0.32–0.46) <0.001
Age(per 5-yr increment) 0.91 (0.87–0.95) <0.001 0.84 (0.80–0.88) <0.001 0.82 (0.78–0.87) <0.001
bT = baseline testosterone; CI = confidence interval; HR = hazard ratio; ncT = noncastrate testosterone (>1.7 nmol/l); nhgT = nonhypogonadal testosterone (>8.0
nmol/l).
a
Time 0 was the end date for androgen deprivation therapy for these analyses. Models were adjusted for androgen deprivation therapy duration and Eastern
Cooperative Oncology Group performance status (1–2 vs 0). Each recovery outcome was evaluated in a separate multivariable Cox regression model.

Multivariable analysis results for the effective castration have clinical implications not only for counseling of patients
period and oncological outcomes are shown in Supplemen- receiving ADT about the duration of adverse effects but also
tary Table 3. There was no association between effective cas- for patients treated with novel GnRH antagonists that allow
tration period and oncological outcomes across the ADT more rapid TR.
durations. To evaluate any potential continuous nonlinear First, we found that time of TR to noncastrate and nonhy-
relationship between effective castration period and MFS, pogonadal levels varied significantly not only by the dura-
we developed adjusted natural cubic spines. The results are tion of ADT received but also by baseline testosterone and
shown in Figure 4. The mathematically defined optimal age, with the latter having large impacts on TR. To the best
effective castration period for MFS benefit was 10.6 mo of our knowledge, our report represents the largest and
(95% CI 6.0–16.4) for 6-mo ADT and 18 mo (95% CI 18.0– most comprehensive analysis of TR by ADT duration for
25.8) for 18-mo ADT. In both cases, the 95% CIs are broad, patients who were treated and prospectively followed
encompassing the entire duration of effective castration peri- within clinical trials. The data build on and confirm prior,
ods included in the analyses. However, the spline for men largely retrospective studies [3–10] by quantifying the sig-
receiving 6 mo of ADT was U-shaped. For men receiving 18 nificant impact of baseline testosterone and age on TR in a
mo of ADT, there was no visual evidence of a potential ben- large cohort of patients who were uniformly treated and
efit to prolonging castration beyond 18 mo. followed. A recent analysis of two randomized trials
reported recovery to ‘‘normal’’ testosterone with qualita-
4. Discussion tively similar results [4]. The authors reported times to TR
measured from baseline testosterone assessment, while
we measured TR from the end of ADT. Furthermore, our
In this pooled analysis of individual patient data from five
analysis included data on the actual ADT duration received
randomized trials, we quantified the time to TR by pre-
(rather than an intention-to-treat analysis). Notably, our
scribed ADT duration and evaluated the impact of the effec-
results highlight that it is important to tailor discussions
tive castration period on MFS and other oncological
on TR kinetics to the individual patient. We used these data
outcomes. We report several important findings that will
54 EUROPEAN UROLOGY 87 (2025) 49–57

Fig. 2 – Natural cubic splines showing the association between testosterone recovery and (A) baseline testosterone and (B) age. From left to right, associations
are shown for the time to recovery of noncastrate, nonhypogonadal, and baseline testosterone. ln(HR) = natural log of the hazard ratio; T = testosterone.

to create nomograms for estimating the probability of TR at duration of effective castration periods studied, the shapes
various time points after ADT on the basis of individual of the splines, as well as the optimal periods derived, were
patient characteristics (Fig. 2). For instance, after receiving noteworthy. For men receiving 6 mo of ADT, the spline was
6 mo of ADT, the probability of TR to a nonhypogonadal U-shaped and the optimal effective castration period was
level for a 70-yr-old man with good performance status 10.6 mo. For men receiving 18 mo of ADT, the optimal effec-
and baseline testosterone of 9 nmol/l would be 45% at 12 tive castration period was 18 mo, with the ln(HR) for MFS
mo and 60% at 18 mo. For a 60-yr-old man with baseline increasing afterwards. To the best of our knowledge, these
testosterone of 12 nmol/l, the probability would increase are novel findings that are immediately relevant in the con-
significantly to >80% at 12 mo and >90% at 18 mo. Such data text of novel GnRH antagonist agents, such as degarelix and
are imperative for effective shared decision-making, with relugolix, which result in significantly more rapid TR fol-
our nomograms being of particular benefit for patient lowing cessation of therapy [13,21]. While the more rapid
counseling. TR profile (and thus a shorter duration of ADT-related side
Second, we found that for any given prescribed ADT effects) has significant appeal for patients and physicians,
duration, shorter effective castration period was not associ- our findings suggest that, at least with shorter ADT dura-
ated with worse MFS. The exception was 28 mo of ADT, for tions (ie, 6 mo), longer effective castration period may be
which only a limited sample of patients was available, associated with optimal outcomes. This may necessitate
potentially skewing the results. We performed natural cubic therapy with a GnRH antagonist for a longer duration (eg,
spline analyses for 6 mo and 18 mo of ADT to assess poten- up to 9 mo) to replicate the same effective castration as
tial nonlinear associations. While the 95% CI for the mathe- seen with 6 mo of a GnRH agonist. With longer ADT dura-
matically identified optimal periods spanned the entire tions (ie, 18 mo) there does not appear to be any further
 EUROPEAN UROLOGY 87 (2025) 49–57 55

Fig. 3 – Nomograms for prediction of the probability of recovery to (A) noncastrate and (B) nonhypogonadal levels of testosterone. The points assigned to each
parameter (baseline testosterone, ADT received, age, ECOG score) are summed to generate a total score corresponding to the recovery probability at 12, 18, 24,
and 36 mo. The C index values were 0.60 and 0.64, respectively. ADT = androgen deprivation therapy; ECOG = Eastern Cooperative Oncology Group
performance status.

benefit from prolonging the effective castration period, and best of our knowledge, our study is still the largest analysis
our data suggest that therapy with 18 mo of a GnRH antag- for this question. While serial testosterone data were col-
onist may be equivalent to therapy with 18 mo of a GnRH lected prospectively at prespecified time points within each
agonist. Pending confirmation in a prospective trial, these clinical trial, there was heterogeneity in the exact date of
data remain exploratory and hypothesis-generating. The testosterone measurement between trials. There was also
more rapid onset of castration with a GnRH antagonist potential heterogeneity in the sample processing and labo-
may also mildly offset the difference in TR with respect to ratory assays used for testosterone measurement across
effective castration period. clinical trials, which may have impacted the testosterone
Our study has several limitations. While the MARCAP levels reported for each trial. In particular, it was noted that
Consortium includes data contributions from multiple ran- approximately half of the men in the GICOR trial had base-
domized trials, data-sharing restrictions mean that the cur- line testosterone of <10.5 nmol/l, which probably explains
rent analyses did not necessarily include all trials on why men who received 4-mo ADT in that trial had longer
radiotherapy and ADT for which prospectively collected TR and effective castration period than would have been
serial testosterone data are available. Nonetheless, to the anticipated, especially considering our findings for men
56 EUROPEAN UROLOGY 87 (2025) 49–57

Fig. 4 – Natural cubic splines showing nonlinear associations between the effective castration period and metastasis-free survival for patients receiving (A) 6
mo and (B) 18 mo of androgen deprivation therapy. ln(HR) = natural log of the hazard ratio.

receiving 6 mo or 18 mo of ADT. There is also heterogeneity onists (which allow more rapid TR) than with GnRH
in the ADT formulation and number of cycles used and the agonists.
use and duration of oral antiandrogens (such as bicalu-
tamide and flutamide; Supplementary Table 1), which Author contributions: Amar U. Kishan had full access to all the data in
may or may not have influenced our findings. For instance, the study and takes responsibility for the integrity of the data and the
there may be pharmacological differences between monthly accuracy of the data analysis.
and 3-monthly ADT formulations with respect to TR, which
could not be accounted for here [8]. There are also varia- Study concept and design: Kishan, Romero, Ong.
tions in the ADT sequencing and timing used, which may Acquisition of data: All authors.
impact oncological outcomes [22]. Furthermore, data from Analysis and interpretation of data: All authors.
the OTT0101 trial suggest that there is potentially a small Drafting of the manuscript: Kishan, Romero, Ong.
delay in TR to noncastrate testosterone levels with concur- Critical revision of the manuscript for important intellectual content: All
rent/adjuvant ADT when compared to neoadjuvant/concur- authors.
rent ADT use [5]. According to the literature, other variables Statistical analysis: Romero, Kishan.
may be associated with TR, such as race, body mass index Obtaining funding: Ong, Kishan, Spratt, Nikitas.
[6], and comorbidities [7], but data for these variables were Administrative, technical, or material support: Kishan.
not uniformly available for our study cohort, so they were Supervision: Kishan.
not included in adjustments for our analyses or in the Other: None.
nomograms.
Financial disclosures: Amar U. Kishan certifies that all conflicts of inter-
est, including specific financial interests and relationships and affiliations
5. Conclusions relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
In conclusion, this pooled analysis of individual patient data
received, or pending), are the following: Amar U. Kishan reports personal
provides the highest level of prospective data on the time to
fees from ViewRay, Varian Medical Systems, and Janssen Pharmaceuticals
TR by prescribed ADT duration. Importantly, baseline
outside the submitted work, and research funding from ViewRay. Daniel
testosterone, age, and ADT duration have the greatest influ- E. Spratt reports personal fees from Janssen Pharmaceuticals and Blue
ence on the TR rate. An understanding of TR kinetics is crit- Earth outside the submitted work. Nicholas Nickols reports research
ical for counseling of men who are starting ADT so that they funding from Progenics. The remaining authors have nothing to disclose.
have realistic expectations regarding the likely time to res-
olution of ADT-related side effects. Traditional multivari-
able Cox analyses did not reveal any association between Funding/Support and role of the sponsor: This work was supported by a
RANZCR-TROG research grant (W.L.O.), National Institutes of Health
effective castration period and oncological outcomes across
grants P50CA09213 (A.U.K.) and P50CA186786 (D.E.S.), Radiological Soci-
the ADT treatment periods. However, there was a nonlinear
ety of North America grant RSD1836 (A.U.K.), STOP Cancer, the Prostate
association between effective castration period and MFS
Cancer Foundation, the Jonsson Comprehensive Cancer Center, US Depart-
whereby a longer effective castration period was associated
ment of Defense grants PC210066 (A.U.K.) and PC151068 (D.E.S.), a Chris-
with better oncological outcomes. This finding is
tiaan W. Schiepers theranostics fellowship (J.N.), and funding from the
hypothesis-generating, and future trials should confirm
whether a longer ADT duration is needed with GnRH antag-
 EUROPEAN UROLOGY 87 (2025) 49–57 57

Chapgier, Bershad, De Silva, and McCarrick Families (A.U.K.). The sponsors neoadjuvant hormone cytoreduction and radical radiotherapy in
played no direct role in the study. localized prostate cancer. Clin Oncol 2001;13:291–5.
[11] Zapatero A, Alvarez A, Guerrero A, et al. Prognostic value of
testosterone castration levels following androgen deprivation and
Data sharing statement: Data are available for bona fide researchers on high-dose radiotherapy in localized prostate cancer: results from a
phase III trial. Radiother Oncol 2021;160:115–9.
request from the corresponding author.
[12] Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-
deprivation therapy in advanced prostate cancer. N Engl J Med
Supplementary material 2020;382:2187–96.
[13] Dearnaley DP, Saltzstein DR, Sylvester JE, et al. The oral
gonadotropin-releasing hormone receptor antagonist relugolix as
Supplementary data to this article can be found online at neoadjuvant/adjuvant androgen deprivation therapy to external
https://doi.org/10.1016/j.eururo.2024.09.009. beam radiotherapy in patients with localised intermediate-risk
prostate cancer: a randomised, open-label, parallel-group phase 2
trial. Eur Urol 2020;78:184–92.
References [14] Roy S, Zaorsky NG, Bagshaw HP, et al. An expert review on the
combination of relugolix with definitive radiation therapy for
[1] Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy prostate cancer. Int J Radiat Oncol Biol Phys 2022;113:278–89.
use and duration with definitive radiotherapy for localised prostate [15] Xie W, Regan MM, Buyse M, et al. Metastasis-free survival is a
cancer: an individual patient data meta-analysis. Lancet Oncol strong surrogate of overall survival in localized prostate cancer. J
2022;23:304–16. Clin Oncol 2017;35:3097–104.
[2] Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen [16] Denham JW, Steigler A, Lamb DS, et al. Short-term neoadjuvant
deprivation therapy and strategies to mitigate them. Eur Urol androgen deprivation and radiotherapy for locally advanced
2015;67:825–36. prostate cancer: 10-year data from the TROG 96.01 randomised
[3] Nabid A, Carrier N, Martin AG, et al. Duration of androgen trial. Lancet Oncol 2011;12:451–9.
deprivation therapy in high-risk prostate cancer: a randomized [17] Denham JW, Joseph D, Lamb DS, et al. Short-term androgen
phase III trial. Eur Urol 2018;74:432–41. suppression and radiotherapy versus intermediate-term androgen
[4] Nabid A, Carrier N, Vigneault E, et al. Testosterone recovery after suppression and radiotherapy, with or without zoledronic acid, in
androgen deprivation therapy in localised prostate cancer: long-term men with locally advanced prostate cancer (TROG 03.04 RADAR):
data from two randomised trials. Radiother Oncol 2024;195:110256. 10-year results from a randomised, phase 3, factorial trial. Lancet
[5] Roy S, Grimes S, Eapen L, et al. Impact of sequencing of androgen Oncol 2019;20:267–81.
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localized prostate cancer. Int J Radiat Oncol Biol Phys therapy with external-beam radiotherapy in localized prostate
2020;108:1179–88. cancer: a phase III randomized controlled trial. J Clin Oncol
[6] Spiegel DY, Hong JC, Oyekunle T, et al. A nomogram for testosterone 2020;38:593–601.
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for prostate cancer. Int J Radiat Oncol Biol Phys 2019;103:834–42. with short-term or long-term androgen deprivation in localised
[7] Nascimento B, Miranda EP, Jenkins LC, Benfante N, Schofield EA, prostate cancer (DART01/05 GICOR): a randomised, controlled,
Mulhall JP. Testosterone recovery profiles after cessation of phase 3 trial. Lancet Oncol 2015;16:320–7.
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[8] Pai HH, Pickles T, Keyes M, et al. Randomized study evaluating Anal 2009;53:2605–16.
testosterone recovery using short-versus long-acting luteinizing [21] Tutrone R, Saad F, George DJ, et al. Testosterone recovery for
hormone releasing hormone agonists. Can Urol Assoc J 2011;5:173–9. relugolix versus leuprolide in men with advanced prostate cancer:
[9] Murthy V, Norman AR, Shahidi M, et al. Recovery of serum results from the phase 3 HERO study. Eur Urol Oncol. 2023.
testosterone after neoadjuvant androgen deprivation therapy and [22] Ma TM, Sun Y, Malone S, et al. Sequencing of androgen-deprivation
radical radiotherapy in localized prostate cancer. BJU Int therapy of short duration with radiotherapy for nonmetastatic
2006;97:476–9. prostate cancer (SANDSTORM): a pooled analysis of 12 randomized
[10] Shahidi M, Norman AR, Gadd J, Huddart RA, Horwich A, Dearnaley trials. J Clin Oncol 2023;41:881–92.
DP. Recovery of serum testosterone, LH and FSH levels following
 EUROPEAN UROLOGY 87 (2025) 58–59

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Editorial

Referring to the article published on pp. 49–57 of this issue

Transporting Testosterone Home: Navigating the Road to Recovery

Vedang Murthy a,*, Alan Dal Pra b

a
Department of Radiation Oncology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in Cancer, Homi Bhabha National
Institute, Mumbai, India; b Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA

Prostate cancer treatment has been significantly shaped by 36 mo) were associated with a longer time to TR. There
the use of androgen deprivation therapy (ADT) in combina- was wide variability in TR according to ADT duration, a rela-
tion with definitive radiotherapy. Modern approaches, tionship that interestingly seems to be nonlinear. The med-
including gonadotropin-releasing hormone (GnRH) agonists ian time to TR to a non-hypogonadal level (>8.0 nmol/l) was
and antagonists and novel androgen receptor pathway inhi- 20.3 mo, 8.1 mo, 11.8 mo, 27.0 mo, and 44.3 mo for the
bitors (ARPIs), have refined testosterone suppression tech- groups that received 4-mo, 6-mo, 18-mo, 28-mo, and 36-
niques, improving outcomes for both metastatic and mo ADT, respectively. The authors also evaluated the rela-
nonmetastatic disease. Combining ADT with radiotherapy tionship between actual time with castrate-level testos-
improves outcomes by exploiting complementary mecha- terone (<1.7 nmol/l) and oncological outcomes. They
nisms, particularly in high-risk and advanced disease [1]. found that longer ECP may be associated with optimal out-
However, long-term ADT can result in significant side comes only among patients who received a shorter ADT
effects, including fatigue, loss of muscle mass, a decrease course (6 mo). For men who received 6-mo or 18-mo ADT,
in libido, erectile dysfunction, osteoporosis, and cognitive the optimal ECP for metastasis-free survival (MFS) benefits
decline, all of which negatively impact quality of life [2]. was 10.6 mo and 18 mo, respectively.
Testosterone recovery (TR) following treatment cessation The authors must be commended on this effort, which
is important in efforts to reduce these effects. Still, the TR probably represents one of the largest studies on testos-
rate and extent vary widely among patients according to terone kinetics after radiation treatment and stands as a
factors such as ADT duration, age, baseline testosterone, testament to the power of collaborative research. The find-
and comorbidities [3,4]. An understanding of these dynam- ing that higher baseline testosterone and younger age are
ics is essential for optimizing treatment strategies and associated with faster TR is not entirely surprising. Never-
improving patient outcomes. theless, the magnitude of these effects and their interaction
In this issue of European Urology, Ong et al [5] report on with ADT duration can provide useful information for
the TRANSPORT study, a pooled analysis by the Meta-Analy- patient counseling. The authors also developed nomograms
sis of Randomized Trials in Cancer of the Prostate (MARCAP) to estimate the probability of TR at various time points after
Consortium. The TRANSPORT study addresses two funda- ADT on the basis of individual patient characteristics. These
mental questions: how does TR vary among patients follow- offer a practical tool for estimating TR probability and guid-
ing ADT, and what is the oncological impact of the effective ing shared decision-making. However, we need to interpret
castration period (ECP)? By analyzing data for 1444 men these data with some caution. The outcomes of this work
across five randomized trials, the researchers have pro- must be weighed against the heterogeneity in the study
duced the most robust data set to date on TR kinetics and data set, both within and between the trials included. In
their clinical implications. The results show that older age, addition, the variability in testosterone measurement meth-
lower baseline testosterone, and long-term ADT (28 or ods across trials and the lack of data on other variables that

*
Corresponding author. Department of Radiation Oncology, Tata Memorial Hospital and Advanced Centre for Treatment Research and Education in
Cancer, Homi Bhabha National Institute, Mumbai, India.
E-mail address: [email protected] (V. Murthy).

https://doi.org/10.1016/j.eururo.2024.10.016
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
 EUROPEAN UROLOGY 87 (2025) 58–59 59

may influence TR, such as race, body mass index, and despite the potential limitations mentioned by the authors,
comorbidities, could explain some of the more intriguing this study substantially adds to the current literature and
findings. Furthermore, a significant imbalance in baseline can help physicians and patients in making better shared
characteristics essential for TR, such as baseline testos- decisions. It also raises several key questions, such as the
terone, could have impacted the study findings. Patients best way to incorporate TR prediction into treatment plan-
receiving 4-mo ADT took approximately 20 mo for TR to ning and patient counseling, tailoring the ADT duration
non-hypogonadal levels, which was almost twice as long according to individual patient factors to optimize the
as for patients who received 18-mo ADT. The number of ECP, the optimal duration of newer GnRH antagonists, and
patients receiving 4 mo, 28 mo, or 36 mo of ADT accounted consideration of the study findings for patients receiving
for <15% of the entire cohort, which raises the question of newer ARPIs. TRANSPORT encourages us to move beyond
the impact of these subgroups on the overall findings and the simplistic view of ADT as a fixed-duration intervention
their generalizability. Ultimately, the authors could not find and use a more personalized approach that considers indi-
an association between ECP and oncological outcomes vidual patient characteristics to improve the outcomes
across the ADT durations. Previous work by the same group and quality of life for our patients.
showed that ADT use and duration are associated with bet-
ter MFS [6]. Conflicts of interest: The authors have nothing to disclose.
There has been increasing use of luteinizing hormone–
releasing hormone antagonists in injectable or oral forms, References
which are associated with more rapid TR [4,7]. The TRANS-
[1] Locke JA, Dal Pra A, Supiot S, Warde P, Bristow RG. Synergistic action
PORT study found that shorter ADT duration, such as 6 mo, of image-guided radiotherapy and androgen deprivation therapy.
may lead to a longer ECP that is associated with optimal Nat Rev Urol 2015;12:193–204.
outcomes. For men who received 6 mo or 18 mo of ADT, [2] Gudenkauf LM, Gray S, Gonzalez BD, Sachdeva A, Autio K. Balancing
hormone therapy: mitigating adverse effects of androgen-
the optimal ECP for MFS benefits was 10.6 mo and 18 mo, deprivation therapy and exploring alternatives in prostate cancer
respectively. This suggests that the optimal ECP for MFS management. Am Soc Clin Oncol Educ Book 2024;44:e433126.
benefits extends beyond 6 mo, raising concerns about the [3] Spiegel DY, Hong JC, Oyekunle T, et al. A nomogram for testosterone
recovery after combined androgen deprivation and radiation therapy
potential undertreatment of patients receiving a GnRH
for prostate cancer. Int J Radiat Oncol Biol Phys 2019;103:834–42.
antagonist for 6 mo. These findings are intriguing, as no [4] Ho AY, Li EV, Bennett R 4th, et al. Testosterone recovery after
similar observations have been reported for other ADT androgen deprivation therapy. Urol Oncol. In press. https://doi.org/
durations. Again, this discrepancy could reflect variations 10.1016/j.urolonc.2024.08.005.
[5] Ong WL, Romero T, Roy S, et al. Testosterone Recovery Following
in baseline characteristics of the different trials included Androgen Suppression and Prostate Radiotherapy (TRANSPORT): a
in the analysis. As the authors caution, these data are pooled analysis of five randomized trials from the Meta-Analysis of
exploratory and hypothesis-generating. Randomized Trials in Cancer of the Prostate (MARCAP) Consortium.
Although it is well known that the androgen signaling Eur Urol 2025;87:49–57.
[6] Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy
pathway is the primary driver of prostate cancer progres- use and duration with definitive radiotherapy for localised prostate
sion, many of the mechanisms are complex. Full TR is criti- cancer: an individual patient data meta-analysis. Lancet Oncol
cal for offsetting the multitude of ADT-related side effects 2022;23:304–16.
[7] Tutrone R, Saad F, George DJ, et al. Testosterone recovery for
and recovery of quality of life. Unfortunately, most of the
relugolix versus leuprolide in men with advanced prostate cancer:
large randomized trials that used radiation and ADT did results from the phase 3 HERO study. Eur Urol Oncol 2024;7:906–13.
not systematically collect serial testosterone data. Thus,
 EUROPEAN UROLOGY 87 (2025) 60–70

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Original Article – Editor’s Choice

Editorial by Paul Sargos, Evanguelos Xylinas, Jonathan Khalifa on pp. 71–72 of this issue

Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of

the Phase 2 RAIDER Randomised Controlled Trial

Robert Huddart a,b,*, Shaista Hafeez a,b, Clare Griffin a, Ananya Choudhury c, Farshad Foroudi d,
Isabel Syndikus e, Benjamin Hindson f, Amanda Webster g,h, Helen McNair a,b, Alison Birtle i,j,k,
Mohini Varughese l, Ann Henry m,n, Duncan B McLaren o, Omi Parikh i, Ashok Nikapota p,
Colin Tang q, Emma Patel r, Elizabeth Miles r, Karole Warren-Oseni a,b, Tomas Kron s, Courtney Hill t,
Lara Philipps a, Catalina Vassallo-Bonner a, Ka Ching Cheung a, Hannah Gribble a, Rebecca Lewis a,
Emma Hall a
a
The Institute of Cancer Research, Sutton, UK; b The Royal Marsden NHS Foundation Trust, Sutton, UK; c The Christie NHS Foundation Trust, The Christie,
Manchester, UK; d Austin Health, Heidelberg, Victoria, Australia; e The Clatterbridge Cancer Centre, Bebington, UK; f Canterbury Regional Cancer and
Haematology Service, Christchurch Hospital, Christchurch, New Zealand; g University College Hospital, London, UK; h University College Hospitals NHS
Foundation Trust, University College Hospital, London, UK; i Lancashire Teaching Hospitals NHS Trust, Rosemere Cancer Centre, Royal Preston Hospital, Preston,
UK; j University of Manchester, Manchester, UK; k University of Central Lancashire, Preston, UK; l Royal Devon and Exeter NHS Foundation Trust, Royal Devon
and Exeter Hospital, Exeter, UK; m University of Leeds, Leeds, UK; n Leeds Teaching Hospitals NHS Trust, St James’s University Hospital, Leeds, UK; o NHS Lothian,
Western General Hospital, Edinburgh, UK; p Brighton and Sussex University Hospitals NHS Trust, Royal Sussex County Hospital, Brighton, UK; q Sir Charles
Gairdner Hospital, Nedlands, WA, Australia; r National Radiotherapy Trials Quality Assurance Group (RTTQA), Mount Vernon Hospital, Middlesex, UK; s Peter
MacCallum Cancer Centre, Melbourne, VIC, Australia; t TROG Cancer Research, Waratah, NSW, Australia

Article info Abstract

Article history: Background and objective: Delivering radiotherapy to the bladder is challenging as it is a
Accepted September 2, 2024 mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could
improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule.
Associate Editor: Methods: RAIDER is an international phase 2 noncomparative randomised controlled
Amar Kishan trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were
randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose
Keywords: adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two
Adaptive radiotherapy fractionation (f) schedules recruited independently. WBRT and SART dose was
Image-guided radiotherapy 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and
Muscle-invasive bladder cancer DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary end-
Radiotherapy point was the proportion of patients with radiotherapy-related late Common
Randomised controlled trial Terminology Criteria for Adverse Events grade 3 toxicity; the trial was designed to rule
out >20% toxicity with DART.
Key findings and limitations: A total of 345 patients were randomised between October
2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f
Please visit www.eu-acme.org/europeanurology
to answer questions on-line. The EU-ACME cred-
its will then be attributed automatically. * Corresponding author. The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
Tel. +44 208 661 3529.
E-mail address: [email protected] (R. Huddart).

https://doi.org/10.1016/j.eururo.2024.09.006
0302-2838/Ó 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
 EUROPEAN UROLOGY 87 (2025) 60–70 61

cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52%
had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median
follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants
planned for DART met the mandatory medium plan dose constraints. Radiotherapy-
related grade 3 toxicity was reported in one of 58 patients (90% confidence interval
[CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall sur-
vival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard
ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage
cystectomy.
Conclusions and clinical implications: Grade 3 late toxicity was low. DART was safe and
feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are
promising for dose-escalated treatments, with a low salvage cystectomy rate and overall
survival similar to that seen in cystectomy cohorts.
Ó 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).

ADVANCING PRACTICE

What does this study add?

Complex adaptive radiotherapy can be delivered across multiple centres and countries with appropriate training and
quality assurance measures. Most patients require more than one plan to optimise treatment delivery. Adaptive tumour
boost radiotherapy allows dose escalation with low rates of significant toxicity in patients receiving 32- or 20-fraction
schedules. There was no evidence of a detrimental effect of dose escalation on patient-reported outcomes or health-
related quality of life.

Clinical Relevance
Because the bladder is highly mobile and deformable, bladder-sparing (chemo)radiotherapy can be technically challeng-
ing as large planning margins around the target are necessary to achieve good tumor coverage, but will necessarily lead to
more normal tissue exposure to radiation. Adaptive therapy can address this by adjusting the radiotherapy plan based on
the ‘‘anatomy of the day’’, allowing smaller margins and thus less normal tissue dose; further, this might allow dose-
escalation to the gross tumor. The two-stage randomised phase II RAIDER trial evaluated standard whole bladder radio-
therapy (WBRT), standard-dose adaptive radiotherapy (SART), and dose-escalated adaptive radiotherapy (DART), and was
designed to rule out >20% radiotherapy-related late CTCAE grade 3 toxicity with DART. 345 patients were randomised.
Stage 1 showed the clear feasibility of DART. With a median follow-up of 38.2–42.1 months, the incidence of
radiotherapy-related grade 3 toxicity with DART was only 1/114. No salvage cystectomies were done for adverse events,
and the overall rate of salvage cystectomy was 3.8%. Overall, these results are quite promising with lower rates of grade
3 toxicity and salvage cystectomy than in any prior large bladder cancer trial. Limitations are the phase 2, noncompar-
ative design, and the overall small sample size prohibiting comparison of efficacy (though recruiting to a bladder-sparing
trial is difficult and in that regards, this is a large trial). Associate Editor: Amar Kishan

Patient Summary
RAIDER looked at whether it is possible to safely deliver complex adaptive radiotherapy for patients with muscle-invasive
bladder cancer. Serious side effects were low across all treatment groups, and it was safe and feasible to deliver a higher
radiotherapy dose to the tumour alongside a lower dose to the rest of the bladder.

1. Introduction preventing geographical misses [3]. Improving targeting

could help limit toxicity.
Improvement in muscle-invasive bladder cancer (MIBC) Image-guided radiotherapy (IGRT) allows soft tissue
radiotherapy outcomes, with chemosensitisation and visualisation, improving accuracy [4]. IGRT led to adaptive
hypofractionation, means that it is a realistic alternative to radiotherapy strategies that aim to minimise treatment vol-
radical cystectomy with similar cause-specific survival and ume whilst maintaining target coverage [4]. This has been
potential for better quality of life [1,2]. shown to achieve target coverage in >95% of fractions whilst
Bladder radiotherapy is technically challenging due to reducing target volume by 25–40% [5].
changes in shape and position during a radiotherapy course, We hypothesised that better targeting could allow full-
requiring large margins around the tumour target that con- dose radiotherapy to be focused on the gross tumour vol-
tribute to greater than necessary toxicity whilst not reliably ume, which could limit toxicity, in combination with using
62 EUROPEAN UROLOGY 87 (2025) 60–70

smaller margins and treating on a fuller bladder to max- Common Terminology Criteria for Adverse Events (CTCAE)
imise bladder sparing. Mitigation of toxicity could allow v4.0. Follow-up was according to national guidelines [11].
routine dose escalation, potentially improving tumour con- Rigid cystoscopy with biopsy of the tumour bed was per-
trol. A phase 1/2 study showed that dose escalation to formed at 3 mo. Flexible cystoscopy, chest x-ray, late toxic-
70 Gray (Gy) in 32 fractions (f) was feasible in a single cen- ity (CTCAE v4.0), and survival status were assessed at 6, 9,
tre [6]. RAIDER was designed to assess the feasibility of 12, 18, 24, 36, 48, and 60 mo, with abdomen/pelvis CT at
delivering this treatment on a multicentre basis, exclude 6, 12, and 24 mo.
excessive toxicity from dose escalation, and provide prelim- Optional quality of life paper questionnaires were com-
inary efficacy data. pleted at baseline, last radiotherapy fraction, and 3, 6, 12,
18, and 24 mo after radiotherapy. Patient-reported outcome
2. Patients and methods (PRO) instruments were the following: Kings Health Ques-
tionnaire (KHQ) [12], EQ5D-5L [13], Inflammatory Bowel
2.1. Study design Disease Questionnaire (IBDQ; to protocol v2.0 14/02/2018)
[14], and PRO-CTCAE and ALERT-B (from protocol v2.0)
RAIDER is an international multicentre, multiarm, two- [15,16].
stage, phase 2 parallel cohort randomised trial of adaptive,
dose-escalated tumour-focused radiotherapy for MIBC 2.3. Outcomes
(NCT02447549/ISRCTN26779187). Protocol details have
been published [7]. It was conducted at 46 hospitals in For stage I, the primary outcome was the proportion of
the UK, Australia, and New Zealand (Supplementary DART participants meeting the medium plan mandatory
Table 1). radiotherapy dose constraints (Supplementary material)
RAIDER was approved by ethics (UK: 15/LO/0539, Aus- [7]. Recruitment to stage II continued whilst stage I was
tralia: HREC/15/HNE/264–15/07/15/3
04; 2016-041, and evaluated.
New Zealand: 15/STH/226), and participants gave informed For stage II, the primary outcome was the proportion of
consent. evaluable participants with treatment-emergent
Patients with T2-T4aN0M0 unifocal MIBC were ran- radiotherapy-related grade 3 CTCAE v4.0 toxicity 6–
domised (1:1:2) by the Institute of Cancer Research Clinical 18 mo after completing radiotherapy. Treatment-emergent
Trials and Statistics Unit (ICR-CTSU) between standard/con- toxicity was any adverse event (AE) not present before
trol whole bladder single plan radiotherapy (WBRT), radiotherapy or any AE already present that worsened fol-
standard-dose adaptive tumour-focused radiotherapy lowing radiotherapy. Radiotherapy relatedness was estab-
(SART), or dose-escalated adaptive tumour-focused radio- lished by local and central clinical reviews; any grade 3
therapy (DART) using minimisation with a random element. event categorised as ‘‘possibly’’, ‘‘probably’’, or ‘‘definitely’’
Neoadjuvant chemotherapy prior to randomisation was related by either reviewer was a primary endpoint event.
permitted. Balancing factors were treating hospital, neoad- The secondary outcomes included clinician-reported
juvant chemotherapy (yes/no), and concomitant radiosensi- acute and late toxicity (CTCAE v4.0 and Radiation Therapy
tisation (yes/no). Treatment allocation for parallel 20f and Oncology Group [RTOG]), PROs (EQ5D-5L: Visual Analogue
32f cohorts was independent and was not masked. Scale [VAS], a measure of overall health status; KHQ: blad-
der incontinence impact; and PRO-CTCAE: stool frequency),
2.2. Procedures locoregional (invasive) disease control, bladder intact
event-free survival, and overall survival.
The RAIDER radiotherapy planning and delivery protocol
describes treatment details, and a comprehensive radio-
2.4. Statistical analysis
therapy quality assurance programme was implemented
[7,8]. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f; The noncomparative design of stage II ruled out an upper
DART dose was 60 Gy/20f or 70 Gy/32f [7,9]. If medium plan limit of any late treatment-emergent radiotherapy-related
normal tissue dose constraints were not met (Supplemen- grade 3 CTCAE toxicity in each cohort’s DART group. With
tary Table 2) for DART patients, cases were reviewed by 57 participants per DART group, a >20% toxicity rate could
the chief investigator or delegate who recommended either be excluded (WBRT: expected 8%; power 80%; one-sided
proceeding with DART or lowering to SART dose. Before 5% significance; 5% nonevaluable allowance). Evaluable par-
each SART and DART fraction, cone beam computed tomog- ticipants had at least one fraction of allocated treatment and
raphy (CBCT) was performed and the smallest plan that at least one toxicity assessment between 6 and 18 mo after
enabled coverage of the planning target volume (PTV) was radiotherapy and at least 1 mo before death/local/distant
selected by an accredited individual, verified by a second recurrence. Toxicity censoring before recurrence/death
trained individual. Standard concomitant radiosensitisation avoided confounding disease symptoms and radiotherapy-
was encouraged [10]. related toxicity. With a 1:1:2 allocation ratio, 120 partici-
At baseline, participants had chest, abdomen, and pelvis pants per fractionation cohort were required.
computed tomography (CT); histological transitional cell The Independent Data Monitoring Committee (IDMC)
carcinoma confirmation; full blood count; and urea and reviewed accumulating data against prespecified stopping
electrolytes. Acute toxicity was assessed weekly during guidelines (Supplementary material). It recommended inflat-
treatment, at 6 and 10 wk from radiotherapy start, and at ing nonevaluable participant allowance (20f: 20%; 32f: 33%),
3 mo after radiotherapy with National Cancer Institute to achieve 57 evaluable DART participants per cohort.
 EUROPEAN UROLOGY 87 (2025) 60–70 63

The proportion of evaluable participants with mentary material). Of 6222 fractions delivered to SART
radiotherapy-related grade 3 CTCAE toxicity between 6 and DART participants, 2297 (37%) used small plans and
and 18 mo after radiotherapy is presented with 90% two- 1291 (21%) used large (Supplementary Table 4). For partic-
sided exact confidence intervals (CIs; equivalent to one- ipants receiving WBRT, 35/43 20f and 41/48 32f had daily
sided exact binomial 95% CI). CBCT. Of the patients, 70% used, at least once, all the three
Clinician- and patient-reported side effects were anal- plans; 1.6% used the same plan throughout.
ysed descriptively by treatment received and fractionation Concomitant therapy was given to 116/167 (70%) 20f
cohort. Times to first grade 2 CTCAE and grade 3 RTOG and 127/178 (71%) 32f participants. More 32f cohort partic-
genitourinary and gastrointestinal toxicities were analysed ipants received mitomycin C/5-fluorouracil (Supplementary
using the Kaplan-Meier method. Stacked bar charts indicate Table 3).
the distribution of data (severity) at each time point. PRO
items of key interest are EQ5D-5L VAS, KHQ incontinence 3.2. Late toxicity
impact (how much do you think bladder problems affect
3.2.1. Primary endpoint
your life?), and KHQ Symptom Severity Scale.
In the 20f cohort (median follow-up 42.1 mo [interquartile
For disease-related outcomes, fractionation cohorts were
range {IQR} 35.6, 50.1]), grade 3 treatment-emergent
combined and an intention-to-treat population was used.
radiotherapy-related toxicity was reported (urosepsis) in
Locoregional (invasive) disease control was censored at
one of 58 (1.7%, 90% CI 0.1–7.9) patients in the DART group;
metastases, second primary tumour, or death. Patients alive
one WBRT and one SART participant had grade 3
and event free were censored at the date of last follow-up,
radiotherapy-related late CTCAE toxicity (Table 2). In the
with censoring at the date of last cystoscopy for bladder
32f cohort (median follow-up 38.2 mo [IQR 26.2, 50.2]),
intact event-free survival. The Kaplan-Meier method and
no late CTCAE grade 3 radiotherapy-related toxicities
log-rank test stratified by fractionation cohort were used
were reported. In both cohorts, >20% grade 3
for a prespecified exploratory comparison of WBRT and
radiotherapy-related late toxicity with DART was excluded.
SART combined versus DART.
Any late treatment-emergent grade 3 DART toxicity
Estimates of treatment effect (with 95% CIs) were made
rates were 5/58 (8.6%, 90% CI 3.4–17) for 20f and 3/56
with unadjusted and adjusted (by the use of neoadjuvant
(5.4%, 1.5–13) for 32f (Table 2). Any late treatment-
chemotherapy and radiosensitising therapy, respectively)
emergent grade 2 was similar across DART groups, with
Cox regression models (stratified by cohort). A hazard ratio
18/57 (31%) for 20f and 20/56 (36%) for 32f (Table 2). Late
(HR) of <1 favoured DART. Proportional hazards assumption
CTCAE toxicity grades are reported in Supplementary
was tested by examining Schoenfeld residuals and held for
Table 5; the severity and cumulative incidence of gastroin-
all disease outcomes.
testinal and genitourinary toxicity are depicted in Figure 2
Analyses used a snapshot of data taken on May 17, 2022
and Supplementary Figure 1, respectively. The 2-yr cumula-
and were conducted using Stata version 17.0.
tive incidence of RTOG grade 3 toxicity was 2.4% (95% CI
0.8%, 7.4%) for 20f and 1.0% (0.1%, 6.7%) for 32f (Supplemen-
3. Results tary Fig. 2). See Supplementary Figure 3 for acute toxicity
[10].
Between October 21, 2015 and March 18, 2020, 345 partic-
ipants were randomised (20f: 163 from 25 centres: 41 3.3. Participant-reported outcomes
WBRT, 41 SART, and 81 DART; 32f: 182 from 24 centres: The EQ5D-5L VAS was maintained at or above baseline
46 WBRT, 46 SART, and 90 DART). The final four 32f cohort apart from a small drop at the end of treatment in the 20f
participants switched to 20f to reduce treatment time dur- cohort (Supplementary Fig. 4). KHQ symptom severity score
ing the COVID-19 pandemic and were included in 20f and bladder incontinence impact were worst at the end of
cohort analyses (Fig. 1). Participants’ characteristics were radiotherapy, but had improved by 12 mo from pretreat-
balanced between treatment groups (Table 1 and Supple- ment scores (Supplementary Figs. 5 and 6). Stool frequency
mentary Table 3). One participant was ineligible due to was also worse at the end of treatment (Supplementary
bilateral hip replacements but received allocated Fig. 7) for both fractionation cohorts.
radiotherapy.
3.4. Efficacy outcomes
3.1. Treatment details
The 2-yr locoregional disease control rates were 66% (95% CI
Seventy-three of 82 (89%) 20f DART participants and 74 of 57, 73) for WBRT + SART and 74.0% (66, 80) for DART
89 (83%) 32f DART participants received allocated treat- (Fig. 3A). There was no statistical evidence of a difference
ment (Fig. 1). In DART cohorts, 66/77 (86%) 20f and 74/82 between groups (unadjusted HR = 0.80 [95% CI 0.5, 1.17]
(90%) 32f participants planned for DART met the mandatory and adjusted HR = 0.81 [0.55, 1.19]; p = 0.2). For invasive
medium plan dose constraints (Supplementary material). locoregional disease, the 2-yr control rates were 80% (95%
Eleven of 77 (14%) 20f and eight of 82 (10%) 32f participants CI 73, 86) for WBRT + SART and 83% (95% CI 76, 89) for DART
did not meet dose constraints, and of them, four of 11 20f (p = 0.4; Fig. 3B, Supplementary Table 6 and Supplementary
and all 32f participants received SART. The remaining seven Table 7). A post hoc analysis of invasive locoregional disease
20f patients planned for DART but not meeting this dose control by fractionation cohort is provided in Supplemen-
constraint received DART on investigator decision (Supple- tary Figure 8 and that by protocol treatment received is pro-
64 EUROPEAN UROLOGY 87 (2025) 60–70

Fig. 1 – RAIDER CONSORT flowchart: (A) 20f cohort and (B) 32f cohort. COVID-19 = coronavirus disease 2019; DART = dose-escalated adaptive radiotherapy;
f/fr = fractions; RT = radiotherapy; SART = standard-dose adaptive radiotherapy; WBRT = whole bladder radiotherapy.

Fig. 1 (continued)
 EUROPEAN UROLOGY 87 (2025) 60–70 65

Table 1 – Participant and tumour characteristics at trial entry and treatment details by randomised treatment group

20f 32f
WBRT SART DART Total WBRT SART DART Total
(N = 42) (N = 43) (N = 82) (N = 167) (N = 45) (N = 44) (N = 89) (N = 178)
Age (yr), median (IQR) 74 (69–80) 74 (65–80) 71 (65–77) 72 (67–79) 72 (67–78) 73 (65–79) 73 (68–79) 73 (67–79)
Gender, N (%)
Male 32 (76) 35 (81) 67 (82) 134 (80) 35 (78) 37 (84) 69 (78) 141 (79)
WHO performance status, N (%)
0 24 (57) 20 (47) 42 (52) 86 (52) 28 (64) 24 (55) 56 (63) 108 (61)
1 15 (36) 21 (49) 29 (36) 65 (39) 11 (25) 19 (43) 30 (34) 60 (34)
2 3 (7) 2 (5) 10 (12) 15 (9) 5 (11) 1 (2) 3 (3) 9 (5)
Unobtainable 0 0 1 1 0 0 0 0
Clinical stage, N (%)
T2 35 (83) 33 (77) 61 (75) 129 (78) 39 (87) 32 (73) 77 (87) 148 (83)
T3a 2 (5) 7 (16) 9 (11) 18 (11) 1 (2) 4 (9) 8 (9) 13 (7)
3b 5 (12) 2 (5) 9 (11) 16 (10) 3 (7) 8 (18) 3 (3) 14 (8)
T4a 0 1 (2) 2 (2) 3 (2) 2 (4) 0 1 (1) 3 (2)
Unobtainable 0 0 1 1 0 0 0 0
Neoadjuvant chemotherapy, N (%)
Yes 21 (50) 24 (56) 43 (52) 88 (53) 20 (44) 18 (41) 42 (47) 80 (45)
Concomitant therapy given
Yes, N (%) 31 (76) 31 (76) 54 (69) 116 (73) 32 (73) 31 (72) 64 (74) 127 (73)
Unobtainable, N 1 2 4 7 1 1 3 5
CIS = carcinoma in situ; DART = dose-escalated adaptive radiotherapy; f = fractions; IQR = interquartile range; SART = standard-dose adaptive radiotherapy;
WBRT = standard whole bladder radiotherapy; WHO = World Health Organization.
Tumour grade, presence of CIS, presence of residual disease, and type of concomitant therapy given are presented in Supplementary Table 3.

Table 2 – Any grade ≥3 treatment-emergent radiotherapy-related, any grade ≥3 treatment-emergent,

and any grade ≥2 treatment-emergent CTCAE toxicity (occurring 6–18 mo after completing radiother-
apy) in the evaluable patient population

CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse Events; DART = dose-escalated
adaptive radiotherapy; SART = standard-dose adaptive radiotherapy; WBRT = standard whole bladder
radiotherapy.
The shaded row indicates the primary endpoint for the trial.
66 EUROPEAN UROLOGY 87 (2025) 60–70

B Gastrointestinal —32f
A Gastrointestinal —
0 1 2 3 4

6 9 12 18 24
Months since end of treatment

No. of pts
WBRT 35 30 31 23 22
SART 39 37 35 31 28
DART 53 51 45 44 39

C Genitourinar y—20f D Genitourinar y—32f

No. of pts
WBRT 35 31 31 24 22
SART 39 37 35 31 27
DART 53 51 45 44 39

Fig. 2 – Stacked bar charts illustrating treatment-emergent CTCAE (A and B) gastrointestinal and (C and D) genitourinary worst toxicity at each late time point
assessed by treatment received and fractionation cohort. Treatment emergent is defined as any adverse event that was not present prior to radiotherapy or
any adverse event already present that worsened following exposure to trial treatment, that is, grade 0 includes those with CTCAE grade 0 at the time point
assessed and participants with no change in CTCAE score since baseline. CTCAE = Common Terminology Criteria for Adverse Events; DART = dose-escalated
adaptive radiotherapy; f = fractions; pts = patients; SART = standard-dose adaptive radiotherapy; WBRT = whole bladder radiotherapy.

vided in Supplementary Figure 9 and Supplementary 4. Discussion

Table 8.
The 2-yr bladder intact event-free survival estimates were We have confirmed that tumour radiotherapy dose escala-
67% (95% CI 59, 74) for WBRT + SART and 72% (64, 79) for tion can be delivered successfully whilst reducing the dose
DART (Fig. 3C), with no evidence of a difference between to the uninvolved bladder, by multiple international sites,
groups (p = 0.3; Supplementary Tables 6 and 7). Thirteen of without causing excessive late toxicity.
345 (3.8%) participants had cystectomies, 11 due to disease With 82% of patients allocated DART having dose-
recurrence, one for radical bladder cancer treatment instead escalated treatment, stage I demonstrated achievable dose
of allocated radiotherapy, and one for unknown reason. No escalation for most participants within cautious constraints.
cystectomies were reported due to AEs. Stage II successfully excluded >20% grade 3 late
There were 120 deaths—64/174 for WBRT + SART and radiotherapy-related toxicity with DART. In both adaptive
56/171 for DART. The 2-yr overall survival rates were 77% groups, upper 90% CI for any late grade 3 treatment-
(95% CI 70, 82) for WBRT + SART and 80% (73, 85) for DART emergent toxicity was <20%. Adaptive IGRT permits dose
(Fig. 3D). No significant differences were evident in unad- escalation to 60 Gy in 20f or 70 Gy in 32f (9–10% dose
justed (HR = 0.84; 95% CI 0.59, 1.21; p = 0.4) or adjusted increment). This confirms the single-centre dose escalation
(HR = 0.88; 95% CI 0.61, 1.26) models (Supplementary study identifying that 70 Gy/32f could be achieved safely [6]
Table 6). There were 73 bladder cancer deaths; 39 were and a prior prospective study achieving dose escalation to
from other causes, and eight causes were unknown. 68 Gy/32f [17,18].
 EUROPEAN UROLOGY 87 (2025) 60–70 67

Fig. 3 – Kaplan-Meier curves comparing standard dose (WBRT + SART) with dose escalation (DART) for (A) any locoregional disease control, (B) invasive
locoregional disease control, (C) bladder intact event-free survival, and (D) overall survival. Locoregional disease control: events are bladder cancer
recurrence (muscle and non–muscle invasive) and pelvic node recurrence; censoring events are metastases (if occurred ≥30 d before locoregional failure),
second primary tumour, and death. Locoregional invasive disease control: locoregional disease control but excluding noninvasive bladder cancer recurrences
(neither censoring nor counting as events); for these endpoints and overall survival, patients who are alive and event free are censored at the date of last
follow-up. Bladder intact event-free survival: events are muscle-invasive bladder cancer, pelvic node recurrence, distant metastases, cystectomy (for any
reason), and bladder cancer–related death; patients who are event free are censored at the date of last cystoscopy. DART = dose-escalated adaptive
radiotherapy; SART = standard-dose adaptive radiotherapy; WBRT = whole bladder radiotherapy.

Overall toxicity in RAIDER was modest despite dose esca- ing intensity-modulated radiotherapy, and adaptive and
lation. Our previous bladder radiotherapy trial BC2001 tumour focused treatment would be a logical explanation
reported 2-yr 13% cumulative grade 3–4 RTOG toxicity for lower than expected toxicity.
[19], and the BCON trial reported 3-yr 3% genitourinary Variability of the bladder during radiotherapy and the
and 7% gastrointestinal LENT-SOMA toxicity rates [20]. In impact on target coverage have been well documented
RAIDER, despite 50% of patients receiving dose escalation, [4,23,24]. Our data provide additional support for the need
we observed lower 2-yr rates of RTOG grade 3 toxicity in for adaptive planning to optimise target coverage. Most par-
both cohorts. A meta-analysis of RTOG bladder radiotherapy ticipants received treatment with all three plans. PoD radio-
studies reported 7% late grade 3 pelvic toxicity (5.7% geni- therapy is complex, and requires clear guidelines and on-
tourinary and 1.9% gastrointestinal), whilst our results are going quality assurance at the time of its introduction. We
similar to the 3% grade 3 late toxicity reported in a meta- initially found relatively low concordance between the plan
analysis of patients receiving gemcitabine chemoradiother- selected during treatment and a subsequent review [8,25].
apy [21,22]. Though there could be population or reporting Retraining and revised guidance led to improved compli-
differences, technical developments used in RAIDER includ- ance in the later parts of the study. This emphasises the
68 EUROPEAN UROLOGY 87 (2025) 60–70

need for training and peer review when implementing new 5. Conclusions
complex interventions.
As in the BC2001 trial, despite favourable trends, we In this phase 2 study, an image-guided adaptive strategy
could not prove that reducing high dose volume reduces enabled radiotherapy dose escalation to over 86% of
bladder toxicity. Explanations include that the global blad- patients’ bladder tumours without significant increase in
der dose is a less important determinant of toxicity than toxicity. Utilisation of multiple adaptive plans suggests an
previously thought or that bladder sparing remains subop- on-going need for adaptive therapy to optimise treatment
timal even with these techniques. Newer online magnetic delivery. Dose-escalated therapy achieves promising
resonance imaging–based or CT-based real-time adaptive tumour control and survival rates similar to that achieved
techniques with/without functional monitoring may allow with cystectomy, with low rates of salvage cystectomy,
more extreme bladder sparing and could further contribute and should be studied in future trials.
to answering this question.
The standard dose groups had similar 2-yr event-free Author contributions: Robert Huddart had full access to all the data in
rates to those seen in BC2001 chemoradiotherapy arms the study and takes responsibility for the integrity of the data and the
for locoregional (BC2001 63%; RAIDER 65%) and invasive accuracy of the data analysis.
local-regional (BC2001 82%; RAIDER 80%) control [26].
Dose escalation achieved what might be, if confirmed,
Study concept and design: Huddart, Hafeez, Griffin, Choudhury, Foroudi,
meaningful clinical benefits (though not statistically sig-
McNair, Henry, McLaren, Patel, Miles, Lewis, Hall, Vassallo-Bonner.
nificant), with 9% and 4% absolute improvement in 2-yr
Acquisition of data: Huddart, Hafeez, Choudhury, Syndikus, Hindson,
locoregional and invasive locoregional recurrence rates,
Webster, Birtle, Varughese, Parikh, Nikapota, Tang, Henry, McLaren.
respectively. A comparison with cystectomy series is diffi-
Analysis and interpretation of data: Griffin, Hall, Huddart.
cult due to inherent selection biases. Recently, Zlotta and Drafting of the manuscript: Huddart, Griffin, Gribble, Lewis, Cheung, Hall.
colleagues [1] reported survival in a series of cystectomy Critical revision of the manuscript for important intellectual content: All
patients suitable for trimodality therapy. Five-year sur- authors.
vival was 66% and it was around 80% at 2 yr, which is sim- Statistical analysis: Griffin.
ilar to the rates observed in RAIDER in an older less fit Obtaining funding: Hall, Huddart.
cohort (median age 71 yr in cystectomy series vs 73 yr Administrative, technical, or material support: Gribble, Philipps, Cheung,
in RAIDER). This would support that modern high-quality Hill, Lewis, Vassallo-Bonner.
chemoradiotherapy achieves at least equivalent survival Supervision: Miles, Foroudi, Hall, Lewis, Huddart.
results to surgery. Other: None.
To date, 13 (4%) participants have had a cystectomy, and
though follow-up is short, this is similar to that seen in our
Financial disclosures: Robert Huddart certifies that all conflicts of inter-
pilot dose escalation study [29], comparing favourably with
est, including specific financial interests and relationships and affiliations
previously published reports (BC2001 14%; MGH retrospec- relevant to the subject matter or materials discussed in the manuscript
tive series 29%) [1,27,28]. (eg, employment/affiliation, grants or funding, consultancies, honoraria,
One concern of adaptive treatment to the bladder alone stock ownership or options, expert testimony, royalties, or patents filed,
is whether nodal recurrences would be increased due to received, or pending), are the following: Robert Huddart reports grants
reduced ‘‘bystander nodal irradiation’’, but we saw little evi- received by their institution from Cancer Research UK, MSD, and Roche;
dence of this, with 25/345 (7%) having a nodal recurrence; consultation fees from Janssen, Bristol Myers Squibb, Astellas, Roche,
this was the first event in the bladder intact event-free sur- and Nektar Pharmaceuticals; payment or honoraria from Roche, Bristol
vival analysis for only nine (2.6%) participants. This com- Myers Squibb, and Merck; support for attending meetings and/or travel
pares with the 4.9% rate in the BC2001 from MSD, Roche, and Janssen; participation in a data safety monitoring
chemoradiotherapy group. board or advisory board for Biontech, Gilead, and Merck; and leadership
Limitations mainly relate to the phase 2 design—the or fiduciary role at Cancer Centre London, Parkside. Shaista Hafeez reports
study was not designed to compare treatment groups, com- grants from NIHR Biomedical Research Centre at The Royal Marsden NHS
pounded by lower than expected overall toxicity. The Foundation Trust and The Institute of Cancer Research; nonfinancial sup-
assessment of PRO was compromised by the need to change port from Elekta (Stockholm, Sweden); personal fees and nonfinancial
instrument mid-trial, so patient-reported data on gastroin- support from Roche; and nonfinancial support from Merck Sharp &

testinal toxicity are incomplete. Dohme (MSD), outside the submitted work. Ananya Choudhury reports
grants from Prostate Cancer UK for research programme, UK Research
Overall, this trial supports evidence that adaptive
and Innovation, NIHR, Cancer Research UK, and The Urology Foundation,
chemoradiotherapy is a safe alternative to radical cys-
and payments or honoraria for research programmes from Janssen, Bayer,
tectomy, achieving local control for most patients with
AstraZeneca, Roche, Merck, and Elekta AB. Helen McNair is funded by a
low rates of salvage cystectomy and modest toxicity.
National Institute for Health Research and Health Education England
Though these data do not conclusively confirm the supe-
(HEE/NIHR), Senior Clinical Lectureship ICA-SCL-2018-04-ST2-002. Tomas
riority of this approach, these data support on-going
Kron reports grants received by their institution from Australia and New
implementation and further development of Zealand Sarcoma Association, Victorian Cancer Council, and National
adaptive radiotherapy, potentially through approaches Breast Cancer Foundation; associate editor fee from Elsevier and Radia-
of real-time adaption currently under development. tion Measurement; invited speaker expenses for International Workshop
Proof of this benefit will require further randomised on Ionising Radiation Monitoring meeting. Tomas Kron is the president
studies. and board member of the Medical Physics for World Benefits. Emma Hall
 EUROPEAN UROLOGY 87 (2025) 60–70 69

reports grants received by their institution from Varian Medical Systems as agreed by the trial management group and approved by the indepen-
Inc., Accuray Inc., AstraZeneca, Janssen-Cilag, Bayer, Roche Products Ltd, dent data monitoring and steering committee, as required. Restrictions
and Merck Sharp & Dohme, all outside the submitted work; nonfinancial relating to patients’ confidentiality and consent will be limited by aggre-
support (study drug supplies) received by their institution from AstraZe- gating and anonymising identifiable patients’ data. Additionally, all indi-
neca and Bayer, outside the submitted work; and grants received by their rect identifiers that could lead to deductive disclosures will be removed in
institution from Cancer Research UK (within the scope of submitted work line with ICR-CTSU data sharing guidelines.
and outside the submitted work) and Prostate Cancer UK (outside submit-
ted work). Clare Griffin, Farshad Foroudi, Isabel Syndikus, Benjamin Hind-
Supplementary data
son, Amanda Webster, Alison Birtle, Mohini Varughese, Ann Henry,
Duncan McLaren, Omi Parikh, Ashok Nikapota, Colin Tang, Emma Patel,
Elizabeth Miles, Karole Warren-Oseni, Courtney Hill, Lara Philipps, Cata- Supplementary data to this article can be found online at
lina Vassallo-Bonner, Ka Ching Cheung, Hannah Gribble, and Rebecca https://doi.org/10.1016/j.eururo.2024.09.006.
Lewis have no conflicts to declare.
References

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(HEE/NIHR), Senior Clinical Lectureship award (ICA-SCL-2018-04-ST2- [7] Hafeez S, Webster A, Hansen VN, et al. Protocol for tumour-focused
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National Institute of Health and Care Research (NIHR) Biomedical bladder cancer in a multicentre phase II randomised controlled trial
(RAIDER): radiotherapy planning and delivery guidance. BMJ Open
Research Centre at The Royal Marsden NHS Foundation Trust and the
2020;10:e041005.
Institute of Cancer Research, London. The views expressed are those of [8] Webster A, McNair HA, Hansen VN, et al. Recognising the challenges
the authors and not necessarily those of the NIHR or the Department of of implementing multi-centre adaptive plan of the day
Health and Social Care. This work used data provided by patients and col- radiotherapy. Tech Innov Patient Support Radiat Oncol
2022;21:31–5.
lected by the National Health Service as part of their care and support.
[9] Hafeez S, Lewis R, Griffin C, Hall E, Huddart R. Failing to close the
The sponsor and funder are different. The funders reviewed and approved gap between evidence and clinical practice in radical bladder cancer
the trial design but had no role in study development, data collection, radiotherapy. Clin Oncol (R Coll Radiol) 2021;33:46–9.
data analysis, data interpretation, or writing of the report. [10] Huddart R, Hafeez S, Omar A, et al. Acute toxicity of
hypofractionated and conventionally fractionated (chemo)
radiotherapy regimens for bladder cancer: an exploratory analysis
Data sharing statement: Deidentified individual participant data, from the RAIDER trial. Clin Oncol (R Coll Radiol) 2023;35:586–97.
[11] National Institute for Health and Care Excellence. Improving
together with a data dictionary defining each field in the set, will be made
outcomes in urological cancers: the manual. NICE; 2002.
available to other researchers on request. Trial documentation including [12] Reese P, Pleil A, Okano G, Kelleher C. Multinational study of
the protocol is available online. The ICR-CTSU supports wider dissemina- reliability and validity of the King’s Health Questionnaire in
tion of information from the research that it conducts and increased coop- patients with overactive bladder. Qual Life Res 2003;12:427–42.
eration between investigators. Trial data are obtained, managed, stored, [13] Herdman M, Gudex C, Lloyd A, et al. Development and preliminary
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life
shared, and archived according to ICR-CTSU standard operating proce-
Res 2011;20:1727–36.
dures to ensure the enduring quality, integrity, and utility of the data. For- [14] Olopade FA, Norman A, Blake P, et al. A modified inflammatory
mal requests for data sharing are considered in line with ICR-CTSU bowel disease questionnaire and the Vaizey incontinence
procedures, with due regard given to funder and sponsor guidelines. questionnaire are simple ways to identify patients with
significant gastrointestinal symptoms after pelvic radiotherapy. Br
Requests are to be made via a standard proforma describing the nature
J Cancer 2005;92:1663–70.
of the proposed research and extent of data requirements. Data recipients [15] Taylor S, Byrne A, Adams R, et al. The three-item ALERT-B
are required to enter a formal data sharing agreement, which describes questionnaire provides a validated screening tool to detect
the conditions for release and requirements for data transfer, storage, chronic gastrointestinal symptoms after pelvic radiotherapy in
archiving, publication, and intellectual property. Requests are reviewed cancer survivors. Clin Oncol (R Coll Radiol) 2016;28:e139–47.
[16] Basch E, Reeve BB, Mitchell SA, et al. Development of the National
by the trial management group in terms of scientific merit and ethical
Cancer Institute’s patient-reported outcomes version of the
considerations, including patients’ consent. Data sharing is undertaken common terminology criteria for adverse events (PRO-CTCAE). J
if proposed projects have a sound scientific or patients’ benefit rationale, Natl Cancer Inst 2014;106:dju244.
70 EUROPEAN UROLOGY 87 (2025) 60–70

[17] Cowan RA, McBain CA, Ryder WD, et al. Radiotherapy for muscle- coverage with image-guided radiotherapy compared with non-
invasive carcinoma of the bladder: results of a randomized trial image-guided radiotherapy for bladder cancer. Clin Oncol (R Coll
comparing conventional whole bladder with dose-escalated partial Radiol) 2014;26:497–505.
bladder radiotherapy. Int J Radiat Oncol Biol Phys [25] Webster A, Francis M, Gribble H, et al. Impact of on-trial IGRT
2004;59:197–207. quality assurance in an international adaptive radiotherapy trial for
[18] Murthy V, Master Z, Adurkar P, et al. ’Plan of the day’ adaptive participants with bladder cancer. Radiother Oncol
radiotherapy for bladder cancer using helical tomotherapy. 2024;199:110460.
Radiother Oncol 2011;99:55–60. [26] James ND, Hussain SA, Hall E, et al. Radiotherapy with or without
[19] Huddart RA, Hall E, Hussain SA, et al. Randomized noninferiority chemotherapy in muscle-invasive bladder cancer. N Engl J Med
trial of reduced high-dose volume versus standard volume 2012;366:1477–88.
radiation therapy for muscle-invasive bladder cancer: results of [27] Hall E, Hussain S, Porta N, et al. BC2001 long term outcomes: a
the BC2001 trial (CRUK/01/004). Int J Radiat Oncol Biol Phys phase III randomised trial of chemo-radiotherapy versus
2013;87:261–9. radiotherapy (RT) alone and standard RT versus reduced high-
[20] Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with dose volume RT in muscle invasive bladder cancer. J Clin Oncol
concurrent carbogen and nicotinamide in bladder carcinoma. J Clin 2017;35:280.
Oncol 2010;28:4912–8. [28] Giacalone NJ, Shipley WU, Clayman RH, et al. Long-term outcomes
[21] Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after after bladder-preserving tri-modality therapy for patients with
bladder-sparing therapy in patients with invasive bladder cancer: muscle-invasive bladder cancer: an updated analysis of the
RTOG 89–03, 95–06, 97–06, 99–06. J Clin Oncol 2009;27:4055–61. Massachusetts General Hospital experience. Eur Urol
[22] Caffo O, Thompson C, Santis MD, et al. Concurrent gemcitabine and 2017;71:952–60.
radiotherapy for the treatment of muscle-invasive bladder cancer: a [29] Hafeez S, Warren-Oseni K, Jones K, Mohammed K, El-Ghzal A,
pooled individual data analysis of eight phase I-II trials. Radiother Dearnaley D, Harris V, Khan A, Kumar P, Lalondrelle S, McDonald F,
Oncol 2016;121:193–8. Tan M, Thomas K, Thompson A, McNair HA, Hansen VN, Huddart R.
[23] Dees-Ribbers HM, Betgen A, Pos FJ, Witteveen T, Remeijer P, van Bladder tumour focused adaptive radiotherapy: Clinical outcomes
Herk M. Inter- and intra-fractional bladder motion during of a phase I dose escalation study. International Journal of Radiation
radiotherapy for bladder cancer: a comparison of full and empty Oncology*Biology*Physics 2024. https://doi.org/10.1016/j.ijrobp.
bladders. Radiother Oncol 2014;113:254–9. 2024.07.2317.
[24] Foroudi F, Pham D, Bressel M, Hardcastle N, Gill S, Kron T.
Comparison of margins, integral dose and interfraction target
 EUROPEAN UROLOGY 87 (2025) 71–72

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Editorial

Referring to the article published on pp. 60–70 of this issue

From a Storm to Sunshine: The Future of Bladder-sparing Therapy is

Bright

Paul Sargos a,*, Evanguelos Xylinas b, Jonathan Khalifa c

a
Department of Radiotherapy, Bergonie Institute, Bordeaux, France; b Department of Urology, Bichat-Claude Bernard Hospital, AP-HP, Université de Paris Cité,
Paris, France; c Department of Radiotherapy, Oncopole Claudius Rigaud/Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France

Trimodal therapy (TMT), which combines optimal trans- target volumes created to cover the range of expected fill-
urethral resection of bladder tumor (TURBT) and concur- ing and positional variations in the bladder.
rent chemoradiotherapy, has attracted much interest for In this issue of European Urology, Huddart et al [5] report
the management of patients with muscle-invasive blad- results from RAIDER, a phase 2 noncomparative randomized
der cancer (MIBC), as it allows bladder preservation while controlled trial assessing the feasibility (stage I) and safety
ensuring similar oncological outcomes to radical cystec- (stage II) of focused dose escalation to the index tumor
tomy [1]. To achieve such oncological results, local con- and a reduced dose to the uninvolved bladder using
trol is of utmost importance, and may include salvage image-guided adaptive RT via a PoD approach for patients
cystectomy in cases of invasive local recurrence. Salvage with T2–4a N0 M0 MIBC. Patients were randomized to stan-
cystectomy rates as high as 10–40% have been reported dard whole-bladder RT, standard-dose adaptive RT, or dose-
for contemporary, often heterogeneous, TMT series [2], escalated adaptive RT (DART) with the possibility of two
with local relapse frequently occurring at the initial site radiation schedules in either 20 fractions or 32 fractions.
of disease, which could be defined as the index lesion by The primary outcome for stage I was the proportion of DART
analogy with other solid malignancies including prostate patients for whom the RT plan could adhere to the radiation
cancer [3]. Consideration of the radiotherapy (RT) dose- dose constraints according to the protocol. For stage II of the
response effect as suggested in several series [4] provides trial, the primary outcome was the RT-related Common Ter-
a rationale for increasing the focal radiation dose to the minology Criteria for Adverse Events (CTCAE) grade 3 late
index tumor when delivering RT. The main challenge in toxicity rate at 6–18 mo after RT. A total of 345 patients
dose escalation for focal radiation during bladder RT is were included, most of whom had a cT2 tumor (81%); most
related to internal motions in the bladder that lead to of the patients (70%) received concurrent radiosensitizing
changes in the position, volume, and shape of the organ therapy, while 49% received neoadjuvant chemotherapy.
between each fraction (inter-fraction) and within a frac- Results for stage I of the study demonstrated that DART
tion (intra-fraction). Image-guided adaptive RT has been could be delivered successfully in more than 80% of
developed to address such variation and involves modifi- patients, independent of the radiation schedule. This result
cation of the dose distribution before and even during is in line with other prospective DART series, in which the
each RT fraction. One of the most robust adaptive strate- vast majority of patients successfully received such a regi-
gies is the ‘‘plan of the day’’ (PoD) approach, in which two men [6,7]. In stage II, radiation-related grade 3 CTCAE tox-
planning computed tomography scans are performed to icity following DART was <1% (90% confidence interval [CI]
build a library of treatment plans with varying planning 0.1–7.9%) for both fraction schedules, confirming that

* Corresponding author. Department of Radiotherapy, Bergonie Institute, 229 Cours de l’Argonne, 33076 Bordeaux Cedex, France. Tel.+33 5 56333343;
Fax: +33 5 56333276.
E-mail address: [email protected] (P. Sargos).

https://doi.org/10.1016/j.eururo.2024.09.031
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
72 EUROPEAN UROLOGY 87 (2025) 71–72

>20% toxicity with DART could be ruled out according to the after neoadjuvant treatment and testing for genomic alter-
upper 90% CI bound. In the DART arm, the 2-yr cumulative ations in the DNA repair–associated genes ATM, RB1, and
incidence of RTOG grade 3 toxicity was 2.4% (95% CI 0.8– FANCC that predict tumor response to chemotherapy [11]
7.4%) for 20 fractions and 1.0% (95% CI 0.1–6.7%) for 32 frac- could help in selecting suitable candidates for tumor-
tions. These data compare favorably with the BC2001 focused DART.
results (2-yr cumulative incidence of RTOG grade 3 toxic- Overall, the next generation of TMT will probably include
ity 5%) [8] and the RTOG pooled analysis (7% of patients new developments in RT delivery such as those used in the
experienced late grade 3 pelvic toxicity at median fol- RAIDER trial [5], which hopefully will increase interest in
low-up of 5.4 yr) [9]. However, it is worth mentioning that bladder-sparing approaches for MIBC. Future TMT trials will
the median time to late grade 3 toxicity was 18.4 mo have to include these radiation advances in order to offer
(range 9.4–98.8) for genitourinary toxicity and 25.8 mo optimal RT while testing new neoadjuvant, concurrent,
(range 8.0–57.8) for gastrointestinal toxicity in the RTOG and maintenance systemic strategies.
pooled analysis [9], while the primary outcome in the pre-
sent study was late toxicity occurring 6–18 mo after RT, Conflicts of interest: The authors have nothing to disclose.
underlining the need for longer follow-up. In terms of effi-
cacy, DART provided a promising 2-yr locoregional control References
rate of 84%, which compares favorably to the 67% in the
[1] Zlotta AR, Ballas LK, Niemierko A, et al. Radical cystectomy versus
BC2001 trial [8]. trimodality therapy for muscle-invasive bladder cancer: a multi-
Although preliminary, these results are noteworthy as institutional propensity score matched and weighted analysis.
they suggest an improvement in clinical outcome following Lancet Oncol 2023;24:669–81. https://doi.org/10.1016/S1470-
2045(23)00170-5.
TMT solely because of advances in radiation delivery. To the [2] Khalifa J, Supiot S, Pignot G, et al. Recommendations for planning
best of our knowledge, moderate hypofractionation with and delivery of radical radiotherapy for localized urothelial
doses of 2 Gy per fraction is the only other example of carcinoma of the bladder. Radiother Oncol 2021;161:95–114.
https://doi.org/10.1016/j.radonc.2021.06.011.
an oncological benefit related to RT advances [10]. However,
[3] Zietman A, Grocela J, Zehr E, et al. Selective bladder conservation
while implementation is relatively straightforward for using transurethral resection, chemotherapy, and radiation:
hypofractionation, it is challenging for tumor-focused DART management and consequences of Ta, T1, and Tis recurrence
for several reasons. First, the latter requires intensity- within the retained bladder. Urology 2001;58:380–5. https://doi.
org/10.1016/S0090-4295(01)01219-5.
modulated RT via an image-guided approach, which is still [4] Pos FJ, Hart G, Schneider C, Sminia P. Radical radiotherapy for
not available for this indication in many low- and middle- invasive bladder cancer: what dose and fractionation schedule to
income countries. Second, the PoD adaptive strategy choose? Int J Radiat Oncol 2006;64:1168–73. https://doi.org/
requires daily plan selection, which requires implementa- 10.1016/j.ijrobp.2005.09.023.
[5] Huddart RA, Hafeez S, Griffin C, et al. Dose-escalated adaptive
tion of a training program for physicians and radiothera- radiotherapy for bladder cancer : results of the phase 2 RAIDER
pists. The use of online replanning instead of PoD in the randomised controlled trial. Eur Urol 2025;87:60–70.
future, possibly via magnetic resonance imaging (MRI)- [6] Hafeez S, Warren-Oseni K, McNair HA, et al. Prospective study
delivering simultaneous integrated high-dose tumor boost (70
guided RT, could avoid this issue and is a promising techni-
Gy) with image guided adaptive radiation therapy for radical
cal approach. Finally, identification of the index tumor treatment of localized muscle-invasive bladder cancer. Int J Radiat
remains complex in most cases and requires integration of Oncol 2016;94:1022–30. https://doi.org/10.1016/j.
robust imaging and pathological data. To better identify ijrobp.2015.12.379.
[7] Murthy V, Masodkar R, Kalyani N, et al. Clinical outcomes with
the index lesion and increase the accuracy for detection of dose-escalated adaptive radiation therapy for urinary bladder
local relapses, the use of MRI for delineation and treatment cancer: a prospective study. Int J Radiat Oncol Biol Phys
follow-up must be assessed in clinical trials. Current 2016;94:60–6. https://doi.org/10.1016/j.ijrobp.2015.09.010.
[8] James ND, Hussain SA, Hall E, et al. Radiotherapy with or without
advances for index tumor identification include the use of
chemotherapy in muscle-invasive bladder cancer. N Engl J Med
gold fiducial markers or suburothelial injection of lipiodol, 2012;366:1477–88. https://doi.org/10.1056/NEJMoa1106106.
which could also increase the precision of dose delivery in [9] Efstathiou JA, Bae K, Shipley WU, et al. Late pelvic toxicity after
the future. The tumor-focused dose escalation approach bladder-sparing therapy in patients with invasive bladder cancer:
RTOG 89–03, 95–06, 97–06, 99–06. J Clin Oncol 2009;27:4055–61.
should theoretically be limited to unifocal lesions outside https://doi.org/10.1200/JCO.2008.19.5776.
the dome with an adequate index-tumor/whole-bladder [10] Choudhury A, Porta N, Hall E, et al. Hypofractionated radiotherapy
ratio to allow significant sparing of the rest of the bladder in locally advanced bladder cancer: an individual patient data
for optimal bladder function and quality of life after meta-analysis of the BC2001 and BCON trials. Lancet Oncol
2021;22:246–55. https://doi.org/10.1016/S1470-2045(20)30607-0.
treatment. [11] Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair
Because of such issues, and to avoid needless complexity genes predict response to neoadjuvant cisplatin-based
in radiation delivery, selection of the best candidates to chemotherapy in muscle-invasive bladder cancer. Eur Urol
2015;68:959–67. https://doi.org/10.1016/j.eururo.2015.07.009.
benefit from this RT approach is of interest. From this per-
spective, assessment of residual tumor via second TURBT
 EUROPEAN UROLOGY 87 (2025) 73–76

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Brief Report

Editorial by Piet Ost, Shankar Siva, Thomas Zilli on pp. 77–78 of this issue

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)

Loig Vaugier a, Cyrille Morvan b, David Pasquier c,d, Xavier Buthaud e, Nicolas Magné f,
Veronique Beckendorf g, Paul Sargos h, Gilles Crehange i, Pascal Pommier j, Genevieve Loos k,
Ali Hasbini l, Igor Latorzeff m, Marlon Silva n, Julie Paul o, Audrey Blanc-Lapierre o,
Stéphane Supiot a,p,*
a
Department of Radiation Oncology, Institut de Cancérologie de l’Ouest, Saint-Herblain, France; b Department of Nuclear Medicine, Institut de Cancérologie
de l’Ouest, Saint-Herblain, France; c Academic Radiation Oncology Department, Centre Oscar Lambret, Lille, France; d Centre de Recherche en Informatique,
Signal et Automatique de Lille, CRIStAL UMR CNRS 9189, Université de Lille, Lille, France; e Department of Radiation Oncology, Centre Catherine de Sienne,
Nantes, France; f Department of Radiation Oncology, Institut de Cancérologie de la Loire, St. Priest en Jarez, France; g Department of Radiation Oncology, Centre
Alexis Vautrin, Vandoeuvre-lès-Nancy, France; h Department of Radiation Oncology, Institut Bergonié, Bordeaux, France; i Department of Radiation Oncology,
Georges-Francois Leclerc Cancer Center, Dijon, France; j Department of Radiation Oncology, Centre Léon Bérard, Lyon, France; k Department of Radiation
Oncology, Centre Jean Perrin, Clermont-Ferrand, France; l Department of Radiation Oncology, Clinique Pasteur, Brest, France; m Department of Radiation
Oncology, Oncorad Clinique Pasteur, Toulouse, France; n Department of Radiation Oncology, Centre Francois Baclesse, Caen, France; o Department of
Biostatistics, Institut de Cancérologie de l‘Ouest, Saint-Herblain, France; p Laboratoire US2B, Unité en Sciences Biologiques et Biotechnologies, UMR CNRS 6286,
UFR Sciences et Techniques, Nantes, France

Article info Abstract

Article history: Background and Objective: Androgen deprivation therapy (ADT) is a mainstay in meta-
Accepted February 19, 2024 static prostate cancer, while additional salvage radiotherapy may offer prolonged remis-
sion for patients with regional node relapses. We performed an open-label, phase II trial
Associate Editor: Amar Kishan to assess the long-term outcomes and patterns of relapse of 6-months ADT and elective
pelvic radiotherapy in men with oligorecurrent (<6) pelvic nodes in prostate cancer
Keywords: (Oligopelvis GETUG-P07).
Oligometastatic prostate cancer Methods: We analyzed the 5-yr outcomes. Progression was defined as two consecutive
oligorecurrent pelvic nodes prostate-specific antigen levels above the level at inclusion and/or clinical progression
salvage radiotherapy as per RECIST 1.1 and/or death from any cause.
Key Findings and Limitations: Sixty-seven patients were recruited. The median follow-up
was 6.1 yr (95%CI: 5.9-6.3). Grade 2+ 3-yr, 4-yr and 5-yr genito-urinary and gastro-
intestinal toxicities affected 15%, 9%, 4% and 2%, 3%, 4% of non-progressive patients, respec-
tively. 5-yr progression-free, biochemical relapse–free and ADT-free survivals were 39%,
31% and 64%, respectively. In total, 45 patients had progression and 38 had the following
clinical progression: local (18%), N1 (29%), M1a (50%), M1b (32%) and M1c (11%).

* Corresponding author. Radiation Therapy Department, ICO René Gauducheau, Boulevard J. Monod,
44800 Saint Herblain, France. Tel. +33 2 4067 9900.
E-mail address: [email protected] (S. Supiot).

https://doi.org/10.1016/j.eururo.2024.02.013
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.
74 EUROPEAN UROLOGY 87 (2025) 73–76

Conclusions and Clinical Implications: Finally, combined elective pelvic radiotherapy and
ADT appeared to prolong tumor control with limited toxicity. At 5 years, one third of
patients had not relapsed biochemically. The major site of relapse was para-aortic lymph
nodes.
Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.

ADVANCING PRACTICE

What does this study add?

This study describes the long-term results for high-dose salvage radiotherapy in case of oligorecurrent pelvic nodes in
prostate cancer. This study confirms that salvage pelvic radiotherapy is well tolerated even at longer time points and leads
to prolonged complete remission in approximately one third of patients.

Clinical Relevance
This nonrandomized phase 2 trial provides prospective evidence for 5-year biochemical control following a strategy of
elective nodal radiotherapy (ENRT) plus six months of androgen deprivation therapy (ADT) in men with 5 nodes on flu-
orocholine positron emission tomography (PET). At five years, of the 67 men enrolled, nearly one-third of patients
remained disease-free at 5 years, nearly two-thirds remained free from ADT, and <5% experienced significant gastroin-
testinal or genitourinary toxicity. These data provide a benchmark for counseling patients presenting with PET-
positive nodal relapses after prior definitive treatment and are broadly applicable to those who received no prior
prostate/prostate-bed directed radiotherapy (34 patients) and for those who have nodal relapse after prostate/
prostate-bed directed radiotherapy (33 patients), though in this trial the former group did receive prostate/prostate-
bed directed therapy along with ENRT. Further avenues of investigation include comparisons with metastasis-directed
therapy and/or the integration of intensified systemic therapy. Associate Editor: Amar Kishan, M.D.

Patient Summary
We evaluated long-term results for high-dose radiotherapy in patients with recurrence of prostate cancer in pelvic lymph
nodes. We found that this treatment provided prolonged tumor control without significant toxicity. One-third of the
patients were still in complete remission after 5 years.

Pelvic lymph node (PLN) recurrence is frequent in pros- Table 1 – Patient and tumor characteristics for group 1 (first
tate cancer [1]. If relapse is confined to a limited number of biochemical recurrence) and group 2 (prior biochemical recurrence)
sites, this is denoted as oligorecurrence if there are fewer Parameter Group 1 Group 2
than six lesions [2]. The role of regional salvage treatments (n = 37) (n = 30)
is still debated. Androgen deprivation therapy (ADT) is a Median age, yr (IQR) 68 (65–74) 66 (63–72)
mainstay of treatment for metastatic prostate cancer, Median ISUP grade group (IQR) 3 (2–3) 2 (2–3)
Median number of PLNs on PET (IQR) 1 (1–2) 1 (1–2)
while additional salvage nodal-directed treatment may Median PSA at baseline, ng/ml (IQR) 4.2 (1.0–6.4) 3.4 (1.7–4.2)
offer prolonged complete remission for patients with Median PSA doubling time, mo (IQR) 4.4 (3.0–7.8) 5.3 (2.6–7.7)
regional nodal relapses [2]. Elective nodal radiotherapy Prior androgen deprivation therapy, 4 (11) 8 (27)
n (%)
(ENRT) is one of the most attractive options. For the Median time from Dx to sTx initiation, 34.3 77.7
open-label prospective phase 2 OLIGOPELVIS trial of 6 mo (IQR) (11.1-81.5) (46.1–114.9)
mo of ADT combined with ENRT, positive results were Dx = diagnosis; IQR = interquartile range; ISUP = International Society of
obtained for 2-yr outcomes [3,4]. We now report 5-yr out- Urological Pathology; PET = positron emission tomography; PLNs = pelvic
lymph nodes; PSA = prostate-specific antigen; sTx = study treatment.
comes and patterns of relapse.
The treatment modalities for the trial (NCT02274779)
have already been reported [3] (Supplementary material). biochemical recurrence following prostatic bed radiother-
Between August 2014 and July 2016, 67 patients were apy (n = 30).
recruited in 15 centers. The cohort was divided into two The median follow-up for survivors was 6.1 yr (95% con-
groups a posteriori (Table 1): group 1 included patients fidence interval [CI] 5.9–6.3; Fig. 1). The 5-yr progression-
with a first biochemical recurrence (n = 37) following pri- free survival (PFS) rate was 39% (95% CI 29–52%; Fig. 1
mary treatment (either radical prostatectomy or radiother- and Supplementary Fig. 1). Median PFS was 3.8 yr (95% CI
apy) and group 2 included patients with a second 2.8–5.1). At 5 yr, the biochemical relapse-free survival
 EUROPEAN UROLOGY 87 (2025) 73–76 75

Fig. 1 – Each bar represents one subject in the study. Patients were ranked by (1) the absence or presence of relapse and then (2) patient number. Group 1: no
prior biochemical recurrence; group 2: prior biochemical recurrence treated with prostatic bed radiotherapy ± hormone therapy. Castration status was
defined as a testosterone level <0.5 nmol/l and eugonadal status as a testosterone level >0.5 nmol/l. Biochemical relapse was defined as a PSA level greater
than the nadir +0.2 ng/ml. Progression was defined as PSA higher than the level before treatment, confirmed by a second measurement and/or clinical
progression according to Response Evaluation Criteria in Solid Tumors v1.1 and/or death from any cause. In one relapse-free patient (denoted by *) the
testosterone level had not recovered to normal at 5 yr (testosterone at last visit 0.24 nmol/l). ADT = androgen deprivation therapy; PSA = prostate-specific
antigen.

(BRFS) rate was 31% (95% CI 22–45%), with median BRFS of had a longer history of prostate cancer and a higher rate
2.2 yr (95% CI 1.8–3.5). Other 5-yr survival rates were 43% of prior ADT (Supplementary Table 3). The median dose at
(95% CI 33–57%) for second-line treatment–free survival which N1 nodal relapses occurred did not significantly dif-
(STFS), 64% (95% CI 53–77%) for ADT restart–free survival fer between group 1 (47.5 Gy, interquartile range [IQR]
(ARFS), 49% (95% CI 38–62%) for event-free survival (EFS), 13–53.5) and group 2 (21 Gy, IQR 6–54.5; p = 0.96). Among
and 59% (95% CI 48–72%) for metastasis-free survival the N1 recurrences, 39% were high-dose (50 Gy), 28% were
(MFS). Median STFS and ARFS were not reached. Median geographically missed within the Radiation Therapy Oncol-
EFS was 4.5 yr (95% CI 3.8–not applicable) and median ogy Group (RTOG) template, and 33% were geographically
MFS was 6.6 yr (95% CI 4.5–not applicable). The 5-yr overall missed outside the RTOG template (Supplementary Fig. 4).
survival rate was 92% (95% CI 86–99%). The results reported here confirm the favorable trial out-
Among patients without progression, grade 2+ toxicity comes over the longer term, with a prolonged time without
rates at 3, 4, and 5 yr were 15%, 9%, 4% for genitourinary tox- ADT and a trend for a complete remission plateau for
icities, and 2%, 3%, and 4% for gastrointestinal toxicities, approximately one-third of the OLIGOPELVIS patients,
respectively (Supplementary Table 1). together with limited toxicity. Prior biochemical recurrence
No prognostic factor could predict progression or bio- remained predictive of worse outcomes. Importantly, issues
chemical complete response, but PFS was significantly arising from ENRT at the junction with prior prostatic-bed
worse for group 2 than for group 1 with a hazard ratio radiotherapy (ie, potentially large cumulative doses) were
[HR] of 2.12 (95% CI 1.17–3.86; Supplementary Table 2 and not associated with either higher risk of regional relapses
Supplementary Fig. 2). For patients in group 2, neither prior or greater toxicity.
ADT (HR 1.93, 95% CI 0.77–4.84) nor time from primary diag- These outcomes are in line with results from other studies,
nosis (HR 0.99, 95% CI 0.98–1.002) was associated with PFS. which were retrospective or investigated oligorecurrence set-
In total, 45 patients experienced progression, of whom tings other than PLN-only [5,6]. The results also compare
seven had only prostate-specific antigen progression and favorably to those from salvage nodal steretactic body radia-
38 had relapses for which the following TNM progression tion therapy (SBRT) or lymphadenectomy, such as a median
was identified: M1a, 50%; M1b, 32%; N1, 29%; local, 18%; time before ADT reintroduction of 68 mo, especially as most
and M1c, 11% (Supplementary Figs. 3 and 4). Bone metas- patients in other trials had a single oligorecurrent node
tases were more frequent for group 2 patients, who also [5,7,8]. The grade 2+ urinary toxicity rate of 13% following
76 EUROPEAN UROLOGY 87 (2025) 73–76

ENRT is similar to that in other studies but is greater than the Financial disclosures: Stéphane Supiot certifies that all conflicts of inter-
rate with SBRT (5%) [5,8]. Results from the PEACE est, including specific financial interests and relationships and affiliations
V-STORM trial, investigating 6-mo ADT combined with either relevant to the subject matter or materials discussed in the manuscript
ENRT or SBRT for oligorecurrent PLNs, are expected to help in (eg, employment/affiliation, grants or funding, consultancies, honoraria,

comparisons of the two radiation strategies [9]. stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: Stéphane Supiot has financial
Interestingly, most of the relapses in our trial were in
relationships with Astellas, Janssen, Bayer, Ipsen, MSD, AstraZeneca, Cur-
para-aortic nodes. Prophylactic para-aortic lymph node
ium, AAA Novartis, Takeda, and Ferring. The remaining authors have
radiation concomitant to pelvis radiation is currently being
nothing to disclose.
assessed in the PEARLS (ISRCTN 36344989) and PART (NCT
03079323) trials. The regional relapse rate in our trial was
approximately 16%, which is higher than the rate in another Funding/Support and role of the sponsor: This study was supported by
series (<10%) [5]. Most of these relapses occurred at subop- Astellas Pharmaceuticals. The sponsor played a role in the design and con-
timal radiation doses (<50 Gy), but some of them should duct of the study.
have been included in the pelvic delineation according to
the RTOG guidelines, stressing the importance of stringent Supplementary data
quality assurance. Perivesical, perirectal, and inguinal
pathological nodes are rare, justifying their exclusion from Supplementary data to this article can be found online at
systematic pelvis delineation. Approximately 6% of all https://doi.org/10.1016/j.eururo.2024.02.013.
relapses were high-dose regional relapses. It should be
noted that 10.5% of patients had local relapse at a median References
time of 83 mo (IQR 60–122) from radical prostate treat-
[1] Valle L, Shabsovich D, de Meerleer G, et al. Use and impact of
ment, in line with results reported in the literature [10].
positron emission tomography/computed tomography prior to
The absence of randomization, the use of choline rather salvage radiation therapy in men with biochemical recurrence
than prostate-specific membrane antigen for PET imaging, after radical prostatectomy: a scoping review. Eur Urol Oncol
heterogeneity regarding the number of biochemical recur- 2021;4:339–55. https://doi.org/10.1016/j.euo.2021.01.007.
[2] Zilli T, Achard V, Dal Pra A, et al. Recommendations for radiation
rences following prostate primary treatment, the limited therapy in oligometastatic prostate cancer: an ESTRO-ACROP Delphi
cohort size, the short ADT duration, and the lack of ADT consensus. Radiother Oncol 2022;176:199–207. https://doi.org/
intensification are the main limitations of our study. Some 10.1016/j.radonc.2022.10.005.
[3] Supiot S, Vaugier L, Pasquier D, et al. OLIGOPELVIS GETUG P07, a
of these limitations will be overcome in a prospective phase
multicenter phase II trial of combined high-dose salvage
3 trial (OLIGOPELVIS2, GETUG-P12; NCT03630666) radiotherapy and hormone therapy in oligorecurrent pelvic node
comparing 6-mo ADT alone versus ADT + ENRT, and in the relapses in prostate cancer. Eur Urol 2021;80:405–14. https://doi.
CARLHA-2 GETUG-33 (NCT04181203) and PRIMORDIUM org/10.1016/j.eururo.2021.06.010.
[4] Vaugier L, Palpacuer C, Rio E, et al. Early Toxicity of a phase 2 trial of
(NCT04557059) trials comparing RT + luteinizing hor-
combined salvage radiation therapy and hormone therapy in
mone–releasing hormone agonists ± apalutamide. oligometastatic pelvic node relapses of prostate cancer
In conclusion, combined high-dose salvage ENRT and 6- (OLIGOPELVIS GETUG P07). Int J Radiat Oncol Biol Phys
mo ADT appeared to prolong tumor control with limited 2019;103:1061–7. https://doi.org/10.1016/j.ijrobp.2018.12.020.
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toxicity for oligorecurrent prostate cancer in PLNs. After 5 therapy in treating nodal oligorecurrent prostate cancer: a multi-
yr, approximately one-third of the patients were still in institutional analysis comparing the outcome and toxicity of
complete remission. stereotactic body radiotherapy and elective nodal radiotherapy. Eur
Urol 2019;76:732–9. https://doi.org/10.1016/j.eururo.2019.07.009.
[6] Fodor A, Brombin C, Deantoni CL, et al. Extended nodal radiotherapy
Author contributions: Stéphane Supiot had full access to all the data in for prostate cancer relapse guided with [11C]-choline PET/CT: ten-
the study and takes responsibility for the integrity of the data and the year results in patients enrolled in a prospective trial. Eur J Nucl Med
accuracy of the data analysis. Mol Imaging 2024;51:590–603. https://doi.org/10.1007/s00259-023-
06445-4.
[7] Siva S, Bressel M, Murphy DG, et al. Stereotactic ablative body
Study concept and design: Blanc-Lapierre, Supiot. radiotherapy (SABR) for oligometastatic prostate cancer: a
prospective clinical trial. Eur Urol 2018;74:455–62. https://doi.
Acquisition of data: Vaugier, Morvan, Pasquier, Buthaud, Magné, Beck-
org/10.1016/j.eururo.2018.06.004.
endorf, Sargos, Crehange, Pommier, Loos, Hasbini, Latorzeff, Silva, [8] Miszczyk M, Rajwa P, Yanagisawa T, et al. The efficacy and safety of
Blanc-Lapierre, Supiot. metastasis-directed therapy in patients with prostate cancer: a
Analysis and interpretation of data: Vaugier, Paul, Blanc-Lapierre, Supiot. systematic review and meta-analysis of prospective studies. Eur
Drafting of the manuscript: Vaugier, Blanc-Lapierre, Supiot. Urol 2024;85:125–38. https://doi.org/10.1016/j.eururo.2023.10.012.
[9] Ost P, Siva S, Brabrand S, et al. PEACE V—Salvage treatment of
Critical revision of the manuscript for important intellectual content: g Vau-
oligorecurrent nodal prostate cancer metastases (STORM): acute
gier, Blanc-Lapierre, Supiot. toxicity of a randomized phase 2 trial. Eur Urol Oncol. In press.
Statistical analysis: Paul, Blanc-Lapierre. https://doi.org/10.1016/j.euo.2023.09.007
Obtaining funding: Supiot. [10] Kishan AU, Chu FI, King CR, et al. Local failure and survival after
definitive radiotherapy for aggressive prostate cancer: an individual
Administrative, technical, or material support: Vaugier, Blanc-Lapierre.
patient-level meta-analysis of six randomized trials. Eur Urol
Supervision: Supiot. 2020;77:201–8. https://doi.org/10.1016/j.eururo.2019.10.008.
Other: None.
 EUROPEAN UROLOGY 87 (2025) 77–78

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Editorial
Referring to the article published on pp. 73–76 of this issue

OLIGOPELVIS and the ‘‘All You Can Eat’’ Strategy for Oligorecurrent
Nodal Prostate Cancer: Are We Already Full?

Piet Ost a,b,*, Shankar Siva c, Thomas Zilli d,e

a
Department of Radiation Oncology, Iridium Network, Wilrijk, Belgium; b Department of Human Structure and Repair, Ghent University, Ghent, Belgium;
c
Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; d Department of Radiation
Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; e Faculty of Biomedical Sciences, Università della
Svizzera Italiana, Lugano, Switzerland

With the greater sensitivity of novel radioligands for posi- GETUG-AFU 16, in which 80% of patients were free from
tron emission tomography (PET)/computed tomography recurrence at 5 yr [4]. This indicates that patients with
(CT), detection rates for nodal recurrence have increased PET-visible nodal recurrence reflect a group with poorer
and the number of nodes is often limited [1]. Different treat- prognosis that might require a more intensive salvage treat-
ment options are available, ranging from focused local ment. The pattern of relapse in OLIGOPELVIS might help in
treatment such as stereotactic body radiotherapy (SBRT) pointing to the direction in which we need to move forward.
to more extensive options such as salvage lymph node dis- After pelvic radiotherapy, 21% of patients (n = 14) expe-
section and elective nodal radiotherapy (ENRT) [2]. For most rienced subsequent nodal failure and seven (10%) had fail-
of these approaches, long-term outcomes from prospective ure in the prostate bed, which raises the question of
trials are lacking. whether we could further optimize treatment. Interestingly,
This issue of European Urology includes long-term results some of these relapses occurred within the Radiation Ther-
from the OLIGOPELVIS (GETUG-P07) trial [3]. This nonran- apy Oncology Group (RTOG) radiotherapy template (n = 5,
domized phase 2 trial evaluated ENRT with 6 mo of andro- 7%) but were not delineated and thus not covered by the
gen deprivation therapy (ADT) in patients with up to five treatment dose. This highlights the importance of radiother-
pelvic node relapses detected via fluorocholine PET imaging. apy standardization and quality assurance, as such relapses
Several findings are of interest and provide important infor- should be avoidable. Achard et al [5] observed a protocol
mation for patient counseling. deviation rate of up to 46% for delineation of the nodal ENRT
Importantly, longer follow-up confirmed that the inci- volume in the PEACE V-STORM trial, which was reduced by
dence of severe late genitourinary toxicity was low and training. Another group of patients experienced nodal
declined over time. For gastrointestinal complaints, the recurrence (n = 4, 6%) or local prostate bed recurrence
incidence of late toxicity remained below 5%. At 5 yr, (10%) within the area that received the intended elective
approximately one-third of the patients remained disease- dose of 54 Gy in 1.8-Gy fractions, indicating that this lower
free without a prostate-specific antigen (PSA) relapse; these dose might not have been sufficient in some patients. Nota-
patients probably reflect the true patients with limited bly, all of the notes that were initially PET-positive at inclu-
recurrence that is curable. These rates are comparable to sion that received a higher dose were locally controlled. A
surgical series, with 5-yr PSA relapses rates of 25% [2]. larger proportion of patients (n = 8, 12%) had recurrence
However, the findings compare very unfavorably to trials outside the RTOG template, with M1a recurrence (eg, ingu-
on pure salvage radiotherapy following radical prostatec- inal, common iliac, para-aortic nodes) indicating that
tomy for a first biochemical recurrence (BCR), such as expansion of the radiotherapy field might be indicated in

DOI of original article: https://doi.org/10.1016/j.eururo.2024.02.013

* Corresponding author. Department of Radiation Oncology, Iridium Network, Oosterveldlaan 24, 2610 Wilrijk, Belgium. Tel. +32 3 4433737; Fax: +32 3
4433009.
E-mail address: [email protected] (P. Ost).

https://doi.org/10.1016/j.eururo.2024.03.039
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.
78 EUROPEAN UROLOGY 87 (2025) 77–78

order to avoid such recurrences. The high likelihood of a randomized trials will further explore the potential of sys-
new nodal recurrence, even in the case of an elective field, temic therapy intensification on top of radiotherapy in the
indicates that patients with a first nodal recurrence typi- oligometastatic recurrent setting. The upcoming phase 3
cally continue to experience relapse in the nodal areas. An ESCALATE-RT trial, which is exploring the role of intermit-
alternative approach to ENRT would be to selectively irradi- tent ARTA with or without metastasis-directed therapy, will
ate visible lesions via SBRT and repeat this procedure for certainly help in further defining the best treatment strat-
new relapses [2]. The downside could be that these patients egy for patients with high-risk BCR after local therapy.
might experience a higher number of repeat investigations
and retreatments. The benefit might be that toxicity in the Conflicts of interest: The authors have nothing to disclose.
short term is lower, as the radiotherapy fields are smaller.
However, the difference in toxicity between SBRT and ENRT References
might be small, especially when the prostate bed would also
[1] De Bruycker A, De Bleser E, Decaestecker K, et al. Nodal
require radiotherapy [6]. The PEACE V-STORM trial compar- oligorecurrent prostate cancer: anatomic pattern of possible
ing SBRT to ENRT, both combined with 6 months of ADT, treatment failure in relation to elective surgical and radiotherapy
will report late toxicity results in 2024. treatment templates. Eur Urol 2019;75:826–33. https://doi.org/
10.1016/j.eururo.2018.10.044.
One in four patients (n = 16) experienced progression to [2] Miszczyk M, Rajwa P, Yanagisawa T, et al. The efficacy and safety of
bone metastases (n = 12) or visceral metastases (n = 4), or a metastasis-directed therapy in patients with prostate cancer: a
combination with nodal recurrences (n = 8), suggesting that systematic review and meta-analysis of prospective studies. Eur
Urol 2024;85:125–38. https://doi.org/10.1016/j.
a more intensive systemic treatment could be of interest.
eururo.2023.10.012.
Both the EMBARK and PRESTO trials investigated systemic [3] Vaugier L, Morvan C, Pasquier D, et al. Long-term outcomes and
therapy intensification for patients with BCR and high-risk patterns of relapse following high-dose elective salvage
features, mainly determined in terms of the PSA doubling radiotherapy and hormone therapy in oligorecurrent pelvic nodes
in prostate cancer: OLIGOPELVIS (GETUG-P07). Eur Urol
time [7,8]. In both trials, addition of an androgen recep- 2025;87:73–76.
tor–targeting agent (ARTA) to the standard treatment with [4] Carrie C, Magné N, Burban-Provost P, et al. Short-term androgen
ADT led to improvements in outcomes. These trials were deprivation therapy combined with radiotherapy as salvage
conducted before wide implementation of PET/CT in the treatment after radical prostatectomy for prostate cancer (GETUG-
AFU 16): a 112-month follow-up of a phase 3, randomised trial.
BCR setting. Nevertheless, simulations suggest that the Lancet Oncol 2019;20:1740–9. https://doi.org/10.1016/S1470-2045
majority of these patients would have had detectable dis- (19)30486-3.
ease on PET/CT, mostly locoregional or oligometastatic dis- [5] Achard V, Jaccard M, Vanhoutte F, et al. Oligorecurrent nodal
prostate cancer: Radiotherapy quality assurance of the randomized
ease [9]. When looking at the OLIGOPELVIS results in light
PEACE V-STORM phase II trial. Radiother Oncol 2022;172:1–9.
of these trials, it is important to realize that most patients https://doi.org/10.1016/j.radonc.2022.04.020.
in OLIGOPELVIS had high-risk BCR with a median PSA dou- [6] Ost P, Siva S, Brabrand S, et al. PEACE V-Salvage treatment of
bling time of 4–5 mo and a median absolute PSA level of 3– oligorecurrent nodal prostate cancer metastases (STORM): acute
toxicity of a randomized phase 2 trial. Eur Urol Oncol. In press.
4 ng/ml at inclusion. In EMBARK, 9 mo of ADT monotherapy https://doi.org/10.1016/j.euo.2023.09.007.
resulted in a possible treatment suspension of 17 mo. In [7] Aggarwal R, Heller G, Hillman DW, et al. PRESTO: a phase III, open-
OLIGOPELVIS, using only 6 mo of ADT, the treatment sus- label study of intensification of androgen blockade in patients with
high-risk biochemically relapsed castration-sensitive prostate
pension period seems to be longer, with a median time to
cancer (AFT-19). J Clin Oncol. In press. https://doi.org/10.1200/
BCR of 26 mo and a 5-year ADT-free survival rate of 64%. JCO.23.01157.
The same was observed in the EXTEND trial comparing a [8] Freedland SJ, de Almeida LM, De Giorgi U, et al. Improved outcomes
minimum of 6 mo of ADT to ADT + SBRT for oligometastatic with enzalutamide in biochemically recurrent prostate cancer. N
Engl J Med 2023;389:1453–65. https://doi.org/10.1056/
recurrences: the median treatment suspension period was NEJMoa2303974.
more than doubled in the ADT + SBRT arm [10]. What might [9] Armstrong WR, Clark KJ, Smith CP, et al. PSMA PET findings in an
be even more important is that progression-free survival ‘‘EMBARK-like’’ cohort of patients with high-risk non-metastatic
time, but with normal testosterone levels, was also longer hormone-sensitive prostate cancer: a single center post-hoc
retrospective analysis. J Clin Oncol 2023;41(16 Suppl):5091.
with SBRT. https://doi.org/10.1200/JCO.2023.41.16_suppl.5091.
Although OLIGOPELVIS is a single-arm phase 2 trial, the [10] Tang C, Sherry AD, Haymaker C, et al. Addition of metastasis-
results can be used to counsel patients regarding expected directed therapy to intermittent hormone therapy for
oligometastatic prostate cancer: the EXTEND phase 2 randomized
outcomes from conventional radiotherapy for nodal recur-
clinical trial. JAMA Oncol 2023;9:825–34. https://doi.org/
rences. These findings will help in further tailoring of treat- 10.1001/jamaoncol.2023.0161.
ment options. As mentioned in the publication, newer
 EUROPEAN UROLOGY 87 (2025) 79–83

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Brief Report
Editorial by Scott M. Haake, Brian I. Rini on pp. 84–85 of this issue

Sample Site Impacts RNA Biomarkers for Renal Cell Carcinoma

Lennert Eismann a,b,y, Amy X. Xie c,y, Cerise Tang c, Andrea Knezevic d, Irina Ostrovnaya d,
Fengshen Kuo a, A. Ari Hakimi a, Ed Reznik c,*, Ritesh R. Kotecha e,*
a
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; b Department of Urology, University Hospital
Munich, LMU, Munich, Germany; c Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; d Department of Epidemiology
& Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA; e Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA

Article info Abstract

Article history: Immunotherapy (ICIs) remains a mainstay for treatment of advanced clear-cell renal cell
Accepted September 4, 2024 carcinoma (ccRCC). Biomarker analyses have demonstrated that gene expression profiles
are associated with regimen-specific outcomes. These transcriptomic analyses used
mixed sample cohorts (primary and metastatic tumor specimens) and it is unknown
Keywords: whether the clinical relevance of transcriptomic signatures is impacted by tissue site.
Renal cell carcinoma We evaluated data for 1132 patients with metastatic ccRCC treated with ICI in prior
Transcriptomics studies (IMmotion151 and CheckMate-009, -010, and -025). We identified significant
Biomarkers and reproducible differences in gene expression by tissue site. We tested the association
between previously described molecular tissue clusters (MTCs) by tissue site (MTC1-
primary and MTC1-metastasis) and progression-free survival (PFS) and objective
response to systemic therapy. In IMmotion151, MTC2-metastasis was significantly asso-
ciated with better PFS on sunitinib (hazard ratio [HR] 3.39, 95% confidence interval [CI]
1.32–8.69; p = 0.01) in comparison to MTC2-primary (HR 0.95, 95% CI 0.65–1.38;
p = 0.80; pinteraction = 0.02). Evaluation of known RNA signatures in the CheckMate trials
revealed that JAVELIN-metastasis was associated with better PFS on ICI (HR 0.77, 95% CI
0.62–0.97; p = 0.03) in comparison to JAVELIN-primary (HR 1.04, 95% CI 0.91–1.19;
p = 0.56; pinteraction = 0.02). These results indicate that tissue site may be a relevant con-
founder in biomarker analyses.
Ó 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).

y
These authors share first authorship.
* Corresponding authors. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275
York Avenue, New York, NY, USA. Tel. +1 646 4224839; Fax: +1 646 2272417. (R.R. Kotecha).
Computational Oncology, Memorial Sloan Kettering Cancer Center, 321 East 61st Street, New York,
NY USA. (E. Reznik).
E-mail addresses: [email protected] (E. Reznik), [email protected] (R.R. Kotecha).

https://doi.org/10.1016/j.eururo.2024.09.004
0302-2838/Ó 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
80 EUROPEAN UROLOGY 87 (2025) 79–83

ADVANCING PRACTICE

What does this study add?

We investigated gene expression profiles for patients with metastatic clear-cell renal cell carcinoma treated with
immunotherapy. Comparison of samples from primary tumors and metastatic sites revealed differences in gene expres-
sion profiles. Using previously established clusters associated with progression-free survival, we identified that the asso-
ciation varied by tissue sample site. The findings highlight that tissue site may impact the clinical significance in
biomarker analyses.

Clinical Relevance
In an era of rapidly expanding therapeutic options for patients with metastatic renal cell carcinoma, there is intense inter-
est in developing and validating prognostic biomarkers to guide treatment selection and sequencing. Many studies to date
have opportunistically leveraged available banked tissue that may come from diverse tumor locations, tissue types, and
after variable lengths of exposure to one or more agents. The findings in this study highlight the importance of consid-
ering specimen location as a potential important confounder when evaluating the prognostic value of a biomarker, and
underscore the need for methodologic rigor when evaluating biomarkers derived from different tissue types given hetero-
geneous responses to therapy across variable tumor source locations. Associate Editor: Sarah P. Psutka MD MS.

Patient Summary
We analyzed gene expression in tumor samples from patients with metastatic kidney cancer treated in clinical trials. We
found differences in associations of biomarkers between primary tumor samples and metastatic tumor samples. Our find-
ings highlight an important factor to take into account when developing biomarkers for patients with kidney cancer.

single-sample GSEA. Patient characteristics were analyzed

The therapeutic landscape for advanced clear-cell renal
using the Wilcoxon rank-sum test and Pearson’s v2 test.
cell carcinoma (ccRCC) includes immune checkpoint inhibi-
Progression-free survival (PFS) was estimated via the
tors (ICIs) and VEGF-targeted agents. Retrospective analyses
Kaplan-Meier method and compared between groups using
of tissue samples from clinical trials using these therapies
the log-rank test. Hazard ratios (HRs) were calculated using
have demonstrated that microenvironment-associated
Cox proportional-hazards regression for previously estab-
transcriptomic signatures quantified in mixed cohorts of
lished signatures, including T-effector, myeloid, inflamma-
primary tumor and metastasis sites correlate with
tion, and the JAVELIN score [3] in the ICI treatment arm of
treatment-specific responses and survival [1–4]. For
the CheckMate studies. Data on the objective response rate
instance, in IMmotion151, ccRCC tumors classified as the
(ORR) were collected and odds ratios (ORs) for response ver-
T-effector/proliferative phenotype had better clinical out-
sus no response were calculated, with logistic regression
comes with atezolizumab plus bevacizumab (Az/Bv) than
used to test for association. Patients assigned to cluster 7
with sunitinib [1]. We hypothesized that different gene
in IMmotion151 were omitted from the analysis owing to
expression patterns in primary tumor and metastasis sam-
the limited sample size. Heterogeneity between estimates
ples at baseline could potentially confound the identifica-
for primary tumor or metastasis tissue groups was assessed
tion of robust biomarkers.
using an interaction term in multivariate Cox or logistic
We analyzed two publicly available data sets represent- regressions. Statistical analyses were conducted using R
ing four clinical trials of ICI therapy: Immotion151 [1] and SAS v9.4.
(n = 823) and CheckMate-009, -010, and -025 [4] Motivated by the intrinsically distinct biology of primary
(n = 309). Thus, our cohort comprised 1132 patients with RCC and distant metastases, we hypothesized that baseline
metastatic ccRCC treated with ICI monotherapy nivolumab gene expression in primary tumor and metastasis samples
(CheckMate trials) or an ICI + VEGF Az/Bv combination would be different. Despite heterogeneity among metasta-
(IMmotion151) for whom clinical and RNA sequencing data sis samples, we identified 614 genes with reproducible dif-
for 850 primary tumor and 283 metastasis sites were avail- ferential expression between primary tumor and metastasis
able. Clinical characteristics by tissue site are presented in samples in this cohort (Fig. 1A). Genes consistently upregu-
Supplementary Table 1 for IMmotion151 and in Supple- lated in metastasis samples were concentrated in the coag-
mentary Table 2 for the pooled CheckMate cohort. We ulation pathway, while genes consistently downregulated
obtained the RNA sequencing gene expression matrix. Path- in metastasis samples were concentrated in the hypoxia,
way enrichment analysis involved identification of differen- TNF signaling, P53, and MYC pathways (Fig. 1B). These
tially expressed genes followed by gene set enrichment results demonstrate that metastatic ccRCC tumors exhibited
analysis (GSEA) using the MSigDB hallmark gene set. Gene reproducible metastasis-specific gene expression patterns
expression signature scores were deconvoluted using across multiple cohorts.
 EUROPEAN UROLOGY 87 (2025) 79–83 81

Fig. 1 – (A) Primary and metastatic ccRCC samples from the IMmotion151 and CheckMate cohorts show reproducible patterns of differential gene expression.
Genes in red are consistently and significantly enriched (FDR-adjusted p < 0.1; Wilcoxon rank-sum test) in metastasis samples from both cohorts. Genes in
blue are consistently and significantly enriched in primary tumor samples. (B) Specific pathways show consistent differential gene expression between
primary and metastatic ccRCC samples. Normalized enrichment scores (NES) for 50 gene pathways from the MSigDB hallmark gene set are shown. Gene
pathways in red are significant (FDR-adjusted p < 0.1). (C) Association between gene expression–derived MTCs and PFS in the IMmotion151 cohort depends on
the site of the tissue are shown for reference. (D) Association between gene expression–derived MTCs and ORR in IMmotion151 depends on the site of the
tissue source. The log odds ratio was calculated for responders (complete response or partial response) versus nonresponders (stable disease or progressive
disease) assigned to MTCs by tissue site. Log odds ratio <0 indicates favorable outcomes with Atezo + Bev, while log odds ratio >0 indicates favorable outcomes
with sunitinib. The p values are for statistical interaction between primary tumor/metastasis status and MTCs. Atezo + Bev = atezolizumab + bevacizumab;
ccRCC = clear-cell renal cell carcinoma; CI = confidence interval; FDR = false discovery rate; MTC = molecular tissue cluster; ORR = objective response rate; PFS =
progression-free survival. source. HRs were calculated for median PFS for patients receiving Atezo + Bev versus sunitinib by MTC. HR <1 indicates a favorable
outcome with Atezo/Bev, while HR >1 indicates a favorable outcome with sunitinib. PFS HRs by cluster from the original report [1]

We hypothesized that gene expression differences across MTC2-metastasis was associated with superior PFS with
tissue sites could impact the predictive significance of sunitinib (HR 3.39, 95% confidence interval [CI] 1.32–8.69;
patient clusters or transcriptomic signatures derived from p = 0.01), and this association was significantly different
RNA sequencing data. We found that International to that for MTC2-primary (HR 0.95, 95% CI 0.65–1.38;
Metastatic RCC Database Consortium (IMDC) risk group dif- p = 0.80; pinteraction = 0.02). By contrast, the association
fered between primary tumor and metastasis samples in between PFS and Az/Bev was similar for MTC4-primary
IMmotion151 (Supplementary Table 1), but we did not (HR 0.50, 95% CI 0.29–0.85; p = 0.01) and MTC4-
observe a significant difference in PFS by tissue site (Supple- metastasis (HR 0.55, 95% CI 0.22–1.42; p = 0.22), with pinter-
mentary Fig. 1A). We then reclassified tumors according to action = 0.64 (Fig. 1C). After adjustment for IMDC risk, we
new integrative molecular tissue clusters (MTCs) defined found similar estimates of the association between MTCs
using the original IMmotion151 cluster scheme and the and PFS (Supplementary Fig. 2). We found that the associa-
tissue source (eg, MTC1-primary and MTC1-metastasis). tion between MTCs and ORR also varied by tissue site
We modeled the association between these MTCs and out- (Fig. 1D). For instance, MTC2-metastasis (OR 6.11, 95% CI
comes under the assumption that tumor samples from dif- 1.76–21.23; p = 0.004) and MTC3-metastasis (OR 10.67,
ferent tissue sites sharing a common molecular subtype 95% CI 1.71–66.72; p = 0.01) were both associated with
may not share common effects. We observed that associa- superior ORR to sunitinib, while MTC2-primary (OR 1.26,
tions between MTCs and therapeutic outcomes in IMmo- 95% CI 0.69–2.30; p = 0.46) and MTC3-primary (OR 0.71,
tion151 varied by tissue site. For instance,
82 EUROPEAN UROLOGY 87 (2025) 79–83

95% CI 0.34–1.50; p = 0.36) were not (pinteraction = 0.03 and Our data showcase the distinct biology of ccRCC metas-
pinteraction = 0.007, respectively). tasis and underscore the importance of the tissue site dur-
To evaluate the prognostic differences of other RNA sig- ing biomarker assessments. The results warrant further
natures, we evaluated four established RNA signatures in analyses for contemporary trials of combination agents to
the ICI treatment arms of the CheckMate trials. We noted validate these findings for ccRCC in larger data sets. Our
no differences in clinical characteristics (Supplementary study highlights the tissue site as a potential confounder
Table 2) or PFS (Supplementary Fig. 1B) by tissue site. We during biomarker development using transcriptomics as
observed that JAVELIN-metastasis was associated with bet- clinical tools across solid tumors for patient care.
ter PFS with ICI therapy (HR 0.77, 95% CI 0.62–0.97;
p = 0.03) in comparison to JAVELIN-primary (HR 1.04, 95% Author contributions: Ritesh R. Kotecha had full access to all the data in
CI 0.91–1.19; p = 0.56), with pinteraction =0.02 (Supplemen- the study and takes responsibility for the integrity of the data and the
tary Fig. 3). accuracy of the data analysis.
Transcriptomic analyses have promising clinical utility
as regimen-specific biomarkers for ccRCC. Trials using pre- Study concept and design: Kotecha, Reznik, Hakimi.
treatment gene expression classification to enrich clinical Acquisition of data: Hakimi, Eismann, Xie, Tang, Kuo.
outcomes are feasible [5], and efforts to use molecular sub- Analysis and interpretation of data: Kotecha, Reznik, Hakimi, Kuo, Tang,
typing for contemporary therapies are under way [6]. Our Xie, Eismann, Ostrovnaya, Knezevic.
results show that primary and metastatic tumor tissues Drafting of the manuscript: Eismann, Kotecha, Reznik, Xie, Tang.
have distinct gene expression profiles and that tissue site Critical revision of the manuscript for important intellectual content: Kote-
impacts the association between transcriptomic biomarkers cha, Reznik, Hakimi, Ostrovnaya, Knezevic, Xie.
and outcomes in this cohort. These findings support previ- Statistical analysis: Eismann, Knezevic, Ostrovnaya, Reznik.
ous work demonstrating molecular differences between pri- Obtaining funding: Reznik, Kotecha.
mary tumor and other sites of disease [7] and highlight this Administrative, technical, or material support: Hakimi, Reznik, Kotecha.
as a variable to consider when evaluating biomarkers for Supervision: Reznik, Kotecha.
clinical application. Other: None.
Our study is limited to the specific treatment regimens
used for the patient cohort. While the IMmotion151 ccRCC Financial disclosures: Ritesh R. Kotecha certifies that all conflicts of inter-
tumor clustering has been reproducible in other data sets est, including specific financial interests and relationships and affiliations
[8], the clinical relevance may be regimen-specific given relevant to the subject matter or materials discussed in the manuscript
the different mechanisms of action among VEGF-targeted (eg, employment/affiliation, grants or funding, consultancies, honoraria,
therapies. In addition, primary tumor and metastasis tissues stock ownership or options, expert testimony, royalties, or patents filed,
may reflect other aspects of cohort heterogeneity (eg, received, or pending), are the following: Ritesh R. Kotecha reports a con-
nephrectomy status), and overall specimen availability for sultancy role for Eisai and institutional research funding from Pfizer,
each cluster and treatment arm limits our analysis. For Takeda, Xencor, Novartis, Allogene Therapeutics, and Exelixis. A. Ari
instance, we had to exclude cluster 7, the smallest group Hakimi reports a consultancy role for Merck. Ed Reznik reports a consul-
with a strong association with a favorable response to Az/ tancy role for Xontogeny LLC. The remaining authors have nothing to
Bev, from our analyses as only four patients (2 in each treat- disclose.
ment arm) had data available for metastasis samples. This
limited sample size also constrained adjustments for MTC Funding/Support and role of the sponsor: This work was supported in
testing. part by a National Institutes of Health (NIH)/National Cancer Institute
While tissue availability remains a practical limitation, cancer center support grant (P30 CA008748). Lennert Eismann was sup-
recognition of concordant and discordant relationships ported by a postdoctoral research grant from the German Research Foun-
may bolster biomarker discovery. For instance, the original dation (project number EI 1252/1-1). Ed Reznik was supported in part by
cluster 2 (angiogenic) was not significantly associated with the Department of Defense Kidney Cancer Research Program (HT9425-
ORR or PFS with either Az/Bv or sunitinib [1] (PFS HR 1.16, 23-1-0995), a Cycle for Survival Equinox Innovation Award, a Kidney Can-
95% CI 0.82–1.63; p = 0.397), but MTC2-metastasis was cer Association Young Investigator Award, the Brown Performance Group
associated with superior ORR and PFS with sunitinib. Simi- Innovation in Cancer Informatics Fund, and NIH grant R37 CA276200.
larly, the original cluster 4 (T-effector/proliferative) was sig- Ritesh R. Kotecha is supported in part by a Department of Defense Early
nificantly associated with superior outcomes with Az/Bv, Career Investigator grant (KCRP-AKCI, W81XWH-21-1-0942). The spon-
and this association was comparable for both MTC4- sors played no direct role in the study.

primary and MTC4-metastasis. While limited by sample

size, similar or different MTC estimates may suggest con- Supplementary material
served or distinct biological mechanisms underlying treat-
ment sensitivity. Studies investigating the concordance or Supplementary data to this article can be found online at
discordance between matched primary tumor and metasta- https://doi.org/10.1016/j.eururo.2024.09.004.
sis specimens from individual patients, and confirmation of
these associations with other relevant clinical endpoints References
such as overall survival [9], will be critically informative
in optimizing biomarker applications and trial design. [1] Motzer RJ, Banchereau R, Hamidi H, et al. Molecular subsets in renal
cancer determine outcome to checkpoint and angiogenesis blockade.
Cancer Cell 2020;38:803–817.e4.
 EUROPEAN UROLOGY 87 (2025) 79–83 83

[2] McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and [6] Beckermann K, Haake S, Reddy A, et al. Optimal treatment by
molecular correlates of response to atezolizumab alone or in invoking biologic clusters in renal cell carcinoma (OPTIC RCC).
combination with bevacizumab versus sunitinib in renal cell Oncologist 2023;28(Suppl 1):S14.
carcinoma. Nat Med 2018;24:749–57. [7] Barata P, Gulati S, Elliott A, et al. Renal cell carcinoma histologic
[3] Motzer RJ, Robbins PB, Powles T, et al. Avelumab plus axitinib versus subtypes exhibit distinct transcriptional profiles. J Clin Invest
sunitinib in advanced renal cell carcinoma: biomarker analysis of the 2024;134:e178915.
phase 3 JAVELIN Renal 101 trial. Nat Med 2020;26:1733–41. [8] Saliby RM, Labaki C, Jammihal TR, et al. Impact of renal cell
[4] Braun DA, Hou Y, Bakouny Z, et al. Interplay of somatic alterations carcinoma molecular subtypes on immunotherapy and targeted
and immune infiltration modulates response to PD-1 therapy outcomes. Cancer Cell 2024;42:732–5.
blockade in advanced clear cell renal cell carcinoma. Nat Med [9] Motzer RJ, Powles T, Atkins MB, et al. Final overall survival and
2020;26:909–18. molecular analysis in IMmotion151, a phase 3 trial comparing
[5] Vano YA, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab- atezolizumab plus bevacizumab vs sunitinib in patients with
ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line previously untreated metastatic renal cell carcinoma. JAMA Oncol
treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): 2022;8:275–80.
a biomarker-driven, open-label, non-comparative, randomised,
phase 2 trial. Lancet Oncol 2022;23:612–24.
 EUROPEAN UROLOGY 87 (2025) 84–85

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Editorial
Referring to the article published on pp. 79–83 of this issue

Refining the Tissue Source for Biomarker-based Approaches

in Renal Cell Carcinoma

*
Scott M. Haake, Brian I. Rini
Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

Immune checkpoint inhibitors (ICIs) have revolutionized (NCT05361720), which uses a tissue-based gene expression
care for advanced clear-cell renal cell carcinoma (ccRCC). biomarker to assign patients to one of two ICI-containing
ICI therapies can induce deep, durable responses in patients treatment regimens [4,5]. OPTIC RCC and the previously
and are now a standard of care for untreated ccRCC. How- completed BIONIKK study have shown that such trials are
ever, up to 20% of patients may have progressive disease feasible.
as their best treatment response [1] and only a minority An important aspect of any tissue-based biomarker is the
of patients achieve a durable complete remission [2]. Pre- tissue source. In many of these previously mentioned retro-
diction of which patients will experience a robust tumor spective studies, tissue procurement was opportunistic,
response when treated with ICI therapies has proven diffi- meaning that whatever tissue could be procured for a given
cult. Tissue-based biomarkers used to predict tumor patient was sequenced. This resulted in the use of mixed-
response in other cancers, such as PD-L1 expression on source tissues, including both metastatic and primary
tumor cells and/or in the tumor microenvironment, tumor tumor tissue. For example, in IMmotion151, 625 primary
mutational burden, and microsatellite instability, have not tumors and 198 metastatic tumors were sequenced [6].
been clinically useful in ccRCC [3]. The International Meta- The tumors were grouped into one of seven clusters accord-
static RCC Database Consortium (IMDC) risk model, devel- ing to their gene expression pattern. The study noted that
oped as a prognostic tool, has been used to enrich for metastatic tumors were observed across all clusters, sug-
responders to ipilimumab and nivolumab [1], although gesting the classification was not primarily driven by the
use of this tool to predict drug response has fallen out of origin of the tumor. However, the correlations to drug
favor as extended follow-up eroded its ability to distinguish response were not reported separately, depending on
favorable long-term responses. New biomarkers are needed whether the GES was derived from primary or metastatic
so that patients predicted to respond to ICI therapies can be tumor tissue. Thus, there are limited data on whether a sim-
prioritized for treatment and patients unlikely to respond ilar GES detected in primary versus metastatic tissue con-
can be referred for clinical trials. fers different predictive capabilities. The study by Eismann
An emerging biomarker strategy in the ccRCC field is tis- et al [7] presented in this issue of European Urology sought
sue-based gene expression signatures. RNA can be extracted to address this knowledge gap.
from tissue specimens for state-of-the-art next-generation To evaluate whether primary versus metastatic tumor
sequencing to capture gene expression data from all cells tissues with the same GES differ in their correlation with
within the tumor microenvironment. Retrospective studies treatment response, the authors gathered RNA sequencing
correlating ccRCC gene expression patterns with response data for 1132 patients with metastatic ccRCC treated with
to ICI-containing therapies have generated several gene ICIs across four clinical trials: IMmotion151, which investi-
expression signatures (GESs) with predictive capability. gated atezolizumab (anti-PD-L1) plus bevacizumab (anti-
This led to the prospective phase 2 OPTIC RCC trial VEGF) versus sunitinib; and the CheckMate-009, -010, and

* Corresponding author. Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. Tel. +1 615 8758012.
E-mail address: [email protected] (B.I. Rini).

https://doi.org/10.1016/j.eururo.2024.09.029
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
 EUROPEAN UROLOGY 87 (2025) 84–85 85

-025 arms that assessed nivolumab monotherapy (anti- GES, correlation to drug response may be different. The
PD1) [7]. For the IMmotion151 cohort, there were signifi- issue of intratumoral heterogeneity further complicates
cant differences between the primary tumor and metastatic the use of primary tumors for tissue-based GES and other
tissue groups: patients contributing primary tumor tissue tissue-based biomarkers [9]. These data align well with
were younger (median age 64 vs 60 yr; p < 0.001) and were the OPTIC RCC study, in which discordance in cluster types
more likely to have sarcomatoid tumor features (4.4% vs was observed between primary and metastatic tissue from
20%; p < 0.001) and higher IMDC risk scores (favorable the same patient [5]. Thus, a paradigm in which metastatic
43% vs 14%; intermediate 42% vs 69%; poor risk 15% vs tumor tissue is required is reasonable when evaluating and
17%; p < 0.001). Differences in cluster distributions were using tissue-based biomarkers in ccRCC.
statistically significant (p = 0.049): primary tumors were
slightly more likely to be cluster 3 (complement/oxidative Conflicts of interest: Scott M. Haake has nothing to disclose. Brian I. Rini
phosphorylation; 15% vs 20%) and slightly less likely to be reports institutional research funding from AVEO, Arcus, Merck, Dragon-
cluster 6 (stromal/proliferative; 19% vs 11%). A better over- fly Therapeutics, HiberCell, Incyte, Stata Oncology, ADC Therapeutics,
all response rate to sunitinib for the metastatic versus pri- Dracen Pharmaceuticals, Janssen, Adela, AstraZeneca, Tempus, Gilead,
mary tissue was observed for cluster 2 tumors POINT Biopharma, BMS, Pfizer, Daiichi Sankyo, Genentech, Exelixis,

(angiogenic; odds ratio [OR] 1.26 vs 6.11; pinteraction = 0.03) and Surface Oncology; and a consulting role for Eisai, BMS, Pfizer, Genen-
tech, AstraZeneca, Aveo, Merck, Debiopharm, Exelixis, and MashupMD.
and cluster 3 tumors (OR 0.71 vs 10.67; pinteraction = 0.007).
Assessment of progression-free survival (PFS) revealed that
References
only primary cluster 2 tumors exhibited better outcomes
with sunitinib (hazard ratio [HR] 2.15 vs 0.95; pinteraction [1] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus
test = 0.02). When PFS was adjusted for IMDC risk group, ipilimumab versus sunitinib in advanced renal-cell carcinoma. N
no clusters differed in outcome between primary and meta- Engl J Med 2018;378:1277–90. https://doi.org/10.1056/
NEJMoa1712126.
static tumors. Thus, given the small sample size for some of [2] Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus
the subsets and the differences between the primary and ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of
metastatic cohorts (eg, age, sarcomatoid features, IMDC advanced renal cell carcinoma (aRCC): long-term follow-up data
from the phase 3 CheckMate 214 trial. J Clin Oncol 2024;42(4
scores), it is difficult to be certain that GESs from primary
Suppl):363. https://doi.org/10.1200/JCO.2024.42.4_suppl.363.
versus metastatic tumors differ in predictive capabilities. [3] Tucker MD, Rini BI. Predicting response to immunotherapy in
However, the data are compelling and highly suggestive of metastatic renal cell carcinoma. Cancers 2020;12:2662. https://doi.
inherent differences. Of note, even with limited numbers org/10.3390/cancers12092662.
[4] Chen YW, Beckermann K, Haake SM, et al. Optimal treatment by
and adjustment for differences in IMDC distributions, clus- invoking biologic clusters in renal cell carcinoma (OPTIC RCC). J Clin
ter 4 (T effector) was associated with superior PFS for both Oncol 2023;41(6 Suppl):TPS742. https://doi.org/10.1200/
primary (HR 0.36, 95% CI 0.13–1.00) and metastatic (HR JCO.2023.41.6_suppl.TPS742.
[5] Haake SM, Beckermann K, Chen YW, et al. Initial screening efforts for
0.39, 95% CI 0.20–0.74) tumors, consistent with a robust
the OPTIC RCC trial. J Clin Oncol 2024;42(4 Suppl):478. https://doi.
and highly predictive GES. org/10.1200/JCO.2024.42.4_suppl.478.
For the CheckMate-009, -010, and -025 studies, the [6] Motzer RJ, Banchereau R, Hamidi H, et al. Molecular subsets in renal
authors aggregated RNA sequencing data for 84 metastatic cancer determine outcome to checkpoint and angiogenesis blockade.
Cancer Cell 2020;38:803–817.e4. https://doi.org/10.1016/j.
and 225 primary tumors. The primary tumor and metastatic ccell.2020.10.011.
groups were balanced for clinical and IMDC variables. Four [7] Eismann L, Xie AX, Tang C, et al. Sample site impacts RNA biomarkers
previously published GESs were compared across the for renal cell carcinoma. Eur Urol. 2025;87:79–83.
groups. For all GESs evaluated, HRs showed a trend for bet- [8] Gulati S, Barata PC, Elliott A, et al. Molecular analysis of primary and
metastatic sites in patients with renal cell carcinoma. J Clin Invest
ter PFS for metastatic tumors than for primary tumors. 2024;134:e176230. https://doi.org/10.1172/jci176230.
In summary, the authors showed that primary and meta- [9] Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity
static tumors exhibit differential gene expression patterns, and branched evolution revealed by multiregion sequencing. N Engl J
Med 2012;366:883–92. https://doi.org/10.1056/NEJMoa1113205.
consistent with other RCC data sets [8]. Moreover, even
when primary and metastatic tumors exhibit the same
 EUROPEAN UROLOGY 87 (2025) 86–88

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journal homepage: www.europeanurology.com

Cutting Edge Communication

Sensitive Detection of Urothelial Cancer via High-volume Urine DNA

Analysis

Jussi Nikkola a,b,c,*,y, Lauri Ryyppö a,y, Juuso Vuorinen a,y, Heini Kallio a, Hanna Selin a, Pyry Jämsä b,
Jonne Åkerla b, Tuomo Virtanen a, Tarmo Pekkarinen b, Antti Kaipia b, Johanna Pulkkinen d,
Gillian Vandekerkhove c, David C. Müller c, Alexander W. Wyatt c, Peter C. Black c, Matti Nykter a,
Thea Veitonmäki b,à, Matti Annala a,*,à

Cystoscopy and imaging are the gold standard for urothelial 64% of surveillance samples) were analyzed blind to diag-
cancer (UC) detection and surveillance, but cystoscopy is an nosis (Supplementary Fig. 4).
uncomfortable procedure with a low diagnostic yield, as In the diagnostic setting, the assay achieved high sensi-
only 10% of patients with hematuria have UC [1]. Urine tivity for T1 stage bladder cancer (37/37 detected, 100%),
tumor DNA (utDNA) is a noninvasive UC biomarker that Ta bladder cancer (77/82, 94%), and UTUC (23/25, 92%), with
has historically suffered from poor sensitivity for Ta stage an average of 6.0 somatic mutations detected in positive
tumors (<80%) (Supplementary Table 1). We hypothesized samples (Fig. 1B and Supplementary Table 5). All 18 tumors
that high-volume urine analysis with a multigene panel containing carcinoma in situ and eight tumors representing
could overcome this limitation and developed a 100-ml rare histological subtypes were detected (Supplementary
utDNA laboratory platform (UroScout) that analyzes 25 Table 3). Sensitivity for PUNLMP was poor (1/3 detected).
genes commonly mutated in UC and eight loci with somatic Of the five utDNA-negative bladder cancer cases, four were
copy-number alterations for detection of UC (Supplemen- 10-mm Ta low-grade tumors, and one was a Ta high-grade
tary Table 2). tumor with urine atypically collected after hexaminolevuli-
Between January 2021 and January 2024, we enrolled nate instillation. The two utDNA-negative UTUC cases were
281 patients (157 bladder cancer, 31 upper tract UC ureteral Ta low-grade tumors with hydronephrosis. Urine
[UTUC], 5 papillary urothelial neoplasm of low malignant DNA concentrations and the utDNA fraction correlated with
potential [PUNLMP], 88 UC-negative) and analyzed 497 tumor stage and grade (Supplementary Fig. 5). Assay speci-
urine samples (255 diagnostic, 242 surveillance; Fig. 1A ficity was 88%, with utDNA detected in 10/83 samples from
and Supplementary Table 3). Patient characteristics UC-negative patients who were evaluated because of hema-
reflected an all-comer population (Supplementary Table 4). turia or imaging findings (1 had multiple mutations
Median follow-up was 16.5 mo. Patients self-collected detected, and 7 had a TERT promoter or KDM6A mutation).
most of the urine samples at home or in the clinic, with Since a urine DNA test with high UC specificity could
23% collected via catheter immediately before cystoscopy allow expedited access to curative treatment, we tested a
or surgery. The median urine volume was 75 ml for secondary utDNA detection threshold requiring detection
home-collected samples and the median time since last of at least two mutations with an allele fraction 5%. All
void was 3.5 h. We tested three different DNA extraction 100 patients whose diagnostic urine sample met this
methods, of which extraction from the urine cell pellet threshold required surgery (n = 99) or had metastatic dis-
provided the highest DNA yield (Supplementary Figs. 1–3 ease (n = 1), yielding a positive predictive value of 100%.
and Supplementary material). Samples were sequenced to Diagnostic urine from 69% of UC patients met this thresh-
a median unique fragment depth of 4426. Samples old, indicating potential for a three-tier diagnostic workflow
collected after February 1, 2023 (68% of diagnostic and (Fig. 1C).

y
These authors contributed equally to this work.
à
These authors jointly supervised this work.

https://doi.org/10.1016/j.eururo.2024.10.014
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
 EUROPEAN UROLOGY 87 (2025) 86–88 87

Fig. 1 – Urothelial cancer (UC) detection and surveillance via measurement of mutations in urine tumor DNA (utDNA). (A) Consolidated Standards of
Reporting Trials (CONSORT) diagram of the study population. (B) Diagnostic utDNA results and clinical characteristics for 145 patients diagnosed with UC. (C)
Proposed diagnostic workflow for utDNA-based screening before cystoscopy and predictive modeling of outcomes. (D) Results for 162 postoperative utDNA
samples collected from 97 patients at time points coinciding with surveillance cystoscopy or cytology examinations or follow-up surgery. Blue lines indicate
the allele fraction threshold for utDNA positivity for each sample (Supplementary material). Samples shown on the right were analyzed without access to
mutation profiles from earlier samples. Results for time-matched cystoscopy, surgery, and cytology are shown on top. (E) Somatic gene mutation frequency in
muscle-invasive (MIBC) and non–muscle-invasive (NMIBC) bladder cancer. Only samples with a utDNA fraction ≥5% were included in the analysis. (F) Time to
recurrence after first transurethral resection of bladder tumor (TURBT) in all bladder cancer patients. Recurrence was defined as any visualization of tumor
on cystoscopy or surgery, unless cancer was ruled out via later histopathological examination. Numbers in parentheses indicate the 95% confidence interval
for the hazard ratio (HR). UTUC = upper tract urothelial cancer; PUNLMP = papillary urothelial neoplasm of low malignant potential.
88 EUROPEAN UROLOGY 87 (2025) 86–88

For postoperative surveillance, we used preoperative of Finland Center of Excellence Program (project 312043), the Finnish
utDNA mutation profiles to boost detection sensitivity Cultural Foundation, the Finnish Medical Foundation, Academy of Finland
without patient-specific assays. A surveillance sample was project funding, the Orion Research Foundation, Competitive State
classed as positive if prior mutations were detected at a Research Funding for Tampere University Hospital, and the iCANDOC

higher allele fraction than in negative control samples Doctoral Education Pilot in Precision Cancer Medicine. The sponsors had
no direct role in the study.
(p < 0.05) or if new mutations were found. This approach
detected 18/20 (90%) recurrent tumors identified via time-
matched cystoscopy, surgery, or cytology, and missed two Acknowledgments: We thank Biocenter Finland and the Tampere Geno-
low-grade Ta recurrences (Fig. 1D). 47/108 (44%) surveil- mics Facility for their service and the CSC–IT Center for Science, Finland,
lance samples were utDNA-positive despite time-matched for computational resources. We would like to thank the clinicans who
negative cystoscopy or surgery, which probably reflects contributed to patient recruitment for this study, including Panu
field cancerization and the >40% recurrence rate for non– Antinmaa, Mika Ala-Lipasti, Juha Koskimäki, Tomi Pakarainen, Heini
muscle-invasive bladder cancer [2]. Subsequent surveil- Pajunen, Leena Saaristo, Bilal Sumrein, Antti Tuokko, Jaakko Valli, and
lance samples remained positive in 23/27 (85%) patients Samuli Virtanen. We are grateful to all the participating patients and their
without intervening surgical treatment (Supplementary families.
Fig. 6). Sensitivity was lower for surveillance samples ana-
lyzed without prior mutation profiles (11/14, 79%). Data sharing statement: The raw sequencing data generated in this study
TP53 mutations and lack of FGFR3 mutations were asso- have been deposited in the European Genome-Phenome Archive under
ciated with muscle-invasive high-grade disease and poor accession number EGAD50000000891.
prognosis (Fig. 1E, F and Supplementary Figs. 7–9). Copy-
number alterations were detected in 31/186 diagnostic Supplementary data
urine samples (Supplementary Fig. 10), all of which also
had utDNA mutations detected. The assay also detected
Supplementary data to this article can be found online at
Lynch syndrome (LS) in three UTUC patients, as supported
https://doi.org/10.1016/j.eururo.2024.10.014.
by immunohistochemistry or a prior LS diagnosis (Supple-
mentary Fig. 11). References
Our results show that high volume urine cell pellet DNA
analysis using the UroScout multigene assay achieves state- [1] Woldu SL, Ng CK, Loo RK, et al. Evaluation of the new American
Urological Association Guidelines risk classification for hematuria. J
of-the-art accuracy for UC diagnosis and surveillance, with
Urol 2021;205:1387–93.
strong potential for easing the burden on patients and [2] Ma J, Roumiguie M, Hayashi T, et al. Long-term recurrence rates of
reducing health care costs. Noninvasive utDNA testing low-risk non-muscle-invasive bladder cancer—how long is
could eliminate most cystoscopies and expedite care while cystoscopic surveillance necessary? Eur Urol Focus 2024;10:189–96.
[3] Siefker-Radtke AO, Necchi A, Park SH, et al. Efficacy and safety of
providing predictive biomarkers for targeted therapies [3] erdafitinib in patients with locally advanced or metastatic urothelial
and identifying cancer predisposition syndromes [4]. These carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol
results are being validated in the multicenter UROSCOUT-1 2022;23:248–58.
study (NCT06310759). [4] Lonati C, Necchi A, Gómez RJ, et al. Upper tract urothelial carcinoma in
the Lynch syndrome tumour spectrum: a comprehensive overview
from the European Association of Urology-Young Academic Urologists
and the Global Society of Rare Genitourinary Tumors. Eur Urol Oncol
Conflicts of interest: Juuso Vuorinen is a co-founder of Fluivia. Gillian
2022;5:30–41.
Vandekerkhove has an advisory/consulting role for Janssen Canada, and
has received research funding from Gilead Sciences, and travel expenses
and honoraria from Gilead Sciences, Janssen Canada, and EMD Serono. a
Faculty of Medicine and Health Technology, Tampere University and Tays
Alexander Wyatt has an advisory/consulting role for AstraZeneca, Pfizer, Cancer Centre, Tampere, Finland
Merck, and Bayer, and has institutional research contracts with ESSA b
Department of Urology, Tampere University Hospital, Tampere, Finland
c
Pharma and Tyra Biosciences. Peter Black has had a consulting role for Vancouver Prostate Centre, Department of Urologic Sciences, University of
AbbVie, Astellas Pharma, AstraZeneca, EMD-Serono, EnGene, Ferring, Pfi- British Columbia, Vancouver, Canada
d
zer, Janssen Oncology, Bayer, Merck, Bristol-Myers Squibb, Prokarium, CG Department of Pathology, Fimlab Laboratories, Tampere, Finland

Oncology, Combat, Nonagen, Nanobot, NanOlogy, Photocure, Sumitomo,

*
TerSera, and Tolmar, and shares a patent with Veracyte. Matti Annala is Corresponding authors. Faculty of Medicine and Health Technology,
Tampere University, Tampere, Finland.
a co-founder of Fluivia. The remaining authors have nothing to disclose.
E-mail addresses: [email protected] (J. Nikkola),
[email protected] (M. Annala).
Funding/Support and role of the sponsor: This work was funded by
October 11, 2024
research grants from the Jane and Aatos Erkko Foundation, the Academy
 EUROPEAN UROLOGY 87 (2025) 89–95

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Words of Wisdom

Re: International Survey on Urodynamic Investigations in would have been interesting to capture the views of the sur-
Women Undergoing Stress Urinary Incontinence geons who actually treat these patients. In addition, we
SurgeryRubilotta E, Gubbiotti M, Castellani D, et al challenge the concluding statement by the authors, which
raises the usual illogical question about the ability of UDS
to influence outcomes. Unlike evaluations for therapies,
Urology 2023;176:16–20
attempts to judge the value of a diagnostic test on the basis
of the eventual treatment success are conceptually flawed
Experts’ summary: [2]. Moreover, as we have highlighted in the past, it seems
The authors conducted a survey to capture global illogical to presume that a preoperative test can improve
trends for the use of preoperative urodynamics (UDS) in the outcome of a surgical intervention if the surgery goes
women with stress urinary incontinence (SUI). A specifi- ahead anyway, regardless of the preoperative UDS, as in
cally designed questionnaire was circulated to urologists many highly publicized RCTs [4,5].
and gynecologists in several international and national
societies. There were 500 responses across 69 countries
Conflicts of interest: The authors have nothing to disclose.
to this first ever global survey on UDS before surgery
for female SUI. More than 50% of the respondents stated References
that they commonly perform UDS in this setting, includ-
ing ‘‘uncomplicated’’ cases (24%). In addition, >80% con- [1] Nager CW, Brubaker L, Litman H, et al. A randomized trial of
firmed that UDS findings influenced or modified plans urodynamic testing before stress-incontinence surgery. N Engl J Med
2012;366:1987–97.
for surgery, and almost all stated that UDS improved
[2] Tarcan T, Finazzi-Agrò E, Kessler TM, Serati M, Solomon E, Rosier
patient counseling. The authors conclude that ‘‘UDS influ- PFW. How should prospective research be designed to legitimately
ences surgical management, but whether it influences assess the value of urodynamic studies in female urinary
outcomes is unclear’’. incontinence? Neurourol Urodyn 2023;42:1639–46.
[3] James MB, Theofanides MC, Sui W, Onyeji I, Badalato GM, Chung DE.
Sling procedures for the treatment of stress urinary incontinence:
comparison of national practice patterns between urologists and
Experts’ comments: gynecologists. J Urol 2017;198:1386–91.
Over the past 15 yr, the role of UDS before surgery for SUI [4] Serati M, Braga A, Torella M, Soligo M, Finazzi-Agro E. The role of
has been the subject of strong debate, and many interna- urodynamics in the management of female stress urinary
incontinence. Neurourol Urodyn 2019;38(Suppl 4):S42–50.
tional guidelines and research publications take the view [5] Serati M, Cantaluppi S, Coluccia AC, et al. Is urodynamic evaluation
that UDS is only necessary in cases considered to be ‘‘com- able to change and improve the management of women with
plicated’’ [1]. However, no data on real-world use of preop- idiopathic overactive bladder? Minerva Urol Nephrol
erative UDS worldwide have been available. The authors of 2021;73:823–30.
this study deserve credit for designing the first global sur-
Maurizio Serati a,*
vey on this topic. The results reveal that many urologists
Tufan Tarcan b,c
and gynecologists routinely perform UDS for these patients, Enrico Finazzi Agrò d,e
and that UDS often influences their surgical planning and
enhances patient counseling. This is an important message a
Department of Obstetrics and Gynecology, Del Ponte Hospital, University of
for a contentious topic, so we congratulate the authors on Insubria, Varese, Italy
b
their mission. However, we observed that the methodology Department of Urology, Marmara University School of Medicine, Istanbul,
Turkey
used can skew results, just as it did with well-known ran- c
Department of Urology, Koç University School of Medicine, Istanbul, Turkey
domized controlled trials (RCTs) in this field [2]. The major- d
Department of Surgical Sciences, Tor Vergata University of Rome, Rome, Italy
ity of survey respondents were young urologists, aged 25– e
Urology Unit, Policlinico Tor Vergata University Hospital, Rome, Italy
45 yr (possibly because the survey was disseminated via
social media, which mainly reaches a younger demo- * Corresponding author. Department of Obstetrics and Gynecology, Del
graphic). The results are not in accordance with previous Ponte Hospital, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy.
findings that more than 70% of surgical procedures for SUI E-mail address: [email protected] (M. Serati).

are performed by urogynecologists aged 40 yr [3]. It

90 EUROPEAN UROLOGY 87 (2025) 89–95

Associate Editor: 0302-2838/Ó 2024 European Association of Urology. Published by

George Thalmann Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
Accepted 3 July 2024 https://doi.org/10.1016/j.eururo.2024.07.018

Re: Integrative Multi-Region Molecular Profiling of Nonetheless, the findings reported have profound implica-
Primary Prostate Cancer in Men with Synchronous Lymph tions for pretreatment risk stratification and subsequent
Node Metastasis interventions, including focal therapy for the prostate.
The parallels in the pathogenesis and molecular classifi-
Singhal U, Nallandhighal S, Tosoian JJ, et al
cation of breast and prostate cancers suggest a potential
role for focal therapy in localized prostate cancer. Halste-
Nat Commun 2024;15:4341 dian principles of whole-gland treatment in breast cancer
have evolved into Fischer’s concept of partial-gland treat-
ment thanks to decades of clinical trials, robust debates,
Experts’ summary:
and refinement of surgical techniques [5].
Singhal et al [1] sought to answer two key questions in
However, the ability to reliably identify biologically
their study: (1) Are synchronous nodal metastases in
aggressive prostatic lesions remains elusive, complicating
high-risk multifocal prostate cancer monoclonal? And if
the delivery of precise focal treatments. Insights from this
so, (2) can we identify the responsible clone within the
study indicate that current focal therapy techniques, which
prostate gland? They analyzed ten patients (65 primary
are predominantly guided by radiological and pathological
tumor lesions and 16 nodal metastases) using multiplat-
features, may not always adequately target the clone most
form molecular methods. First, the authors confirmed what
likely to disseminate (an approximate 10% risk of undertreat-
several prior landmark studies have shown [2–4], that pros-
ment). It remains to be seen whether a more nuanced, subto-
tate cancer metastases are indeed monoclonal, despite the
tal focal surgical approach can offer some advantages [6].
multifocality and multiclonality of primary tumors. Regard-
Finally, while the study has broad biological and clinical
ing the second question, the authors found that while cer-
ramifications, we must acknowledge that none of the
tain pathological features such as high tumor grade,
patients included in the analysis would be candidates for
extraprostatic extension, and cribriform pattern were gen-
focal therapy in practice, so the findings must be inter-
erally useful in determining the dominant biological clone,
preted accordingly. Nevertheless, the study underscores
these criteria were not perfect. Of particular interest in this
our nascent understanding of and limited ability to identify
context is patient #38 (Supplementary Fig. 8 [1]), who had a
the dominant prostate cancer lesion on biopsy and raises
single metastasis arising from a grade group 3 lesion, but
pertinent questions. Are we effectively managing patients
harbored grade group 5 lesions elsewhere in the prostate.
with intermediate-risk disease, for which the role of focal
The lesion that gave rise to metastasis did not exhibit
therapy is expanding? What are the odds that a metachro-
extraprostatic extension either but did have an associated
nous index lesion could emerge after the initial index lesion
cribriform growth pattern. The other nine patients (90%)
has been treated?
seemed to have metastasis from an admixture of primary
lesions that included the highest-grade disease.
Conflicts of interest: The authors have nothing to disclose.

Experts comments: References

This study marks a significant advance in ongoing efforts
to decipher the molecular and pathological attributes that [1] Singhal U, Nallandhighal S, Tosoian JJ, et al. Integrative multi-region
could delineate the dominant prostate cancer lesion—the molecular profiling of primary prostate cancer in men with
lesion responsible for metastasis. The investigators adeptly synchronous lymph node metastasis. Nat Commun 2024;15:4341.
[2] Liu W, Laitinen S, Khan S, et al. Copy number analysis indicates
highlight the inherent challenges of this endeavor, as they monoclonal origin of lethal metastatic prostate cancer. Nat Med
were unable to identify a single genomic, anatomic, or 2009;15:559–65.
histopathological determinant that could consistently iden- [3] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of
tify the dominant nodule. As noted above, high-grade dis- lethal metastatic prostate cancer. Nature 2015;520:353–7.
[4] Woodcock DJ, Riabchenko E, Taavitsainen S, et al. Prostate cancer
ease features were generally associated with the dominant
evolution from multilineage primary to single lineage metastases
lesion (90% of the time), but this was not always the case. with implications for liquid biopsy. Nat Commun 2020;11:5070.
Furthermore, it is important to note that the study used tis- [5] Labbate CV, Klotz L, Morrow M, Cooperberg M, Esserman L, Eggener
sue from radical prostatectomy specimens, suggesting that SE. Focal therapy for prostate cancer: evolutionary parallels to breast
determining these features from biopsy samples would cancer treatment. J Urol 2023;209:49–57.
[6] Sood A, Jeong W, Palma-Zamora I, et al. Description of surgical
probably be even more challenging. On that note, it would technique and oncologic and functional outcomes of the precision
have been beneficial to have details on the preoperative prostatectomy procedure (IDEAL stage 1–2b study). Eur Urol
imaging and biopsy characteristics of these patients. 2022;81:396–406.
90 EUROPEAN UROLOGY 87 (2025) 89–95

Associate Editor: 0302-2838/Ó 2024 European Association of Urology. Published by

George Thalmann Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
Accepted 3 July 2024 https://doi.org/10.1016/j.eururo.2024.07.018

Re: Integrative Multi-Region Molecular Profiling of Nonetheless, the findings reported have profound implica-
Primary Prostate Cancer in Men with Synchronous Lymph tions for pretreatment risk stratification and subsequent
Node Metastasis interventions, including focal therapy for the prostate.
The parallels in the pathogenesis and molecular classifi-
Singhal U, Nallandhighal S, Tosoian JJ, et al
cation of breast and prostate cancers suggest a potential
role for focal therapy in localized prostate cancer. Halste-
Nat Commun 2024;15:4341 dian principles of whole-gland treatment in breast cancer
have evolved into Fischer’s concept of partial-gland treat-
ment thanks to decades of clinical trials, robust debates,
Experts’ summary:
and refinement of surgical techniques [5].
Singhal et al [1] sought to answer two key questions in
However, the ability to reliably identify biologically
their study: (1) Are synchronous nodal metastases in
aggressive prostatic lesions remains elusive, complicating
high-risk multifocal prostate cancer monoclonal? And if
the delivery of precise focal treatments. Insights from this
so, (2) can we identify the responsible clone within the
study indicate that current focal therapy techniques, which
prostate gland? They analyzed ten patients (65 primary
are predominantly guided by radiological and pathological
tumor lesions and 16 nodal metastases) using multiplat-
features, may not always adequately target the clone most
form molecular methods. First, the authors confirmed what
likely to disseminate (an approximate 10% risk of undertreat-
several prior landmark studies have shown [2–4], that pros-
ment). It remains to be seen whether a more nuanced, subto-
tate cancer metastases are indeed monoclonal, despite the
tal focal surgical approach can offer some advantages [6].
multifocality and multiclonality of primary tumors. Regard-
Finally, while the study has broad biological and clinical
ing the second question, the authors found that while cer-
ramifications, we must acknowledge that none of the
tain pathological features such as high tumor grade,
patients included in the analysis would be candidates for
extraprostatic extension, and cribriform pattern were gen-
focal therapy in practice, so the findings must be inter-
erally useful in determining the dominant biological clone,
preted accordingly. Nevertheless, the study underscores
these criteria were not perfect. Of particular interest in this
our nascent understanding of and limited ability to identify
context is patient #38 (Supplementary Fig. 8 [1]), who had a
the dominant prostate cancer lesion on biopsy and raises
single metastasis arising from a grade group 3 lesion, but
pertinent questions. Are we effectively managing patients
harbored grade group 5 lesions elsewhere in the prostate.
with intermediate-risk disease, for which the role of focal
The lesion that gave rise to metastasis did not exhibit
therapy is expanding? What are the odds that a metachro-
extraprostatic extension either but did have an associated
nous index lesion could emerge after the initial index lesion
cribriform growth pattern. The other nine patients (90%)
has been treated?
seemed to have metastasis from an admixture of primary
lesions that included the highest-grade disease.
Conflicts of interest: The authors have nothing to disclose.

Experts comments: References

This study marks a significant advance in ongoing efforts
to decipher the molecular and pathological attributes that [1] Singhal U, Nallandhighal S, Tosoian JJ, et al. Integrative multi-region
could delineate the dominant prostate cancer lesion—the molecular profiling of primary prostate cancer in men with
lesion responsible for metastasis. The investigators adeptly synchronous lymph node metastasis. Nat Commun 2024;15:4341.
[2] Liu W, Laitinen S, Khan S, et al. Copy number analysis indicates
highlight the inherent challenges of this endeavor, as they monoclonal origin of lethal metastatic prostate cancer. Nat Med
were unable to identify a single genomic, anatomic, or 2009;15:559–65.
histopathological determinant that could consistently iden- [3] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of
tify the dominant nodule. As noted above, high-grade dis- lethal metastatic prostate cancer. Nature 2015;520:353–7.
[4] Woodcock DJ, Riabchenko E, Taavitsainen S, et al. Prostate cancer
ease features were generally associated with the dominant
evolution from multilineage primary to single lineage metastases
lesion (90% of the time), but this was not always the case. with implications for liquid biopsy. Nat Commun 2020;11:5070.
Furthermore, it is important to note that the study used tis- [5] Labbate CV, Klotz L, Morrow M, Cooperberg M, Esserman L, Eggener
sue from radical prostatectomy specimens, suggesting that SE. Focal therapy for prostate cancer: evolutionary parallels to breast
determining these features from biopsy samples would cancer treatment. J Urol 2023;209:49–57.
[6] Sood A, Jeong W, Palma-Zamora I, et al. Description of surgical
probably be even more challenging. On that note, it would technique and oncologic and functional outcomes of the precision
have been beneficial to have details on the preoperative prostatectomy procedure (IDEAL stage 1–2b study). Eur Urol
imaging and biopsy characteristics of these patients. 2022;81:396–406.
 EUROPEAN UROLOGY 87 (2025) 89–95 91

Associate Editor:
Rajvi Goradia a
Firas Abdollah b George Thalmann
Akshay Sood a,*
Accepted 21 July 2024
a
Department of Urology, James Cancer Hospital and Solove Research Institute,
Ohio State University Wexner Medical Center, Columbus, OH, USA 0302-2838/Ó 2024 European Association of Urology. Published by
b
Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA
Elsevier B.V. All rights are reserved, including those for text and data

* Corresponding author. Department of Urology, James Cancer Hospital mining, AI training, and similar technologies.
and Solove Research Institute, Ohio State University Wexner Medical https://doi.org/10.1016/j.eururo.2024.07.014
Center, Columbus, OH 43212, USA.
E-mail address: [email protected] (A. Sood).

Re: Propensity-matched Analysis of Open Versus Robotic ated with better perioperative outcomes without compro-
Primary Retroperitoneal Lymph Node Dissection for mising oncological efficacy.
Clinical Stage II Testicular Cancer
Chavarriaga J, Atenafu EG, Mousa A, et al
Experts’ comments:
Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2024. Robotic RPLND in patients with testicular cancer presents a
01.006 considerable challenge, especially in the postchemotherapy
setting (PC-RPLND). The surgical approach for RPLND has
evolved over time, beginning with a thoracoabdominal
Experts’ summary:
approach used before and in the early 2000s, followed by
Chavarriaga et al [1] reported outcomes of robotic primary
an open transperitoneal strategy, which is now considered
retroperitoneal lymph node dissection (RPLND) cases
the gold standard for this procedure. Owing to the patient
(n = 26) in comparison to a propensity score–matched open
morbidity associated with this approach, efforts have been
RPLND series (n = 38) for clinical stage II testicular cancer.
made to improve perioperative outcomes using alternate
Robotic RPLND was associated with a shorter length of stay
approaches such as open extraperitoneal and minimally
(LOS) and lower estimated blood loss (EBL), but longer oper-
invasive (eg, robotic) techniques [2]. The most recent
ative time. Perioperative complications were similar
advance in this setting is outpatient robotic PC-RPLND using
between the two groups. At median follow-up of 2 yr, both
enhanced recovery after surgery (ERAS) protocols [3] (Fig. 1).
groups had comparable relapse-free survival rates. No in-
The main advantages of robotic RPLND in comparison to
field recurrence was noted. The authors concluded that in
the conventional open approaches are a reduction in mor-
comparison to the open approach, robotic RPLND is associ-

Fig. 1 – Evolution of surgical techniques for postchemotherapy retroperitoneal lymph node dissection over time, our suggested protocol for outpatient
robotic PC-RPLND (box), and an example workflow of robotic PC-RPLND. (A) Port placement; (B) slight Trendenburg position with low pneumoperitoneum;
(C) lymph node dissection with non–tumor touch technique; (D) proper clip and biopolar use to avoid lymphorrhea; and (E) retroperitoneal view after
completion of dissection. intra-op = intraoperative; Post-op = postoperative; PRN = pro re nata; LN = lymph node; IVC = inferior vena cava; Ao = aorta; LRV =
left renal vein.
 EUROPEAN UROLOGY 87 (2025) 89–95 91

Associate Editor:
Rajvi Goradia a
Firas Abdollah b George Thalmann
Akshay Sood a,*
Accepted 21 July 2024
a
Department of Urology, James Cancer Hospital and Solove Research Institute,
Ohio State University Wexner Medical Center, Columbus, OH, USA 0302-2838/Ó 2024 European Association of Urology. Published by
b
Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA
Elsevier B.V. All rights are reserved, including those for text and data

* Corresponding author. Department of Urology, James Cancer Hospital mining, AI training, and similar technologies.
and Solove Research Institute, Ohio State University Wexner Medical https://doi.org/10.1016/j.eururo.2024.07.014
Center, Columbus, OH 43212, USA.
E-mail address: [email protected] (A. Sood).

Re: Propensity-matched Analysis of Open Versus Robotic ated with better perioperative outcomes without compro-
Primary Retroperitoneal Lymph Node Dissection for mising oncological efficacy.
Clinical Stage II Testicular Cancer
Chavarriaga J, Atenafu EG, Mousa A, et al
Experts’ comments:
Eur Urol Oncol. In press. https://doi.org/10.1016/j.euo.2024. Robotic RPLND in patients with testicular cancer presents a
01.006 considerable challenge, especially in the postchemotherapy
setting (PC-RPLND). The surgical approach for RPLND has
evolved over time, beginning with a thoracoabdominal
Experts’ summary:
approach used before and in the early 2000s, followed by
Chavarriaga et al [1] reported outcomes of robotic primary
an open transperitoneal strategy, which is now considered
retroperitoneal lymph node dissection (RPLND) cases
the gold standard for this procedure. Owing to the patient
(n = 26) in comparison to a propensity score–matched open
morbidity associated with this approach, efforts have been
RPLND series (n = 38) for clinical stage II testicular cancer.
made to improve perioperative outcomes using alternate
Robotic RPLND was associated with a shorter length of stay
approaches such as open extraperitoneal and minimally
(LOS) and lower estimated blood loss (EBL), but longer oper-
invasive (eg, robotic) techniques [2]. The most recent
ative time. Perioperative complications were similar
advance in this setting is outpatient robotic PC-RPLND using
between the two groups. At median follow-up of 2 yr, both
enhanced recovery after surgery (ERAS) protocols [3] (Fig. 1).
groups had comparable relapse-free survival rates. No in-
The main advantages of robotic RPLND in comparison to
field recurrence was noted. The authors concluded that in
the conventional open approaches are a reduction in mor-
comparison to the open approach, robotic RPLND is associ-

Fig. 1 – Evolution of surgical techniques for postchemotherapy retroperitoneal lymph node dissection over time, our suggested protocol for outpatient
robotic PC-RPLND (box), and an example workflow of robotic PC-RPLND. (A) Port placement; (B) slight Trendenburg position with low pneumoperitoneum;
(C) lymph node dissection with non–tumor touch technique; (D) proper clip and biopolar use to avoid lymphorrhea; and (E) retroperitoneal view after
completion of dissection. intra-op = intraoperative; Post-op = postoperative; PRN = pro re nata; LN = lymph node; IVC = inferior vena cava; Ao = aorta; LRV =
left renal vein.
92 EUROPEAN UROLOGY 87 (2025) 89–95

bidity and better perioperative outcomes. Our multicenter [3] Sanchez D, Ghoreifi A, Sheybaee Moghaddam F, Muhideen M, Gill IS,
group has reported results for the largest PC-RPLND cohort Djaladat H. Outpatient robotic post-chemotherapy retroperitoneal
lymph node dissection using enhanced recovery after surgery
to date (90 patients), with median EBL of 150 ml and median protocol. J Urol 2024;211:e996. https://doi.org/10.1097/01.
LOS of 2 d [2]. The 90-d complication rate was 17%, most of JU.0001009480. 90141.21.06.
which were of low grade, and no readmission was required. [4] Li R, Duplisea JJ, Petros FG, et al. Robotic postchemotherapy
Similar findings were reported for a comparative study of 30 retroperitoneal lymph node dissection for testicular cancer. Eur
Urol Oncol 2021;4:651–8. https://doi.org/10.1016/j.euo.2019.01.014.
robotic versus 63 open PC-RPLND cases [4]. Both studies
[5] Stephenson A, Bass EB, Bixler BR, et al. Diagnosis and treatment of
have also reported comparable early to intermediate-term early-stage testicular cancer: AUA guideline amendment 2023. J Urol
oncological outcomes to open series. Another potential ben- 2024;211:20–5. https://doi.org/10.1097/JU.0000000000003694.
efit of the robotic approach is preservation of antegrade ejac-
ulation, facilitated by enhanced optical magnification for Alireza Ghoreifi a
meticulous tissue dissection and nerve-sparing [2]. It is James Porter b
Hooman Djaladat a,*
anticipated that ERAS protocols will optimize the periopera-
tive pathway for these patients. We recently demonstrated a
USC Institute of Urology and Catherine and Joseph Aresty Department of
the feasibility of this approach in PC-RPLND [3]. Urology, Keck School of Medicine, University of Southern California, Los
The recent American Urological Association guidelines Angeles, CA, USA
b
highlight that minimally invasive RPLND may be offered Swedish Medical Group, Seattle, WA, USA
to patients while acknowledging the lack of long-term data
* Corresponding author. USC Institute of Urology and Catherine and
for oncological outcomes [5]. Long-term follow-up for
Joseph Aresty Department of Urology, Keck School of Medicine, University
robotic RPLND studies will shed further light on this contin-
of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
uously evolving field. E-mail address: [email protected] (H. Djaladat).

Conflicts of interest: The authors have nothing to disclose. Associate Editor:

George Thalmann
References
Accepted 21 July 2024
[1] Chavarriaga J, Atenafu EG, Mousa A, et al. Propensity-matched
analysis of open versus robotic primary retroperitoneal lymph node 0302-2838/Ó 2024 European Association of Urology. Published by
dissection for clinical stage II testicular cancer. Eur Urol Oncol. In
Elsevier B.V. All rights are reserved, including those for text and data
press. https://doi.org/10.1016/j.euo.2024.01.006.
[2] Ghoreifi A, Mitra AP, McClintock G, et al. Robotic post-chemotherapy mining, AI training, and similar technologies.
retroperitoneal lymph node dissection for testicular cancer: a https://doi.org/10.1016/j.eururo.2024.07.012
multicenter collaborative study. Urol Oncol 2023;41:111.e7–14.
https://doi.org/10.1016/j.urolonc.2022.11.006.

Re: Impact of Relugolix Versus Leuprolide on the Quality Experts’ comments:

of Life of Men with Advanced Prostate Cancer: Results While relugolix was associated with a 54% lower risk of major
from the Phase 3 HERO Study adverse cardiovascular events in comparison to leuprolide, it
Tombal B, Collins S, Morgans AK, et al did not improve other QoL aspects, including cognitive
decline [1,2]. This highlights the need for additional strategies
Eur Urol 2023;84:579–87
to address cognitive decline in men undergoing androgen
deprivation therapy (ADT). Cognitive decline may also be
Experts’ summary: exacerbated by addition of androgen receptor signaling inhi-
HERO was a phase 3 randomized controlled trial that bitors such as enzalutamide [3]. Data from the extensive COS-
included 934 men with advanced prostate cancer (PCa). The MOS trial suggest that daily multivitamin supplementation in
median age was 72 yr in the relugolix group (n = 622) and 573 participants aged >60 yr was associated with an improve-
71 yr in the leuprolide group (n = 308). The primary endpoint ment in global cognition, potentially reversing the equivalent
was testosterone suppression. Secondary endpoints included of approximately 2 yr of age-related cognitive decline [4].
safety and health-related quality of life (HRQoL), measured Furthermore, a large meta-analysis revealed that dietary
using the EORTC QLQ-C30 and EORTC QLQ-PR25 question- interventions including flavonoids significantly enhanced
naires. Relugolix was noninferior to leuprolide in achieving cognitive performance, with cocoa, ginkgo, and berries show-
and maintaining testosterone suppression over 48 wk. There ing the most notable benefits [5].
were no significant differences in changes in QoL scores In conclusion, while relugolix was not associated with a
between the relugolix and leuprolide groups from the start significant improvement in overall QoL in comparison to a
to the end of the 49-wk treatment period. Both groups expe- luteinizing hormone–releasing hormone agonist, results
rienced declines in role, cognitive, physical, and social func- from HERO underscore the need for effective supportive
tioning. In particular, the mean change from baseline to therapies to address the multifaceted challenges faced by
week 49 in the cognitive functioning score was 3.7 (stan- men receiving ADT. Cognitive decline can be a subtle yet
dard deviation 16.77) for the relugolix group and 3.8 (stan- clinically significant and challenging consequence of hor-
dard deviation 16.37) for the leuprolide group.
92 EUROPEAN UROLOGY 87 (2025) 89–95

bidity and better perioperative outcomes. Our multicenter [3] Sanchez D, Ghoreifi A, Sheybaee Moghaddam F, Muhideen M, Gill IS,
group has reported results for the largest PC-RPLND cohort Djaladat H. Outpatient robotic post-chemotherapy retroperitoneal
lymph node dissection using enhanced recovery after surgery
to date (90 patients), with median EBL of 150 ml and median protocol. J Urol 2024;211:e996. https://doi.org/10.1097/01.
LOS of 2 d [2]. The 90-d complication rate was 17%, most of JU.0001009480. 90141.21.06.
which were of low grade, and no readmission was required. [4] Li R, Duplisea JJ, Petros FG, et al. Robotic postchemotherapy
Similar findings were reported for a comparative study of 30 retroperitoneal lymph node dissection for testicular cancer. Eur
Urol Oncol 2021;4:651–8. https://doi.org/10.1016/j.euo.2019.01.014.
robotic versus 63 open PC-RPLND cases [4]. Both studies
[5] Stephenson A, Bass EB, Bixler BR, et al. Diagnosis and treatment of
have also reported comparable early to intermediate-term early-stage testicular cancer: AUA guideline amendment 2023. J Urol
oncological outcomes to open series. Another potential ben- 2024;211:20–5. https://doi.org/10.1097/JU.0000000000003694.
efit of the robotic approach is preservation of antegrade ejac-
ulation, facilitated by enhanced optical magnification for Alireza Ghoreifi a
meticulous tissue dissection and nerve-sparing [2]. It is James Porter b
Hooman Djaladat a,*
anticipated that ERAS protocols will optimize the periopera-
tive pathway for these patients. We recently demonstrated a
USC Institute of Urology and Catherine and Joseph Aresty Department of
the feasibility of this approach in PC-RPLND [3]. Urology, Keck School of Medicine, University of Southern California, Los
The recent American Urological Association guidelines Angeles, CA, USA
b
highlight that minimally invasive RPLND may be offered Swedish Medical Group, Seattle, WA, USA
to patients while acknowledging the lack of long-term data
* Corresponding author. USC Institute of Urology and Catherine and
for oncological outcomes [5]. Long-term follow-up for
Joseph Aresty Department of Urology, Keck School of Medicine, University
robotic RPLND studies will shed further light on this contin-
of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
uously evolving field. E-mail address: [email protected] (H. Djaladat).

Conflicts of interest: The authors have nothing to disclose. Associate Editor:

George Thalmann
References
Accepted 21 July 2024
[1] Chavarriaga J, Atenafu EG, Mousa A, et al. Propensity-matched
analysis of open versus robotic primary retroperitoneal lymph node 0302-2838/Ó 2024 European Association of Urology. Published by
dissection for clinical stage II testicular cancer. Eur Urol Oncol. In
Elsevier B.V. All rights are reserved, including those for text and data
press. https://doi.org/10.1016/j.euo.2024.01.006.
[2] Ghoreifi A, Mitra AP, McClintock G, et al. Robotic post-chemotherapy mining, AI training, and similar technologies.
retroperitoneal lymph node dissection for testicular cancer: a https://doi.org/10.1016/j.eururo.2024.07.012
multicenter collaborative study. Urol Oncol 2023;41:111.e7–14.
https://doi.org/10.1016/j.urolonc.2022.11.006.

Re: Impact of Relugolix Versus Leuprolide on the Quality Experts’ comments:

of Life of Men with Advanced Prostate Cancer: Results While relugolix was associated with a 54% lower risk of major
from the Phase 3 HERO Study adverse cardiovascular events in comparison to leuprolide, it
Tombal B, Collins S, Morgans AK, et al did not improve other QoL aspects, including cognitive
decline [1,2]. This highlights the need for additional strategies
Eur Urol 2023;84:579–87
to address cognitive decline in men undergoing androgen
deprivation therapy (ADT). Cognitive decline may also be
Experts’ summary: exacerbated by addition of androgen receptor signaling inhi-
HERO was a phase 3 randomized controlled trial that bitors such as enzalutamide [3]. Data from the extensive COS-
included 934 men with advanced prostate cancer (PCa). The MOS trial suggest that daily multivitamin supplementation in
median age was 72 yr in the relugolix group (n = 622) and 573 participants aged >60 yr was associated with an improve-
71 yr in the leuprolide group (n = 308). The primary endpoint ment in global cognition, potentially reversing the equivalent
was testosterone suppression. Secondary endpoints included of approximately 2 yr of age-related cognitive decline [4].
safety and health-related quality of life (HRQoL), measured Furthermore, a large meta-analysis revealed that dietary
using the EORTC QLQ-C30 and EORTC QLQ-PR25 question- interventions including flavonoids significantly enhanced
naires. Relugolix was noninferior to leuprolide in achieving cognitive performance, with cocoa, ginkgo, and berries show-
and maintaining testosterone suppression over 48 wk. There ing the most notable benefits [5].
were no significant differences in changes in QoL scores In conclusion, while relugolix was not associated with a
between the relugolix and leuprolide groups from the start significant improvement in overall QoL in comparison to a
to the end of the 49-wk treatment period. Both groups expe- luteinizing hormone–releasing hormone agonist, results
rienced declines in role, cognitive, physical, and social func- from HERO underscore the need for effective supportive
tioning. In particular, the mean change from baseline to therapies to address the multifaceted challenges faced by
week 49 in the cognitive functioning score was 3.7 (stan- men receiving ADT. Cognitive decline can be a subtle yet
dard deviation 16.77) for the relugolix group and 3.8 (stan- clinically significant and challenging consequence of hor-
dard deviation 16.37) for the leuprolide group.
 EUROPEAN UROLOGY 87 (2025) 89–95 93

monal therapy in patients with prostate cancer. There is Outcomes Study (COSMOS) randomized clinical trial and meta-
sufficient scientific evidence for nutritional interventions, analysis of 3 cognitive studies within COSMOS. Am J Clin Nutr
2024;119:692–701. https://doi.org/10.1016/j.ajcnut.2023.12.011.
such as flavonoid and/or multivitamin supplementation, to [5] Cheng N, Bell L, Lamport DJ, Williams CM. Dietary flavonoids and
warrant consideration on a case-by-case basis in clinical human cognition: a meta-analysis. Mol Nutr Food Res 2022;66:
practice. These interventions are generally safe, inexpen- 2100976. https://doi.org/10.1002/mnfr.202100976.
sive, and readily available. However, large randomized con-
trolled trials are needed to thoroughly investigate the Giuseppe Di Lorenzo a,b,*
Carlo Buonerba b
benefit-risk ratio, potential adverse reactions, and interac-
tions with pharmacological therapies. a
Oncology Unit, Andrea Tortora Hospital, ASL Salerno, Pagani, Italy
b
Associazione O.R.A. ETS, Oncology Research Assistance, Salerno, Italy
Conflicts of interest: The authors have nothing to disclose.
* Corresponding author. Oncology Unit, Andrea Tortora Hospital, ASL
References
Salerno, Pagani, Italy.
E-mail address: [email protected] (G. Di Lorenzo).
[1] Tombal B, Collins S, Morgans AK, et al. Impact of relugolix versus
leuprolide on the quality of life of men with advanced prostate cancer:
results from the phase 3 HERO study. Eur Urol 2023;84:579–87. Associate Editor:
https://doi.org/10.1016/j.eururo.2023.09.007. George Thalmann
[2] Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-
deprivation therapy in advanced prostate cancer. N Engl J Med
Accepted 10 July 2024
2020;382:2187–96. https://doi.org/10.1056/NEJMoa2004325.
[3] Stockler MR, Martin AJ, Davis ID, et al. Health-related quality of life in
metastatic, hormone-sensitive prostate cancer: ENZAMET (ANZUP 0302-2838/Ó 2024 European Association of Urology. Published by
1304), an international, randomized phase III trial led by ANZUP. J Elsevier B.V. All rights are reserved, including those for text and data
Clin Oncol 2022;40:837–46. https://doi.org/10.1200/JCO.21.00941.
mining, AI training, and similar technologies.
[4] Vyas CM, Manson JE, Sesso HD, et al. Effect of multivitamin-mineral
supplementation versus placebo on cognitive function: results from https://doi.org/10.1016/j.eururo.2024.07.017
the clinic subcohort of the Cocoa Supplement and Multivitamin

Re: Long-term Prostate Cancer–specific Mortality After our responsibility to guide patients—as ‘‘playmakers’’ do—
Prostatectomy, Brachytherapy, External Beam Radiation towards the best possible treatment on the basis of contem-
Therapy, Hormonal Therapy, or Monitoring for Localized porary medical literature.
Prostate Cancer In this regard, several critical areas require our ongoing
Herlemann A, Cowan JE, Washington 3rd SL, et al efforts and attention:
Eur Urol 2024;85:565–73
- Reducing the number of grade group (GG) 1 PCa diag-
noses, which inevitably lead to overtreatment: the cur-
Experts’ summary: rent practice results in too many patients undergoing
In a cohort study from the multicenter, prospective, largely prostate biopsies on the sole basis of a single elevated
community-based CaPSURE registry, Herlemann et al [1] prostate-specific antigen level, leading to overdiagnosis
compared long-term prostate cancer–specific mortality and subsequent overtreatment of GG 1 disease [2].
(PCSM) among men with localized prostate cancer (PCa) - Promoting active surveillance: for every patient with
treated with radical prostatectomy (RP), brachytherapy GG 1 PCa and selected GG 2 cases, AS should be consis-
(BT), external beam radiation therapy (EBRT), primary tently offered as a viable alternative to avoid unneces-
androgen deprivation therapy (pADT), or active surveil- sary and potentially harmful curative treatments [3].
lance/watchful waiting (AS/WW). In a cohort of 11 864 PCa - Addressing bias in treatment selection: as urologists, we
patients followed for a median of 9.4 yr, RP was associated must be humble and honest enough with ourselves to
with significantly lower PCSM in comparison to BT, EBRT, recognize a tendency to select the most favorable
pADT, and AS/WW after adjusting for age and clinical risk patients for RP while diverting less optimal candidates
using the Cancer of the Prostate Risk Assessment (CAPRA) to EBRT [4]. This bias probably impacts long-term out-
score. PCSM differences were more pronounced for patients comes and needs to be addressed for a more equitable
with higher-risk disease. The authors highlighted the non- treatment approach.
randomized design of the study and the need for ongoing tri- - Counseling on the risk of short- and long-term side
als to validate these findings over longer follow-up periods. effects: we should provide our patients with a compre-
hensive overview of the risks of adverse events related
to each treatment modality. Patients should be able to
Experts’ comments:
decide on the best approach that fits their expectations
While we commend the authors for their diligent analysis
on the basis of accurate knowledge of the toxicity associ-
using balanced and rigorous methodology, we believe that
ated with RP, EBRT, and other therapeutic approaches.
the final message to the readers could be different. In most
This can also be done in the context of PCa multidisci-
countries worldwide, patients diagnosed with PCa are first
plinary teams.
seen by a urologist. Thus, as urologists we should embrace
 EUROPEAN UROLOGY 87 (2025) 89–95 93

monal therapy in patients with prostate cancer. There is Outcomes Study (COSMOS) randomized clinical trial and meta-
sufficient scientific evidence for nutritional interventions, analysis of 3 cognitive studies within COSMOS. Am J Clin Nutr
2024;119:692–701. https://doi.org/10.1016/j.ajcnut.2023.12.011.
such as flavonoid and/or multivitamin supplementation, to [5] Cheng N, Bell L, Lamport DJ, Williams CM. Dietary flavonoids and
warrant consideration on a case-by-case basis in clinical human cognition: a meta-analysis. Mol Nutr Food Res 2022;66:
practice. These interventions are generally safe, inexpen- 2100976. https://doi.org/10.1002/mnfr.202100976.
sive, and readily available. However, large randomized con-
trolled trials are needed to thoroughly investigate the Giuseppe Di Lorenzo a,b,*
Carlo Buonerba b
benefit-risk ratio, potential adverse reactions, and interac-
tions with pharmacological therapies. a
Oncology Unit, Andrea Tortora Hospital, ASL Salerno, Pagani, Italy
b
Associazione O.R.A. ETS, Oncology Research Assistance, Salerno, Italy
Conflicts of interest: The authors have nothing to disclose.
* Corresponding author. Oncology Unit, Andrea Tortora Hospital, ASL
References
Salerno, Pagani, Italy.
E-mail address: [email protected] (G. Di Lorenzo).
[1] Tombal B, Collins S, Morgans AK, et al. Impact of relugolix versus
leuprolide on the quality of life of men with advanced prostate cancer:
results from the phase 3 HERO study. Eur Urol 2023;84:579–87. Associate Editor:
https://doi.org/10.1016/j.eururo.2023.09.007. George Thalmann
[2] Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-
deprivation therapy in advanced prostate cancer. N Engl J Med
Accepted 10 July 2024
2020;382:2187–96. https://doi.org/10.1056/NEJMoa2004325.
[3] Stockler MR, Martin AJ, Davis ID, et al. Health-related quality of life in
metastatic, hormone-sensitive prostate cancer: ENZAMET (ANZUP 0302-2838/Ó 2024 European Association of Urology. Published by
1304), an international, randomized phase III trial led by ANZUP. J Elsevier B.V. All rights are reserved, including those for text and data
Clin Oncol 2022;40:837–46. https://doi.org/10.1200/JCO.21.00941.
mining, AI training, and similar technologies.
[4] Vyas CM, Manson JE, Sesso HD, et al. Effect of multivitamin-mineral
supplementation versus placebo on cognitive function: results from https://doi.org/10.1016/j.eururo.2024.07.017
the clinic subcohort of the Cocoa Supplement and Multivitamin

Re: Long-term Prostate Cancer–specific Mortality After our responsibility to guide patients—as ‘‘playmakers’’ do—
Prostatectomy, Brachytherapy, External Beam Radiation towards the best possible treatment on the basis of contem-
Therapy, Hormonal Therapy, or Monitoring for Localized porary medical literature.
Prostate Cancer In this regard, several critical areas require our ongoing
Herlemann A, Cowan JE, Washington 3rd SL, et al efforts and attention:
Eur Urol 2024;85:565–73
- Reducing the number of grade group (GG) 1 PCa diag-
noses, which inevitably lead to overtreatment: the cur-
Experts’ summary: rent practice results in too many patients undergoing
In a cohort study from the multicenter, prospective, largely prostate biopsies on the sole basis of a single elevated
community-based CaPSURE registry, Herlemann et al [1] prostate-specific antigen level, leading to overdiagnosis
compared long-term prostate cancer–specific mortality and subsequent overtreatment of GG 1 disease [2].
(PCSM) among men with localized prostate cancer (PCa) - Promoting active surveillance: for every patient with
treated with radical prostatectomy (RP), brachytherapy GG 1 PCa and selected GG 2 cases, AS should be consis-
(BT), external beam radiation therapy (EBRT), primary tently offered as a viable alternative to avoid unneces-
androgen deprivation therapy (pADT), or active surveil- sary and potentially harmful curative treatments [3].
lance/watchful waiting (AS/WW). In a cohort of 11 864 PCa - Addressing bias in treatment selection: as urologists, we
patients followed for a median of 9.4 yr, RP was associated must be humble and honest enough with ourselves to
with significantly lower PCSM in comparison to BT, EBRT, recognize a tendency to select the most favorable
pADT, and AS/WW after adjusting for age and clinical risk patients for RP while diverting less optimal candidates
using the Cancer of the Prostate Risk Assessment (CAPRA) to EBRT [4]. This bias probably impacts long-term out-
score. PCSM differences were more pronounced for patients comes and needs to be addressed for a more equitable
with higher-risk disease. The authors highlighted the non- treatment approach.
randomized design of the study and the need for ongoing tri- - Counseling on the risk of short- and long-term side
als to validate these findings over longer follow-up periods. effects: we should provide our patients with a compre-
hensive overview of the risks of adverse events related
to each treatment modality. Patients should be able to
Experts’ comments:
decide on the best approach that fits their expectations
While we commend the authors for their diligent analysis
on the basis of accurate knowledge of the toxicity associ-
using balanced and rigorous methodology, we believe that
ated with RP, EBRT, and other therapeutic approaches.
the final message to the readers could be different. In most
This can also be done in the context of PCa multidisci-
countries worldwide, patients diagnosed with PCa are first
plinary teams.
seen by a urologist. Thus, as urologists we should embrace
94 EUROPEAN UROLOGY 87 (2025) 89–95

We believe that our priority should be identification of [3] Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-
ESUR-ISUP-SIOG guidelines on prostate cancer—2024 update. Part I:
patients who truly require curative treatment while adher- screening, diagnosis, and local treatment with curative intent. Eur
ing strictly to contemporary guidelines. Specifically, for Urol. In press. https://doi.org/10.1016/j.eururo.2024.03.027.
patients with high-risk PCa, it is essential to communicate [4] Miccio JA, Talcott WJ, Jairam V, et al. Quantifying treatment selection
that surgery may be just the first step in their therapeutic bias effect on survival in comparative effectiveness research: findings
from low-risk prostate cancer patients. Prostate Cancer Prostat Dis
journey, with adjuvant treatments being a probable neces-
2020;24:414–22. https://doi.org/10.1038/s41391-020-00291-3.
sity. At the same time, it is crucial to explain that RT must
be combined with ADT to achieve optimal outcomes. Fur- Francesco Montorsi a,b
thermore, patients generally understand that surgeries per- Mattia Longoni a,b
formed in high-volume centers are associated with better Alberto Briganti a,b
results. However, according to our experience, this under- Giorgio Gandaglia a,b,*
standing often does not extend to radiation therapy, and a
Gianfranco Soldera Prostate Cancer Laboratory, Unit of Urology/Division of
this perception needs to be addressed and clarified.
Oncology, IRCCS San Raffaele Scientific Institute, IRCCS Ospedale San Raffaele,
In conclusion, we respectfully suggest that the field does Milan, Italy
not need further sophisticated analyses of nonrandomized b
Vita-Salute San Raffaele University, Milan, Italy
data in attempts to demonstrate the superiority of one tech-
nique over another. Instead, we should collectively focus on * Corresponding author. Gianfranco Soldera Prostate Cancer Laboratory,
personalizing the management of PCa and prioritizing IRCCS Ospedale San Raffaele, Via Olgettina 58, Milan 20132, Italy.
E-mail address: [email protected] (G. Gandaglia).
patient-specific needs and outcomes over professional
interests.
Associate Editor:
George Thalmann
Conflicts of interest: The authors have nothing to disclose.
Accepted 21 July 2024
References
0302-2838/Ó 2024 European Association of Urology. Published by
[1] Herlemann A, Cowan JE, Washington SL, et al. Long-term prostate
Elsevier B.V. All rights are reserved, including those for text and data
cancer–specific mortality after prostatectomy, brachytherapy,
external beam radiation therapy, hormonal therapy, or monitoring mining, AI training, and similar technologies.
for localized prostate cancer. Eur Urol 2024;85:565–73. https://doi. https://doi.org/10.1016/j.eururo.2024.07.009
org/10.1016/j.eururo.2023.09.024.
[2] Vickers AJ, Cooperberg MR, Eggener SE. Removing the designation of
cancer from grade group 1 disease will do more good than harm. Eur
Urol 2023;83:304–6. https://doi.org/10.1016/j.eururo.2022.10.001.

Re: Metastasis and Recurrence Patterns in the Molecular whereas bone metastases seemed to predominate if the pri-
Subtypes of Urothelial Bladder Cancer mary UC was of the Uro subtype.
Sjödahl G, Eriksson P, Holmsten K, et al
Experts’ comments:
Int J Cancer 2024;154:180–90
Surgical pathology has shown that some UC subtypes have
a tendency to metastasize to specific loci [5]. Sjödahl et al
Experts’ summary: [4] conducted a gene expression analysis with robust
Urothelial carcinoma (UC) can metastasize, especially in results. Their approach in investigating the metastatic pat-
muscle-invasive bladder cancer [1]. Most UC metastases terns of specific UC molecular classes is interesting and
develop via lymphatic pathways, with some subtypes more new. The authors described differences in gene alterations
aggressive than others (eg, micropapillary UC) [2]. Despite according to the pattern of metastasis development: lumi-
the existence of molecular UC classifications [3], there have nal and nonluminal variants seemed to follow different
been no studies on differences in the development of metastatic pathways, which has not been shown before.
metastases among these UC molecular variants. The most These findings are interesting from both a clinical and a
frequent metastatic sites in UC are local lymph nodes, fol- pathological perspective, and could potentially be impor-
lowed by bone, lung, and liver. There are very few data on tant for better follow-up for patients, with the possibility
the metastatic potential of UC variants or the RNA status of focusing on the most probable metastatic sites accord-
of these metastases. Sjödahl and colleagues [4] investigated ing to an individual patient’s UC RNA expression profile.
differences among UC variants in terms of their recurrence The findings might also aid pathologists, as biopsies from
and metastasis to specific sites. The authors also compared metastatic sites are often small and sometimes only a
their results to the Consensus and Lund UC classifications, few complementary immunohistochemical tests can be
and found a better fit to the Lund scheme. The Lund Uro conducted. Focusing on the correct diagnosis from the
(urothelial-like; A, B and C grouped together), GU (geneti- start will spare time and resources and increase the diag-
cally unstable), and BA/Sq (basal/squamous) subtypes nostic accuracy. The study findings also contribute to a
exhibited four significant patterns of metastasis. The Ba/Sq better understanding of the metastatic pathways of differ-
variant seemed to have poor tropism towards bone, ent UC variants.
94 EUROPEAN UROLOGY 87 (2025) 89–95

We believe that our priority should be identification of [3] Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-
ESUR-ISUP-SIOG guidelines on prostate cancer—2024 update. Part I:
patients who truly require curative treatment while adher- screening, diagnosis, and local treatment with curative intent. Eur
ing strictly to contemporary guidelines. Specifically, for Urol. In press. https://doi.org/10.1016/j.eururo.2024.03.027.
patients with high-risk PCa, it is essential to communicate [4] Miccio JA, Talcott WJ, Jairam V, et al. Quantifying treatment selection
that surgery may be just the first step in their therapeutic bias effect on survival in comparative effectiveness research: findings
from low-risk prostate cancer patients. Prostate Cancer Prostat Dis
journey, with adjuvant treatments being a probable neces-
2020;24:414–22. https://doi.org/10.1038/s41391-020-00291-3.
sity. At the same time, it is crucial to explain that RT must
be combined with ADT to achieve optimal outcomes. Fur- Francesco Montorsi a,b
thermore, patients generally understand that surgeries per- Mattia Longoni a,b
formed in high-volume centers are associated with better Alberto Briganti a,b
results. However, according to our experience, this under- Giorgio Gandaglia a,b,*
standing often does not extend to radiation therapy, and a
Gianfranco Soldera Prostate Cancer Laboratory, Unit of Urology/Division of
this perception needs to be addressed and clarified.
Oncology, IRCCS San Raffaele Scientific Institute, IRCCS Ospedale San Raffaele,
In conclusion, we respectfully suggest that the field does Milan, Italy
not need further sophisticated analyses of nonrandomized b
Vita-Salute San Raffaele University, Milan, Italy
data in attempts to demonstrate the superiority of one tech-
nique over another. Instead, we should collectively focus on * Corresponding author. Gianfranco Soldera Prostate Cancer Laboratory,
personalizing the management of PCa and prioritizing IRCCS Ospedale San Raffaele, Via Olgettina 58, Milan 20132, Italy.
E-mail address: [email protected] (G. Gandaglia).
patient-specific needs and outcomes over professional
interests.
Associate Editor:
George Thalmann
Conflicts of interest: The authors have nothing to disclose.
Accepted 21 July 2024
References
0302-2838/Ó 2024 European Association of Urology. Published by
[1] Herlemann A, Cowan JE, Washington SL, et al. Long-term prostate
Elsevier B.V. All rights are reserved, including those for text and data
cancer–specific mortality after prostatectomy, brachytherapy,
external beam radiation therapy, hormonal therapy, or monitoring mining, AI training, and similar technologies.
for localized prostate cancer. Eur Urol 2024;85:565–73. https://doi. https://doi.org/10.1016/j.eururo.2024.07.009
org/10.1016/j.eururo.2023.09.024.
[2] Vickers AJ, Cooperberg MR, Eggener SE. Removing the designation of
cancer from grade group 1 disease will do more good than harm. Eur
Urol 2023;83:304–6. https://doi.org/10.1016/j.eururo.2022.10.001.

Re: Metastasis and Recurrence Patterns in the Molecular whereas bone metastases seemed to predominate if the pri-
Subtypes of Urothelial Bladder Cancer mary UC was of the Uro subtype.
Sjödahl G, Eriksson P, Holmsten K, et al
Experts’ comments:
Int J Cancer 2024;154:180–90
Surgical pathology has shown that some UC subtypes have
a tendency to metastasize to specific loci [5]. Sjödahl et al
Experts’ summary: [4] conducted a gene expression analysis with robust
Urothelial carcinoma (UC) can metastasize, especially in results. Their approach in investigating the metastatic pat-
muscle-invasive bladder cancer [1]. Most UC metastases terns of specific UC molecular classes is interesting and
develop via lymphatic pathways, with some subtypes more new. The authors described differences in gene alterations
aggressive than others (eg, micropapillary UC) [2]. Despite according to the pattern of metastasis development: lumi-
the existence of molecular UC classifications [3], there have nal and nonluminal variants seemed to follow different
been no studies on differences in the development of metastatic pathways, which has not been shown before.
metastases among these UC molecular variants. The most These findings are interesting from both a clinical and a
frequent metastatic sites in UC are local lymph nodes, fol- pathological perspective, and could potentially be impor-
lowed by bone, lung, and liver. There are very few data on tant for better follow-up for patients, with the possibility
the metastatic potential of UC variants or the RNA status of focusing on the most probable metastatic sites accord-
of these metastases. Sjödahl and colleagues [4] investigated ing to an individual patient’s UC RNA expression profile.
differences among UC variants in terms of their recurrence The findings might also aid pathologists, as biopsies from
and metastasis to specific sites. The authors also compared metastatic sites are often small and sometimes only a
their results to the Consensus and Lund UC classifications, few complementary immunohistochemical tests can be
and found a better fit to the Lund scheme. The Lund Uro conducted. Focusing on the correct diagnosis from the
(urothelial-like; A, B and C grouped together), GU (geneti- start will spare time and resources and increase the diag-
cally unstable), and BA/Sq (basal/squamous) subtypes nostic accuracy. The study findings also contribute to a
exhibited four significant patterns of metastasis. The Ba/Sq better understanding of the metastatic pathways of differ-
variant seemed to have poor tropism towards bone, ent UC variants.
 EUROPEAN UROLOGY 87 (2025) 89–95 95

Conflicts of interest: The authors have nothing to disclose.

Department of Pathology, Medical University of Vienna, General Hospital
Vienna, Vienna, Austria
References
* Corresponding author. Department of Pathology, Medical University of
[1] Witjes JA et al. European Association of Urology guidelines on Vienna, General Hospital Vienna, Vienna, Austria.
muscle-invasive and metastatic bladder cancer: summary of the E-mail address: [email protected] (E. Compérat).
2023 guidelines. Eur Urol 2024;85:17–31.
[2] Compérat E et al. Micropapillary urothelial carcinoma of the urinary
bladder: a clinicopathological analysis of 72 cases. Pathology 2010;42: Associate Editor:
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[3] Kamoun A et al. A consensus molecular classification of muscle-
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Accepted 2 August 2024
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[5] Huang W et al. Clinical and pathological characteristics of metastatic 0302-2838/Ó 2024 European Association of Urology. Published by
tumors to the urinary bladder. Ann Diagn Pathol 2023;66:152–79. Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
Eva Compérat * https://doi.org/10.1016/j.eururo.2024.08.002
Gabriel Wasinger
Johannes Kläger
 EUROPEAN UROLOGY 87 (2025) 96

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Corrigendum

Corrigendum to ‘‘Cabozantinib Plus Nivolumab in Patients with

Non–Clear Cell Renal Cell Carcinoma: Updated Results from a Phase
II Trial’’ [Eur. Urol. 86(2) (2024) 90–94]

Kelly N. Fitzgerald a,y, Chung-Han Lee a,y, Martin H. Voss a, Maria I. Carlo a, Andrea Knezevic b,
Laura Peralta a, Yingbei Chen c, Robert A. Lefkowitz d, Neil J. Shah a, Colette N. Owens a,
Deaglan J. McHugh a, David H. Aggen a, Andrew L. Laccetti a, Ritesh R. Kotecha a,
Darren R. Feldman a,à, Robert J. Motzer a,*,à
a
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; b Department of Epidemiology and Biostatistics, Memorial Sloan
Kettering Cancer Center, New York, NY, USA; c Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; d Department
of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

The authors regret that four incorrect estimates pertaining to adverse event (AE) incidence were stated in the text, discrepant
from the corresponding tables where correct estimates were included. Specifically, incorrect values were stated in the text
for incidence of the following treat treatment-related AEs: 1) AEs of any grade, 2) grade 3-4 AEs, 3) grade 3-4 AST events, and
4) grade 3-4 ALT events. Correct values were included the corresponding supplemental tables 2 and 4, and are stated here:
Treatment-related AEs of any grade were experienced by 40 patients (100%); grade 3-4 AEs were experienced by 20 patients
(50%). Treatment-related grade 3-4 AST and ALT elevations were 13% and 15% respectively.
The authors would like to apologise for any inconvenience caused.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.eururo.2024.10.002.

DOI of original article: https://doi.org/10.1016/j.eururo.2024.04.025

y
These authors contributed equally and are joint first authors.
à
These authors contributed equally and are joint senior authors.
* Corresponding author at: Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Tel. +1 646
8885418; Fax: +1 646 2272417.
E-mail address: [email protected] (R.J. Motzer).

https://doi.org/10.1016/j.eururo.2024.10.002
0302-2838/Ó 2024 Published by Elsevier B.V. on behalf of European Association of Urology.
 EUROPEAN UROLOGY 87 (2025) 97–99

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Corrigendum

Corrigendum to ‘‘Impact of Prostate-specific Membrane Antigen

Positron Emission Tomography/Computed Tomography on Prostate
Cancer Salvage Radiotherapy Management: Results from a
Prospective Multicenter Randomized Phase 3 Trial (PSMA-SRT
NCT03582774)’’ [Eur Urol. 86(1) (2024) 52–60]

Wesley R. Armstrong a,b, Amar U. Kishan c,d, Kiara M. Booker a, Tristan R. Grogan e, David Elashoff e,
Ethan C. Lam a, Kevyn J. Clark a, Michael L. Steinberg c,d, Wolfgang P. Fendler a,f, Thomas A. Hope g,
Nicholas G. Nickols c,d,h, Johannes Czernin a,d, Jeremie Calais a,d,*
a
Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA; b UCLA-Caltech Medical Scientist Training Program, David Geffen School of Medicine, Los Angeles, CA, USA;
c
Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA; d Jonsson Comprehensive Cancer Center, University of
California Los Angeles, Los Angeles, CA, USA; e Department of Medicine Statistics Core (DOMStat), David Geffen School of Medicine, University of California
Los Angeles, Los Angeles, CA, USA; f Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK) –
University Hospital Essen, Essen, Germany; g Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA;
h
Department of Radiation Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

The authors regret about typological errors in the article found by Feng Qi as published in the letter to the editor of July 25,
2024 in European Urology.
The number (%) of patients with no change in the intervention arm should be 49 (48.0%), not 56 (54.9%) (Results section
and Table 2).
The number of patients in the Control arm number of patients who experienced treatment escalation with addition of RT
fields was swapped with the ones with addition of androgen deprivation therapy (ADT): it should be 4 (5.2%) with addition of
RT fields and not 0, and it should be should be 0 with addition of androgen deprivation therapy (ADT) and not 4 (5.2%)
(Table 2).
In Table 1, The total number of pN0 patient was corrected from 83 to 84 (Table 1).

DOI of original article: https://doi.org/10.1016/j.eururo.2024.01.012

*
Corresponding author at: Department of Molecular and Medical Pharmacology, University of California Los Angeles, 200 Medical Plaza, Los Angeles,
CA 90095-7370, USA.
E-mail address: [email protected] (J. Calais).

https://doi.org/10.1016/j.eururo.2024.10.022
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
98 EUROPEAN UROLOGY 87 (2025) 97–99

Table 1. Baseline Patients Characteristics

Characteristics Intervention, n = 102 Control, n = 76

Age at enrollment, median (y) 69 (range, 48-89) 68 (range, 42-82)
Gleason score
6 6 (5.9%) 2 (2.6%)
7 68 (66.7%) 51 (67.1%)
8 28 (27.5%) 22 (28.9%)
Unknown 0 (0%) 1 (1.3%)
Pathologic primary tumor stage
pT2 56 (54.9%) 35 (46.1%)
pT3a 31 (30.4%) 24 (31.6%)
pT3b 15 (14.7%) 16 (21.1%)
pT4 0 (0%) 0 (0%)
Unknown 0 (0%) 1 (1.3%)
Pathologic regional Lymph Node stage
pN0 84 (82.4%) 53 (69.7%)
pN1 4 (3.9%) 9 (11.8%)
pNx 14 (13.7%) 14 (18.4%)
Positive margin
R0 58 (56.9%) 44 (57.9%)
R1 41 (40.2%) 30 (39.5%)
Unknown 3 (2.9%) 2 (2.6%)
Initial National Comprehensive Cancer Network risk group*
Low 4 (3.9%) 1 (1.3%)
Intermediate 40 (39.2%) 30 (39.5%)
High 40 (39.2%) 22 (28.9%)
Very High 14 (13.7%) 13 (17.1%)
N1 4 (3.9%) 9 (11.8%)
Unknown 0 (0%) 1 (1.3%)
Prior Androgen deprivation therapy 8 (8%) 6 (8%)
within 3-6 mo prior enrollment 2 (2%) 0 (0%)
Since more than 6 mo prior enrollment 6 (6%) 6 (8%)
Time between surgery and enrollment, median (mo) 28.5 (IQR, 8.9-62.4) 21.6 (IQR, 7.3-73.0)
Last PSA value before enrollment, median (ng/mL) 0.23 (IQR, 0.15-0.54) 0.3 (IQR, 0.19-0.91)
PSA Doubling time (mo)** 5.65 (IQR, 3.0-9.3) 6.0 (IQR, 3.10-9.3)
European Association of Urology (EAU) Biochemical Recurrence Risk Group**
Low 12 (14.6%) 9 (16.3%)
High 70 (85.3%) 46 (83.6%)
*Biopsy core % information not available for NCCN** Data available for 136 patients: 82 in the PSMA arm, 55 in the control arm

Table 2. Management Changes frequency in both arms and causal relationship to PSMA-PET in the intervention arm

Control Arm Intervention arm % Change related to PSMA-PET

N = 76 N = 102 (only for intervention arm)
NO CHANGE 59 (77.6%) 49 (48.0%) -
MAJOR CHANGE 17 (22.4%) 46 (45.1%) 33/46 (72%)
Escalation 9 (12%) 30 (29%) 18/30 (60%)
->Addition of RT fields 4 (5.2%) 17 (16.6%) 12/17 (71%)
-> Alone 3 (3.9%) 10 (9.8%) 7/10 (70%)
-> With additional ADT 1 (1.3%) 6 (5.9%) 4/6 (67%)
-> With addition of ARSi 0 1 (0.9%) 1 (100%)
->Addition ADT 0 9 (9%) 3/9 (33%)
-> Alone 0 7 (6.8%) 2/7 (29%)
-> With reduction of RT fields 0 1 (0.9%) 0 (0%)
-> Change of RT fields 0 1 (0.9%) 1 (100%)
->Switch to ADT only 0 3 (2.9%) 2/3 (67%)
-> Alone 0 2 (2%) 2 (100%)
-> With addition of ARSi 0 1 (0.9%) 0 (0%)
->Addition of ARSi 1 (1.3%) 0 -
 EUROPEAN UROLOGY 87 (2025) 97–99 99

Table 2 (continued)

Control Arm Intervention arm % Change related to PSMA-PET

N = 76 N = 102 (only for intervention arm)
->With reduction of RT fields 1 (1.3%) 0 -
->Chemotherapy 0 1 (0.9%) 1 (100%)
De-escalation 8 (10.5%) 12 (11.8%) 11/12 (92%)
->Switch to Observation 4 (5.2%) 7 (6.9%) 6/7 (86%)
->Switch to ADT only 0 1 (0.9%) 1 (100%)
->Removal of ADT 1 (1.3%) 1 (0.9%) 1 (100%)
-> Alone 1 (1.3%) 0 -
->With addition of RT fields 0 1 (0.9%) 1 (100%)
->Reduction of RT fields 1 (1.3%) 2 (2%) 2 (100%)
-> Alone 0 2 (2%) 2 (100%)
-> Removal of ADT 1 (1.3%) 0 -
->Change of RT fields 0 1 (0.9%) 1 (100%)
->No RT 2 (2.6%) 0 -
Alternative 0 4 (3.9%) 4 (100%)
->Change of RT Fields 0 2 (2%) 2 (100%)
-> With additional ADT 0 1 (0.9%) 1 (100%)
-> With removal of ADT 0 1 (0.9%) 1 (100%)
MINOR CHANGE 0 7 (7%) 7(100%)
Escalation 0 6 (5.8%) 6 (100%)
->In-field dose increase 0 6 (5.8%) 6 (100%)
De-escalation 0 1 (0.9%) 1 (100%)
->In-field dose decrease 0 1 (0.9%) 1 (100%)

ADT = Androgen Deprivation Therapy; ARSI = Androgen Receptor Signaling inhibitor; PET = positron emission tomography; PSMA=
prostate- specific-membrane-antigen; RT = Radiation Therapy
Quantitative results are expressed as n (%),
Finally
A clarification point was made in the legend of Figure 1: ‘‘The patient with incidental rectal cancer detected by the PSMA-
PET scan was classified in M1 category in this figure’’.

Figure 1. Flowchart. *The patient with incidental rectal cancer detected by the PSMA-PET scan was classified in M1 cat-
egory in this figure.
The authors would like to apologise for any inconvenience caused.
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Prevalence of Asymptomatic Coronary Artery Disease
2000 in Men with Vasculogenic Erectile Dysfunction:
Laparoscopic Radical Prostatectomy: Technical and
A Prospective Angiographic Study
Early Oncological Assessment of 40 Operations C. Vlachopoulos, K. Rokkas, N. Ioakeimidis, C. Aggeli, A. Michaelides,
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RPLND or Primary Chemotherapy in Clinical Stage Excellent Long-Term Cancer Control with Elective
IIA/B Nonseminomatous Germ Cell Tumors? Results Nephron-Sparing Surgery for Selected Renal Cell
of a Prospective Multicenter Trial Including Quality of Carcinomas Measuring More Than 4 cm
Life Assessment F. Becker, S. Siemer, M. Hack, U. Humke, M. Ziegler, M. Stöckle
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M. Hartmann, L. Keller &
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Morbidity and Clinical Outcome of Nephron-Sparing
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Laparoscopic Dismembered Pyeloplasty – The Method C. Pfister, M. Soulié, J. Tostain, J.-M. Ferriere, C.C. Abbou, M. Colombel,
of Choice in the Presence of an Enlarged Renal Pelvis A.S. Belldegrun
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European Urology 2002;42:268–275 The Template of the Primary Lymphatic Landing
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The Side Effects of Bacillus Calmette-Guérin in the
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Screening Round of the IMPACT Study
Soomro, J.J. De la Rosette, P.M. Laguna, P.G. Schulam
E.K. Bancroft, E.C. Page, E. Castro, H. Lilja, A. Vickers, D. Sjoberg,
European Urology 2007;52:798–803
M. Assel, C.S. Foster, G. Mitche, K. Drew, L. MÌhle, K. Axcrona,
2009 D.G. Evans, B. Bulman, D. Eles, D. McBride, C. van Asperen,
H. Vasen, L.A. Kiemeney, J. Ringelberg, C. Cybulski, D. Wokolorczyk,
Predictive Factors for Progression in Patients with
C. Selkirk, P.J. Hulick, A. Bojesen, A.-B. Skytte, Jiy Lam, L. Taylor,
Clinical Stage T1a Prostate Cancer in the PSA Era R. Oldenburg, R. Cremers, G. Verhaegh, W.A. van Zelst-Stams,
A. Descazeaud, M. Peyromaure, A. Salin, D. Amsellem-Ouazana, J.C. Oosterwijk, I. Blanco, M. Salinas, Jackie Ck, D.J. Rosario, S. Buys,
T. Flam, A. Viellefond, B. Debré, M. Zerbib T. Conner, M.G. Ausems, K.-r. Ong, J. Homan, S. Domchek,
European Urology 2008;53:355–362 J. Powers, M.R. Teixeira, S. Maia, W.D. Foulkes, N. Taherian, M. Ruijs,
A.T. Helderman-van den Enden, L. Izatt, R. Davidson, M.A. Adank,
2010 L. Walker, R. Schmutzler, K. Tucker, J. Kirk, S. Hodgson, M. Harris,
Should All Patients with Non–Muscle-Invasive Bladder F. Douglas, G.J. Lindeman, J. Zgajnar, M. Tischkowitz, V.E. Clowes,
Cancer Receive Early Intravesical Chemotherapy after R. Susman, T. Ramœn y Cajal, N. Patcher, N. Gadea, A. Spigelman,
Transurethral Resection? The Results of a Prospective T. van Os, A. Liljegren, L. Side, C. Brewer, A.F. Brady, A. Donaldson,
Randomised Multicentre Study V. Stefansdottir, E. Friedman, R. Chen-Shtoyerman, D.J. Amor,
S. Gudjœnsson, L. Adell, F. Merdasa, R. Olsson, B. Larsson, T. Davidsson, L. Copakova, J. Barwell, V.N. Giri, V. Murthy, N. Nicolai, S.-H. Teo,
J. Richthoff, G. Hagberg, M. Grabe, P.O. Bendahl, W. MÍnsson, F. Liedberg L. Grnhalgh, S. Strom, A. Henderson, J. McGrath, D. Gallagher,
European Urology 2009;55:773–780 N. Aaronson, A. Ardern-Jones, C. Bangma, D. Dearnaley, P. Costello,
Sponsored By Eli Lilly J. Eyfjord, J. Rothwell, A. Falconer, H. Gronberg, F.C. Hamdy,
O. Johannsson, V. Kh, Z. Kote-Jarai, J. Lubinski, U. Axcrona, J. Melia,
2011 J. McKinley, A.V. Mitra, C. Moynihan, G. Rennert, M. Suri, P. Wilson,
E. Killick, The IMPACT Collaborators, S. Moss, R.A. Eeles
Complications in 2200 Consecutive Laparoscopic
European Urology 2014;66:489–499
Radical Prostatectomies: Standardized Evaluation and
Analysis of Learning Curves
M. Hruza, H. Weiß, G. Pini, A. Goezen, M. Schulze, D. Teber, J. Rassweiler 2016
European Urology 2010;58:733–741 Molecular Characterization of Enzalutamide-treated
Sponsored by Elsevier Bone Metastatic Castration-resistant Prostate Cancer
E. Efstathiou, M. Titus, S. Wen, A. Hoang, M. Karlou, R. Ashe,
2012 S.M. Tu, A. Aparicio, P. Troncoso, J. Mohler, C.J. Logothetis
Salvage Radical Prostatectomy for Radiation-recurrent European Urology 2015;6:53–60
Prostate Cancer: A Multi-institutional Collaboration
D. Chade, S. Shariat, A. Cronin, C. Savage, J. Karnes, M. Blute,
A. Briganti, F. Montorsi, H. van der Poel, H. Van Poppel, S. Joniau, 2017
G. Godoy, A. Hurtado-Coll, M. Gleave, M. Dall’Oglio, M. Srougi, Tissue-based Genomics Augments Post-prostatectomy
P. Scardino, J. Eastham Risk Stratification in a Natural History Cohort of
European Urology 2011;60:205–210 Intermediate- and High-Risk Men
2013 A.E. Ross, M.H. Johnson, K. Yousefi, E. Davicioni, G.J. Netto,
L. Marchionni, H.L. Fedor, S. Glavaris, V. Choeurng, C. Buerki,
Stage-Specific Impact of Tumor Location on Oncologic
N. Erho, L.L. Lam, E.B. Humphreys, S. Faraj, S.M. Bezerra, M. Han,
Outcomes in Patients With Upper and Lower Tract
A.W. Partin, B.J. Trock, E.M. Schaeffer
Urothelial Carcinoma Following Radical Surgery European Urology 2016;69:157–165
 The Platinum
Hall of Fame

2018 Repo J., Robinsson D., Henningsson A.J., Styrke J., Angelin M.,
SRRM4 Drives Neuroendocrine Transdifferentiation of Lindquist E., Allard A., Becker M., Rudolfsson S., Buckland R.,
Carlsson C.T., Bjartell A., Nilsson A.C., Ahlm C., Connolly A.-M.F.,
Prostate Adenocarcinoma Under Androgen Receptor
Överby A.K., Josefsson A.
Pathway Inhibition
European Urology, Vol 81, Issue 3, p285–293
Y. Li, N. Donme, C. Sahinalp, N. Xie, Y. Wang, H. Xue, F. Mo,
H. Beltran, M. Gleave, Y. Wang, C. Collins, X. Dong
European Urology 2017;71:68–78 Best Scientific Paper on Clinical Research

2019 2007
Intravesical Activation of the Cation Channel TRPV4 Depressed Contractile Responses to Neurokinin A
Improves Bladder Function in a Rat Model for Detrusor in Idiopathic but not Neurogenic Overactive Human
Underactivity Detrusor Muscle
Y. Deruyver, E. Weyne, K. Dewulf, R. Rietjens, S. Pinto, N. Van Ranst, D.J. Sellers, C.R. Chapple, D.P.W. Hay, R. Chess-Williams
J. Franken, M. Vanneste, M. Albersen, T. Gevaert, R. Vennekens, European Urology 2006;49:510–518
D. De Ridder, T. Voets, W. Everaerts
European Urology, Vol. 74, Issue 3, p336–345
2008
2020 Effects of the M3 Receptor Selective Muscarinic
Antagonist Darifenacin on Bladder Afferent Activity of
Antifibrotic Synergy Between Phosphodiesterase Type 5
the Rat Pelvic Nerve
Inhibitors and Selective Oestrogen Receptor Modulatorso
K. Iijima, S. De Wachter, J.-J. Wyndaele
in Peyronie’s Disease Models
European Urology 2007;52:842–849
Marcus M. Ilg , Marta Mateus , William J. Stebbeds , Uros Milenkovic,
Nim Christopher, Asif Muneer, Maarten Albersen, David J. Ralph,
Selim Cellek
2009
European Urology, Vol. 75, Issue 2, Pages p329–340 Marked Gene Transcript Level Alterations Occur Early
During Radical Prostatectomy
T. Schlomm, E. Nðkel, A. Lübke, A. Buness, F.K.-H. Chun, T. Steuber,
M. Graefen, R. Simon, G. Sauter, A. Poustka, H. Huland,
2021
A. Erbersdobler, H. Sültmann, O.J.C. Hellwinkel
Gut Bacteria Composition Drives Primary Resistance to
European Urology 2008;53:333–346
Cancer Immunotherapy in Renal Cell Carcinoma Patients
Lisa Derosa, Bertrand Routy, Marine Fidelle, Valerio Iebba, Laurie
Alla, Edoardo Pasolli, Nicola Segata, Aude Desnoyer, Filippo 2010
Pietrantonio, Gladys Ferrere, Jean-Eudes Fahrner, Emmanuelle Le
Characteristics of Spontaneous Activity in the Bladder
Chatellier, Nicolas Pons, Nathalie Galleron, Hugo Roume, Connie
P.M. Duong, Laura Mondragœn, Kristina Iribarren, Mélodie Bonvalet,
Trigone
A. Roosen, C. Wu, G. Sui, R.A. Chowdhury, P.M. Patel, C.H. Fry
Safae Terrisse, Conrad Rauber, Anne-Gaëlle Goubet, Romain Daillère,
European Urology 2009;56:346–354
Fabien Lemaitre, Anna Reni, Beatrice Casu, Maryam Tidjani Alou,
Sponsored By Elsevier
Carolina Alves Costa Silva, Didier Raoult, Karim Fizazi, Bernard
Escudier, Guido Kroemer, Laurence Albiges, Laurence Zitvogel
European Urology, Vol 78, Issue 2, p195-206 2011
Stem Cell Characteristics in Prostate Cancer Cell Lines
M.J. Pfeiffer, J.A. Schalken
2022 European Urology 2010;57:246–255
Integrated Expression of Circulating miR375 and Sponsored By Elsevier
miR371 to Identify Teratoma and Active Germ Cell
Malignancy Components in Malignant Germ Cell 2012
Tumors Transplantation of Autologous Differentiated Urothelium
Lucia Nappi, Marisa Thi, Nabil Adra, Robert J. Hamilton, in an Experimental Model of Composite Cystoplasty
Ricardo Leao, Jean-Michel Lavoie, Maryam Soleimani, A. Turner, R. Subramanian, D. Thomas, J. Hinley, S. Abbas,
Bernhard J. Eigl, Kim Chi, Martin Gleave, Alan So, Peter C. Black, J. Stahlschmidt, J. Southgate
Robert Bell, Siamak Daneshmand, Clint Cary, Timothy Masterson, European Urology 2011;59:447–454
Lawrence Einhorn, Craig Nichols, Christian Kollmannsberger
European Urology, Vol 79, Issue 1, p16–19
2013
2023 Genome-wide Analysis of CpG Island Methylation in
A Phase 2 Trial of the Effect of Antiandrogen Therapy Bladder Cancer Identified TBX2, TBX3, GATA2, and ZIC4
on COVID-19 Outcome: No Evidence of Benefit, as pTa-Specific Prognostic Markers
Supported by Epidemiology and In Vitro Data R. Kandimalla, A.A.G. van Tilborg, L.C. Kompier, D.J.P.M. Stumpel, R.W.
Welén K., Rosendal E., Gisslén M., Lenman A., Freyhult E., Fonseca- Stam, C.H. Bangma, E.C. Zwarthoff
Rodrı́guez O., Bremell D., Stranne J., Balkhed Å.Ö., Niward K., European Urology 2012;61:1245–1256
 The Platinum
Hall of Fame

2014 2021
Indium-111- labeled Girentuximab ImmunoSPECT as Treatment of High-grade Non–muscle-invasive
a Diagnostic Tool in Clear Cell Renal Cell Carcinoma Bladder Carcinoma by Standard Number and Dose
C.H.J. Muselaers, O.C. Boerman, E. Oosterwijk, J.F. Langenhuijsen, of BCG Instillations Versus Reduced Number and
W.J.G. Oyen, P.F.A. Mulders Standard Dose of BCG Instillations: Results of the
European Urology 2013;63:1101–1106 European Association of Urology Research Foundation
Randomised Phase III Clinical Trial NIMBUS
2015 Marc-Oliver Grimm, Antoine G. van der Heijden, Marc Colombel,
Renal Function After Nephron-sparing Surgery Tim Muilwijk, Luis MartÚnez-Piþeiro, Marko M. Babjuk, Levent
Versus Radical Nephrectomy: Results from EORTC N. Türkeri, Joan Palou, Anup Patel, Anders S. Bjartell, Christien
Randomized Trial 30904 Caris, Raymond G. Schipper, Wim P.J. Witjes for the EAU Research
E. Scosyrev, E.M. Messing, R. Sylvester, S. Campbell, H. Van Poppel Foundation NIMBUS Study Group
European Urology 2014;65:372–377 European Urology, Vol 78, Issue 5, p690-698

2016 2022
Combination Treatment with Mirabegron and Solifenacin in Shockwave Lithotripsy Versus Ureteroscopic Treatment
Patients with Overactive Bladder: Efficacy and Safety Results as Therapeutic Interventions for Stones of the Ureter
from a Randomised, Double-blind, Dose-ranging, Phase 2 (TISU): A Multicentre Randomised Controlled Non-
Study (Symphony) inferiority Trial
P. Abrams, C. Kelleher, D. Staskin, T. Rechberger, R. Kay, Ranan Dasgupta, Sarah Cameron, Lorna Aucott, Graeme MacLen-
R. Martina, D. Newgreen, A. Paireddy, R. van Maanen, A. Ridder nan, Ruth E. Thomas, Mary M. Kilonzo, Thomas B.L. Lam, James
European Urology 2015:67:577–588 N Dow, John Norrie, Ken Anson, Neil Burgess, Charles T. Clark,
Francis X. Keeley, Sara J. MacLennan, Kath Starr, Sam McClinton
2017 European Urology, Vol 80, Issue 1, p46–54
PI-RADS Prostate Imaging – Reporting and Data System:
2015, Version 2 2023
J.C. Weinreb*, J.O. Barentsz*, P.L. Choyk, F. Cornu, M.A. Haider, Circumcision and Risk of Febrile Urinary Tract Infection
K.J. Macur, D. Margolis, M.D. Schnall, F. Shtern, C.M. Tempany, H.C. in Boys with Posterior Urethral Valves: Result of the
Thoeny, S. Verma CIRCUP Randomized Trial
European Urology 2016;69:16–40 Harper L., Blanc T., Peycelon M., Michel J.L., Leclair M.D., Garnier S.,
* These authors share first authorship. Flaum V., Arnaud A.P., Merrot T., Dobremez E., Faure A., Fourcade
L., Poli-Merol M.L., Chaussy Y., Dunand O., Collin F., Huiart L.,
Ferdynus C., Sauvat F.
2018 European Urology, Vol 81, Issue 1, p64–72
CheckMate 025 Randomized Phase 3 Study: Outcomes by
Key Baseline Factors and Prior Therapy for Nivolumab
Versus Everolimus in Advanced Renal Cell Carcinoma 2024
B. Escudier, P. Sharma, D.F. McDermott, S. George, H.J. Hammers, Phase 2 Single-arm Trial of Primary Retroperitoneal
S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, Lymph Node Dissection in Patients with Seminomatous
D. Castellano, H. Gurney, F. Donskov, K. Peltola, J. Wagstaff, Testicular Germ Cell Tumors with Clinical Stage IIA/B
T.C. Gauler, T. Ueda, H. Zhao, I.M. Waxman, R.J. Motzer, on behalf of (PRIMETEST)
the CheckMate 025 investigators Andreas Hiester, Yue Che, Achim Lusch, Oliver Ku, Günter Niegisch,
European Urology 2017;72:962–71 Anja Lorch, Christian Arsov, Peter Albers
Eur Urol 2023 Jul;84(1):25–31. doi: 10.1016/j.eururo.2022.10.021.
2019
Metabolic Biosynthesis Pathways Identified from Fecal
Microbiome Associated with Prostate Cancer Best Translational Paper
M.A. Liss, J.R. White, M. Goros, J. Gelfond, R. Leach, T. Johnson-Pais,
Z. Lai, E. Rourke, J. Basler, D. Ankerst, D.P. Shah 2024
European Urology, Vol. 74, Issue 5, p575–582 Spatial Immunephenotypes of Distant Metastases but
not Matched Primary Urothelial Carcinomas Predict
2020 Response to Immune Checkpoint Inhibition
Extended Versus Limited Lymph Node Dissection in Bladder Franziska Erlmeier, Niklas Klümper, Laura Landgraf, Pamela L.
Cancer Patients Undergoing Radical Cystectomy: Survival Strissel, Reiner Strick, Danijel Sikic, Helge Taubert, Sven Wach, Carol
Results from a Prospective, Randomized Trial I. Geppert, Veronika Bahlinger, Johannes Breyer, Manuel Ritter,
Jürgen E. Gschwend, Matthias M. Heck, Jan Lehmann, Herbert Rübben, Christian Bolenz, Florian Roghmann, Philipp Erben, Kristina
Peter Albers, Johannes M. Wolff, Detlef Frohneberg, Patrick de Geeter, Schwamborn, Ralph M. Wirtz, Thomas Horn, Bernd Wullich, Michael
Axel Heidenreich, Tilman Kðlble, Michael Stöckle, Thomas Schnöller, Hölzel, Arndt Hartmann, Jörgen E. Gschwend, Wilko Weichert,
Arnulf Stenzl,, Markus Müller, Michael Truss, Stephan Roth, Uwe- Markus Eckstein
Bernd Liehr, Joachim LeiÔner, Thomas Bregenzer, Margitta Retz Eur Urol 2023 Feb;83(2):133–142. doi: 10.1016/j.eururo.
European Urology, Vol 75, Issue 4, p604–611 2022.10.020.
 The Platinum
Hall of Fame

Young Investigator Award 2011

Midterm Prospective Evaluation of TVT-Secur Reveals
2024 High Failure Rate
Genetic Architecture of Azoospermia—Time to J.N. Cornu, P. Sèbe, L. Peyrat, C. Ciofu, O. Cussenot, F. Haab
Advance the Standard of Care European Urology 2010;58:157–161
Margot J. Wyrwoll, Nils Köckerling , Matthias Vockel, Ann-Kristin &
Dicke , Nadja Rotte, Eva Pohl Jana Emich, Marius Wöste, Christian
HYAL-1 Hyaluronidase: A Potential Prognostic Indicator
Ruckert, Rebecca Wabschke, Jochen Seggewiss, Susanne Ledig, Ann-
for Progression to Muscle Invasion and Recurrence in
Christin Tewes, Yvonne Stratis, Jann F. Cremers, Joachim Wistuba,
Claudia Krallmann, Sabine Kliesch, Albrecht Röpke, Birgit Stall- Bladder Cancer
meyer, Corinna Friedrich, Frank Tüttelmann M.W. Kramer, R. Golshani, A.S. Merseburger, J. Knapp, A. Garcia,
Eur Urol 2023 May;83(5):452–462. doi: 10.1016/j.eururo. J. Hennenlotter, R.C. Duncan, M.S. Soloway, M. Jorda, M.A. Kuczyk,
2022.05.011. A. Stenzl, V.B. Lokeshwar
European Urology 2010;57:86–94
Residents’ Corner
2012
2008 Exosomes as Biomarker Treasure Chests for Prostate
Initial Biopsy Outcome Prediction—Head-to-Head Cancer
Comparison of a Logistic Regression-Based Nomogram D. Duijvesz, T. Luider, C. Bangma, G. Jenster
versus Artificial Neural Network European Urology 2011;59:823–831
F.K.-H. Chun, M. Graefen, A. Briganti, A. Gallina, J. Hopp, &
M.W. Kattan, H. Huland, P.I. Karakiewicz Cancer-Specific and Other-Cause Mortality After Radical
European Urology 2007;51:1236–1243 Prostatectomy Versus Observation in Patients with
& Prostate Cancer: Competing-Risks Analysis of a Large
hK2 and Free PSA, a Prognostic Combination in Predicting North American Population-Based Cohort
Minimal Prostate Cancer in Screen-Detected Men within F. Abdollah, M. Sun, J. Schmitges, Z. Tian, C. Jeldres, A. Briganti,
the PSA Range 4–10 ng/ml L. Shariat, P. Perrotte, F. Montorsi, P. Karakiewicz
R. Raaijmakers, S.H. de Vries, B.G. Blijenberg, M.F. Wildhagen, European Urology 2011;60:920–930
R. Postma, C.H. Bangma, C. Darte, F.H. Schröder
European Urology 2007;52:1358–1364
2013
Prospective Assessment of Prostate Cancer Aggressiveness
2009 Using 3-T Diffusion-Weighted Magnetic Resonance
Evaluation of Prostate Cancer Detection with Ultrasound Imaging–Guided Biopsies Versus a Systematic 10-Core
Real-Time Elastography: A Comparison with Step Section Transrectal Ultrasound Prostate Biopsy Cohort
Pathological Analysis after Radical Prostatectomy T. Hambrock, C. Hoeks, C. Hulsbergen-van de Kaa, T. Scheenen,
G. Salomon, J. Köllerman, I. Thederan, F.K.H. Chun, L. Budðus, J. Fütterer, S. Bouwense, I. van Oort, F. Schröder, H. Huisman, J. Barentsz
T. Schlomm, H. Isbarn, H. Heinzer, H. Huland, M. Graefen European Urology 2012;61:177–184
European Urology 2008;54:1354–1362 &
& Immunocytology Is a Strong Predictor of Bladder
Radical Prostatectomy for Incidental (Stage T1a–T1b) Cancer Presence in Patients With Painless Hematuria:
Prostate Cancer: Analysis of Predictors for Residual A Multicentre Study
Disease and Biochemical Recurrence E.K. Cha, L.-A. Tirsar, C. Schwentner, P.J. Christos, C. Mian,
U. Capitanio, V. Scattoni, M. Freschi, A. Briganti, A. Salonia, A. Gallina, J. Hennenlotter, T. Martini, A. Stenzl, A. Pycha, S.F. Shariat,
R. Colombo, P.I. Karakiewicz, P. Rigatti, F. Montorsi B.J. Schmitz-Drðger
European Urology 2008;54:118–125 European Urology 2012;61:185–192

2010 2014
Influence of Nerve Transsections and Combined Prostate-specific Antigen (PSA) Testing Is Prevalent and
Bladder Filling on Intravesical Electrostimulation- Increasing in Stockholm County, Sweden, Despite No
Induced Bladder Contraction in the Rat Recommendations for PSA Screening: Results from a
L. De Bock, S. De Wachter, J.J. Wyndaele
Population-based Study, 2003 –2011
European Urology 2009;56:527–533
T. Nordström, M. Aly, M.S. Clements, C.E. Weibull, J. Adolfsson,
Sponsored By Eli Lilly
H. Grönberg
& European Urology 2013;63:419–425
The Role of Biopsy Core Number in Selecting Prostate &
Cancer Patients for Active Surveillance Metformin and Prostate Cancer: Reduced Development of
M. Ploussard, E. Xylinas, L. Salomon, Y. Allory, D. Vordos, A. Hoznek,
Castration-resistant Disease and Prostate Cancer Mortality
C.-C. Abbou, A. de la Taille
D.E. Spratt, C. Zhang, Z.S. Zumsteg, X. Pei, Z. Zhang, M.J. Zelefsky
European Urology 2009;56:891–898
European Urology 2013;63:709–716
Sponsored By Eli Lilly
 The Platinum
Hall of Fame

2015 N.A. Sopko, H. Matsui, D.M. Lough, D. Miller, K. Harris, M. Kates,

Propensity-Matched Comparison of Morbidity and X. Liu, K. Billups, R. Redett, A.L. Burnett, G. Brandacher,
T.J. Bivalacqua
Costs of Open and Robot-Assisted Radical Cystectomies:
European Urology 2017;71:584–93
A Contemporary Population-Based Analysis in the
&
United States
Racial Variation in Patient-Reported Outcomes Following
J.J. Leow, S.W. Reese, W. Jiang, S.R. Lipsitz, J. Bellmunt, Q.-D. Trinh,
B.I. Chung, A.S. Kibel, Steven L. Chang
Treatment for Localized Prostate Cancer: Results from
European Urology 2014;66:569–576 the CEASAR Study
& M.D. Tyson, J. Alvarez, T. Koyama, K.E. Hoffman, M.J. Resnick,
X.-C. Wu, M.R. Cooperberg, M. Goodman, S. Greenfield,
Survival Outcome and Treatment Response of Patients
A.S. Hamilton, M. Hashibe, L.E. Paddock, A. Stroup, V.W. Chen,
with Late Relapse from Renal Cell Carcinoma in the D.F. Penson, D.A. Barocas
Era of Targeted Therapy European Urology 2017;72:307–14
N. Kroeger, T.K. Choueiri, J.-L. Lee, G.A. Bjarnason, J.J. Knox,
M.J. MacKenzie, L. Wood, S. Srinivas, U.N. Vaishamayan,
S.-Y. Rha, S.K. Pal, T. Yuasa, F. Donskov, N. Agarwal, M.-H. Tan, 2019
A. Bamias, C.K. Kollmannsberger, S.A. North, B.I. Rini, D.Y.C. Heng Prospective Implementation of Enhanced Recovery After
European Urology 2014;65:1086–1092 Surgery Protocols to Radical Cystectomy
K.H. Pang, R. Groves, S. Venugopal, A.P. Noon, J.W.F. Catto
2016 European Urology, Vol. 73, Issue 3, p363–371
Efficacy of enzalutamide following abiraterone acetate &
in chemotherapy-naive metastatic castration-resistant Substitution Urethroplasty with Closure Versus
prostate cancer patients Nonclosure of the Buccal Mucosa Graft Harvest Site: A
A.A. Azad, B.J. Eigl, R.N. Murray, C. Kollmannsberger, K.N. Chi Randomized Controlled Trial with a Detailed Analysis of
European Urology 2015;67:23–29 Oral Pain and Morbidity
& A. Soave, R. Dahlem, H.O. Pinnschmidt, M. Rink, J. Langetepe,
Preoperative Prostate-specific Antigen Isoform p2PSA O. Engel, L.A. Kluth, B. Loechelt, P. Reiss, S.A. Ahyai, M. Fisch
and Its Derivatives, %p2PSA and Prostate Health Index, European Urology, Vol. 73, Issue 6, p910–922
Predict Pathologic Outcomes in Patients Undergoing
Radical Prostatectomy for Prostate Cancer: Results 2020
from a Multicentric European Prospective Study Prediction of High-grade Prostate Cancer Following
N. Fossati, N.M. Buffi, A. Haese, C. Stephan, A. Larcher, Multiparametric Magnetic Resonance Imaging: Improving
T. McNicholas, A. de la Taille, M. Freschi, G. Lughezzani, the Rotterdam European Randomized Study of Screening
A. Abrate, V. Bini, J. Palou Redorta, M. Graefen, G. Guazzoni, for Prostate Cancer Risk Calculators
M. Lazzeri Arnout R. Alberts, Monique J. Roobol, Jan F.M. Verbeek, Ivo G.
European Urology 2015;68:132–138 Schoots, Peter K. Chiu, Daniël F. Osses, Jasper D. Tijsterman, Harrie
2017 P. Beerlage, Christophe K. Mannaerts, Lars Schimmöller, Peter
Albers, Christian Arsov
Renal Cell Carcinoma Programmed Death-ligand 1,
European Urology, Vol 75, Issue 2, p310–318
a New Direct Target of Hypoxia-inducible Factor-2
&
Alpha, is Regulated by von Hippel–Lindau Gene
Metastasis-directed Therapy in Treating Nodal
Mutation Status
Oligorecurrent Prostate Cancer: A Multi-institutional
Y. Messai, S. Gad, M.Z. Noman, G. Le Teuff, S. Couve, B. Janji,
S.F. Kammerer, N. Rioux-Leclerc, M. Hasmim, S. Ferlicot, V. Baud, Analysis Comparing the Outcome and Toxicity of
A. Mejean, D.R. Mole, S. Richard, A.M.M. Eggermont, L. Albiges, Stereotactic Body Radiotherapy and Elective Nodal
F. Mami-Chouaib, B. Escudier, S. Chouaib Radiotherapy
European Urology 2016;70:623–632 Elise De Bleser, Barbara Alicja Jereczek-Fossab, David Pasquierd,
& Thomas Zillif,, Nicholas Van Ash, Shankar Siva, Andrei Fodor,
Results of a Randomised Controlled Trial Comparing Piet Dirixl, Alfonso Gomez-Iturriaga, Fabio Trippa, Beatrice Dettip
Gianluca Ingrosso, Luca Triggiani, Alessio Bruni, Filippo Along,
Intravesical Chemohyperthermia with Mitomycin C
Dries Reynders, Gert De Meerleer, Alessia Surgo, Kaoutar Loukili,
Versus Bacillus Calmette-Guérin for Adjuvant Treatment
Raymond Miralbellf, Pedro Silvah, Sarat Chander, Nadia Gisella Di
of Patients with Intermediate- and High-risk Non– Muzio, Ernesto Maranzano, Giulio Francolini, Andrea Lancia, Alison
Muscleinvasive Bladder Cancer Treeh,i, Chiara Lucrezia Deantoni, Elisabetta Ponti, Giulia Marvaso,
T.J.H. Arends, O. Nativ, M. Maffezzini, O. de Cobelli, G. Canepa, Els Goetghebeur, Piet Ost
F. Verweij, B. Moskovitz, A.G. van der Heijden, J.A. Witjes European Urology, Vol 76, Issue 6, p732–739
European Urology 2016;69:1046–1052
2021
2018 The Clinicopathologic and Molecular Landscape of Clear
Ex Vivo Model of Human Penile Transplantation and Cell Papillary Renal Cell Carcinoma: Implications in
Rejection: Implications for Erectile Tissue Physiology Diagnosis and Management
 The Platinum
Hall of Fame

Stanley Weng, Renzo G. DiNatale, Andrew Silagy, Roy Mano, K.R. Ghani, D.C. Miller, S. Linsell, A. Brachulis, B. Lane, R. Sarle,
Kyrollis Attalla, Mahyar Kashani, Kate Weiss, Nicole E. Benfante, D. Dalela, M. Menon, B. Comstock, T.S. Lendvay, J. Montie, J.O. Peabody,
Andrew G. Winer, Jonathan A. Coleman, Victor E. Reuter, Paul Russo, for the Michigan Urological Surgery Improvement Collaborative
Ed Reznik, Satish K. Tickoo, A. Ari Hakimi, European Urology 2016;69:547–550
European Urology, Vol 79, Issue 4, p468-477
2018
2022
Multispectral Fluorescence Imaging During
Is There a Detrimental Effect of Antibiotic Therapy in
Robotassisted Laparoscopic Sentinel Node Biopsy: A
Patients with Muscle-invasive Bladder Cancer Treated
First Step Towards a Fluorescence-based Anatomic
with Neoadjuvant Pembrolizumab?
Roadmap
Pederzoli F., Bandini M., Raggi D., Marandino L., Basile G., Alfano M.,
N.S. van den Berg, T. Buckle, G.H. KleinJan, H.G. van der Poel,
Colombo R., Salonia A., Briganti A., Gallina A., Montorsi F., Necchi A.
F.W.B. van Leeuwen
European Urology, Vol 80, Issue 3, p319–322
European Urology 2017;72:110–17
&
Effect of Simulation-based Training on Surgical
2019
Proficiency and Patient Outcomes: A Randomised
Randomized Trial Comparing Open Radical Cystectomy
Controlled Clinical and Educational Trial
and Robot-assisted Laparoscopic Radical Cystectomy:
Aydin A., Ahmed K., Abe T., Raison N., Van Hemelrijck M., Garmo H.,
Ahmed H.U., Mukhtar F., Al-Jabir A., Brunckhorst O., Shinohara N., Oncologic Outcomes
Zhu W., Zeng G., Sfakianos J.P., Gupta M., Tewari A., Gozen A.S., B.H. Bochner, G. Dalbagni, K.H. Marzouk, D.D. Sjoberg, J. Lee,
Rassweiler J., Skolarikos A., Kunit T., Knoll T., Moltzahn F., S.M. Donat, J.A. Coleman, A. Vickers, H.W. Herr, V.P. Laudone
Thalmann G.N., Lantz Powers A.G., Chew B.H., Sarica K., Shamim European Urology, Vol. 74, Issue 4, p465–471
Khan M., Dasgupta P.
European Urology, Vol 80, Issue 4, p385–393
2020
Robot-assisted AMS-800 Artificial Urinary Sphincter
Bladder Neck Implantation in Female Patients with
2023 Stress Urinary Incontinence
First-in-human Intravesical Delivery of Pembrolizumab Benoit Peyronnet, Gregoire Capon, Olivier Belas, Andrea Manunta,
Identifies Immune Activation in Bladder Cancer Clement Allenet, Juliette Hascoet, Jehanne Calves, Michel Belas,
Unresponsive to Bacillus Calmette-Guérin Pierre Callerot, Gregoire Robert, Aurelien Descazeaud, Georges
Meghani K., Cooley L.F., Choy B., Kocherginsky M., Swaminathan S., Fournier
Munir S.S., Svatek R.S., Kuzel T., Meeks J.J. European Urology, Vol 75, Issue 1, p169–175
European Urology, Vol 82, Issue 6, p602–610
& 2021
Updating and Integrating Core Outcome Sets for Outcomes of Gender Affirming Peritoneal Flap
Localised, Locally Advanced, Metastatic, and Vaginoplasty Using the Da Vinci Single Port Versus Xi
Nonmetastatic Castration-resistant Prostate Cancer: Robotic Systems
An Update from the PIONEER Consortium Geolani W. Dy, Min Suk Jun, Gaines Blasdel, Rachel Bluebond-
Beyer K., Moris L., Lardas M., Omar M.I., Healey J., Tripathee S., Langner, Lee C. Zhao
Gandaglia G., Venderbos L.D.F., Vradi E., van den Broeck T., Willemse European Urology, Vol 79, Issue 5, p676-683
P.-P., Antunes-Lopes T., Pacheco-Figueiredo L., Monagas S., Esperto
F., Flaherty S., Devecseri Z., Lam T.B.L., Williamson P.R., Heer R., 2022
Smith E.J., Asiimwe A., Huber J., Roobol M.J., Zong J., Mason M., A DROP-IN Gamma Probe for Robot-assisted
Cornford P., Mottet N., MacLennan S.J., N’Dow J., Briganti A., Radioguided Surgery of Lymph Nodes During Radical
MacLennan S., Van Hemelrijck M., PIONEER Consortium
Prostatectomy
European Urology, Vol 81, Issue 5, p503–514
Paolo Dell’Oglio, Philippa Meershoek, Tobias Maurer,
Esther M.K. Wit, Pim J. van Leeuwen, Henk G. van der Poel,
Best Paper in Robotic Surgery Fijs W.B. van Leeuwen, Matthias N. van Oosterom
European Urology, Vol 79, Issue 1, p124–132
2016
Pilot Validation Study of the European Association of
Urology Robotic Training Curriculum 2023
A. Volpe, K. Ahmed, P. Dasgupta, V. Ficarra, G. Novara, H. van der Poel, Robotic Radical Prostatectomy for Prostate Cancer in
A. Mottrie Renal Transplant Recipients: Results from a Multicenter
European Urology 2015;68:292–299 Series
Giancarlo Marra, Marco Agnello, Andrea Giordano, Francesco Soria,
2017 Marco Oderda, Charles Dariane, Marc-Olivier Timsit, Julien Bran-
Measuring to Improve: Peer and Crowd-sourced chereau, Oussama Hedli, Benoit Mesnard, Derya Tilki, Jonathon
Assessments of Technical Skill with Robot-assisted Olsburgh, Meghana Kulkarni, Veeru Kasivisvanathan, Alberto
Breda, Luigi Biancone, Paolo Gontero
Radical Prostatectomy
European Urology, Vol 82, Issue 6, p639–645
 The Platinum
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2024 3. Pierre Karakiewicz

4. Luis Martinez-Piþeiro
Three-dimensional Virtual Models of the Kidney with 5. Peter Mulders
Colored Perfusion Regions: A New Algorithm-based 6. Maria Ribal
Tool for Optimizing the Clamping Strategy During
Platinum Award Winners 2020
Robot-assisted Partial Nephrectomy 1. Prokar Dasgupta
Daniele Amparore, Federico Piramide, Enrico Checcucci, Paolo Verri, 2. Karim Fizazi
Sabrina De Cillis, Alberto Piana, Gabriele Volpi, Giovanni Busacca, 3. Silke Gillessen
Marco Colombo, Cristian Fiori, Francesco Porpiglia 4. Caroline Moore
Eur Urol2023 Oct;84(4):418–425. doi: 10.1016/j.eururo.2023.04.005. 5. Declan Murphy
6. Karin Plass
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October: Jacques Irani (France) Stephen Boorjian (USA)
November: Apostolos Apostolidis (Greece) Matthew Galsky (USA)

Reviewer of the Year 2009 2014 Reviewers of the Month

Henk van der Poel (The Netherlands) January: Morgan Rouprõt (France)
February: Malte Rieken (Switzerland)
2010 Reviewers of the Month March: Jochen Walz (France)
January: Ricarda Bauer (Germany) April: Noburo Hara (Japan)
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Aidan Noon (UK)
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Michael Kattan (USA)
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February: Theo de Reijke (The Netherlands) May: Kazutaka Saito (Japan)
March: Evangelos Liatsikos (Greece) June: Alessandra Mosca (Italy)
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September: Gianluca Giannarini (Italy)
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Reviewer of the Year 2011 Joseph Chin (Canada)
Alexander Bachmann (Switzerland) Boris Gershman (USA)

2012 Reviewers of the Month 2016 Reviewers of the Month

January: Francesco Greco (Germany) January: Paolo Verze (Italy)
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Jean-Nicolas Cornu (France) Riccardo Bartoletti (Italy)
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2013 Reviewers of the Month 2017 Reviewers of the Month
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June: Zoran Culig (Austria) May: Abdullah Erdem Canda (Turkey)
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November: Bimal Bhindi (Canada) October: Neeraj Agarwal (USA)
Reviewers of the Year 2017 November: Mary Elizabeth Westerman (USA)
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Nicola Fossati (Italy) Hendrik Borgmann (Germany)
Kazuto Ito (Japan) Laura Marandino (Switzerland)
Mary Elizabeth Westerman (USA)
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January: Andrea Necchi (USA) 2022 Reviewers of the Month
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November: Paras Shah (USA) October: Timothy Clinton (USA)
November: Samantha Conroy (UK)
Reviewers of the Year 2018
Andrea Necchi (USA) Reviewers of the Year 2022
Christopher Wallis (Canada) Laura Bukavina (USA)
Alastair Lamb (UK) Timothy Clinton (USA)
Stephanie Gazdovich (CAN)
2019 Reviewers of the Month Zine-Eddine Khene (FR)
January: Keith Lawson (Canada) 2023 Reviewers of the Month
February: Alessandro Antonelli (Italy) January: Gillian Vandekerkhove (CAN)
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July: Adam Weiner (USA) June: Pim van Leeuwen (NL)
August: Stephen Williams (USA) July: Michael Baboudjian (France)
September: Daniel Spratt (USA) August: Kristian Stensland (USA)
October: Jacob Patterson (UK) September: Thomas Van den Broeck (BE)
November: Ryan Hutchinson (USA) October: Francesco Greco (Italy)
Reviewers of the Year 2019 November: Ardalan Ahmad (CAN)
Jacob Patterson (UK) Reviewers of the Year 2023
Daniel Spratt (USA) Ardalan Ahmad (CA)
Stephen Williams (USA) Thomas van den Broeck (BE)
Francesco Greco (IT)
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Michael Baboudjian (FR)
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Lisa Moris (BE)
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Riccardo Campi (Italy)
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Fumitaka Koga (Japan) Arun Azad (AUS)
Umang Swami (USA)
2021 Reviewers of the Month
Elio Mazzone (IT)
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March: David D’Andrea (Austria) January: Alexandra Masson-Lecomte (FR)
 EUROPEAN UROLOGY 87 (2025) e12–e13

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Letter to the Editor

Re: Pieter Vynckier, Lieven Annemans, Sarah Raes, et al. customized screening programs that take geographic and
Systematic Review on the Cost Effectiveness of Prostate ethnic variances into consideration to guarantee fair health
Cancer Screening in Europe. Eur Urol. 2024;86:400–408 care outcomes. This would allow for a program more in line
with the population while preserving the cost effectiveness
of the screening strategy.
We read with interest the review by Vynckier et al [1] on Therefore, we are currently conducting a study to iden-
the cost effectiveness of prostate cancer screening in Eur- tify risk factors in the rural population in Colombia, focusing
ope. Prostate cancer remains a major health concern and on groups with a representative sample of indigenous indi-
is the most prevalent cancer among men in Europe [2]. viduals and those of African descent. This fieldwork is vital
Therefore, it is necessary to devise cost-effective and effi- for populations in countries without personalized recom-
cient screening strategies that help to minimize death rates mendations that consider the local ethnic demographics,
and maximize health care spending. A unified approach as in Colombia. An understanding of these risk factors will
could enhance resource allocation and provide clearer facilitate the development of customized screening strate-
guidelines for health care providers, and would also raise gies that enhance efficacy and equity.
public awareness regarding the benefits and risks associ- There is growing recognition of the importance of indi-
ated with prostate cancer screening. vidualized approaches and recommendations, with a speci-
An assessment of the ERSPC trial found that prostate- fic focus on risk- and/or age-based screening [1].
specific antigen–based screening significantly reduced Personalized screening protocols can significantly improve
prostate cancer mortality but also raised concerns about early detection of prostate cancer by considering the unique
overdiagnosis and overtreatment [3]. A systematic review risk profiles of different population groups. For all of the
by Heijnsdijk et al [4] also found that shorter screening above reasons, we highlight the importance of the work
intervals, such as biennial screening starting at age 55 yr, done by Vynckier et al and encourage research groups in
were more cost effective than longer intervals. These Latin America and other developing countries to adopt
authors reported an incremental cost-effectiveness ratio of these lines of research on the cost effectiveness of prostate
$73 000 per quality-adjusted life year gained, considering cancer screening.
the impact of overdiagnosis and quality of life.
In Latin America, the trend for prostate cancer is similar Conflicts of interest: The authors have nothing to disclose.
to that in European countries: in 2022 it was the most
prevalent cancer among men in both regions (225 985 vs
473 011 cases) [2]. This has allowed us to implement Euro-
pean guideline recommendations in our screening process. References
However, beyond the difficulties previously mentioned,
[1] Vynckier P, Annemans L, Raes S, et al. Systematic review on the cost
we face additional challenges in prostate cancer screening. effectiveness of prostate cancer screening in Europe. Eur Urol
Many recommendations are based on randomized con- 2024;86:400–8.
trolled trials that under-represent diverse ethnic back- [2] International Agency for Research on Cancer. Statistics at a glance,
grounds, such as African Americans, Native Americans, 202Top 5 most frequent cancers, number of new cases. https://gco.
iarc.who.int/media/globocan/factsheets/populations/900-world-
and Hispanics. This complicates the implementation of
fact-sheet.pdf.
screening policies in ethnically diverse countries such as [3] Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-
Colombia. Geographic disparities also exist; while prostate cancer mortality in a randomized European study. N Engl J Med
cancer incidence is higher in urban populations, the mortal- 2009;360:1320–8.
ity rate is higher for rural men diagnosed with the disease [4] Heijnsdijk EAM, De Carvalho TMD, Auvinen A, et al. Cost-
effectiveness of prostate cancer screening: a simulation study
[5]. Moreover, limited access to health care services in rural based on ERSPC data. J Natl Cancer Inst 2015;107:366.
areas exacerbates the difficulties in timely diagnosis and [5] Williams PA, Zaidi SK, Sengupta R. AACR cancer disparities progress
treatment [5]. These discrepancies highlight the need for report 2022. Cancer Epidemiol Biomarkers Prev 2022;31:1249–50.

https://doi.org/10.1016/j.eururo.2024.08.027
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
EUROPEAN UROLOGY 87 (2025) e12–e13 e13

Andrés Gutiérrez a
Julio Cesar Boada b
Sebastián Peña a,*

a
Urology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia
b
Universidad de Los Andes, Bogotá, Colombia

*Corresponding author. Urology Department, Rodríguez University

Hospital, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
E-mail address: [email protected] (S. Peña).

August 7, 2024
 EUROPEAN UROLOGY 87 (2025) e14

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Letter to the Editor

Reply to Andrés Gutiérrez, Julio Cesar Boada, and research efforts to include studies from various parts of
Sebastián Peña’s Letter to the Editor re: Pieter Vynckier, the world.
Lieven Annemans, Sarah Raes, et al. Systematic Review on In conclusion, we are grateful to Gutiérrez and col-
the Cost-effectiveness of Prostate Cancer Screening in leagues for their positive feedback and for highlighting the
Europe. Eur Urol. 2024;86:400–408 broader implications of our research. We believe that inter-
national collaboration and a focus on diverse populations
We want to thank Gutiérrez and colleagues for their are essential steps towards improved screening for PCa.
insightful and supportive letter regarding our recent publi-
cation on the cost-effectiveness of prostate cancer (PCa) Conflicts of interest: The authors have nothing to disclose.
screening in Europe [1].
We agree that our research highlights the potential of a References
risk-based screening approach for the early detection of
PCa. The lessons learned from our systematic review can [1] Vynckier P, Annemans L, Raes S, et al. Systematic review on the cost-
serve as a basis for further studies and can be adapted to effectiveness of prostate cancer screening in Europe. Eur Urol
2024;86:400–8.
various health care systems and patient populations to
improve screening for PCa. Pieter Vynckier a,*
Despite increasing awareness of PCa screening, there Lieven Annemans a
remains a knowledge gap regarding the most suitable Monique Roobol b
approach to screen for PCa. Therefore, there is indeed a need
a
for international research and consideration of different Department of Public Health and Primary Care, Ghent University, Ghent,
Belgium
local ethnic demographics. While our study focused on b
Department of Urology, Erasmus MC Cancer Institute, Erasmus University
European countries, we acknowledge that the burden of Medical Center Rotterdam, The Netherlands
PCa varies significantly across different regions and popula-
tions. This highlights the importance of more localized *Corresponding author. Department of Public Health and Primary Care,
research to identify risk factors and to develop screening Ghent University, Ghent, Belgium.
strategies that are not only cost effective but also tailored E-mail address: [email protected] (P. Vynckier).
to the needs of diverse populations and patient groups. In
August 20, 2024
this context, we strongly support the idea of expanding

https://doi.org/10.1016/j.eururo.2024.08.028
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
 EUROPEAN UROLOGY 87 (2025) e15–e16

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Letter to the Editor

Re: Niklas Klümper, Viktor Grünwald, Arndt Hartmann, tumor purity, as this could affect the reliability of the
et al. The Role of Microsatellite Instability/DNA Mismatch MSIsensor scores. I believe that next-generation sequencing
Repair Deficiency and Tumor Mutational Burden as (NGS) might be a better testing method in mCRPC. NGS can
Biomarkers in Predicting Response to Immunotherapy in detect unexpected biomarkers outside of immunotherapy,
Castration-resistant Prostate Cancer. Eur Urol. and identify biomarkers that are immunotherapy sensitiz-
2025;87:388–390 ers. Moore et al [5] suggested that for patients with both
homologous recombination repair gene mutations and
TMB-H/MSI-H status, ICIs should be considered before PARP
For patients with metastatic castration-resistant prostate
inhibitors. In addition, it has been found that some novel
cancer (mCRPC) who have undergone multiple lines of
molecular axis targets (such as the CCL20-CCR6 axis) are
treatment, immunotherapy might be a potential therapeu-
involved in modulating the tumor microenvironment in
tic option. However, identification of patients who are sen-
prostate cancer immunotherapy.
sitive to immunotherapy remains challenging. Klümper
Lastly, there is currently no consensus on the threshold
et al [1] reported on the predictive role of microsatellite
for high TMB. Most studies use a threshold of 10 muta-
instability (MSI)/DNA mismatch repair (dMMR) deficiency
tions/Mb, although this was established without including
and tumor mutational burden (TMB) in immunotherapy
CRPC patients. Some studies have explored the value of
for patients with CRPC.
using a TMB threshold of 20 mutations/Mb. The optimal
The authors suggested that because of the cost effective-
threshold for identifying potential candidates suitable for
ness and efficiency of TMB testing, along with the observa-
immunotherapy requires further exploration. Furthermore,
tion that 95% of patients with MSI-H CRPC also have TMB-H
even among patients positive for these biomarkers, the
status, immunohistochemistry staining for MSI detection is
ORR to immunotherapy is not very high. Future research
the most effective method for screening for patients who
should focus on identifying more precise immunotherapy
might respond to immune checkpoint inhibitors (ICI). How-
predictors and treatment targets, as well as combination
ever, this probability was derived from a small sample of 23
therapies to enhance immunosensitivity.
cases. A previous study [2] involving 100 000 tumor
patients showed that 83% of MSI-H/dMMR patients were
Conflicts of interest: The author has nothing to disclose.
classified as TMB-H, whereas <16% of TMB-H patients were
classified as MSI-H. This suggests that there is still a propor-
tion of TMB-H patients who are microsatellite stable (MSS).
This is because TMB can also be associated with mutations References
in other genes such as POLE/POLD1 [3].
In the KEYNOTE-158 trial, the objective response rate [1] Klumper N, Grunwald V, Hartmann A, et al. The role of microsatellite
instability/DNA mismatch repair deficiency and tumor mutational
(ORR) was 34% for MSI-H/dMMR patients and 29% for burden as biomarkers in predicting response to immunotherapy in
patients with MSS status and TMB-H solid tumors. This con- castration-resistant prostate cancer. Eur Urol l2024;86:388–90.
firms that patients with at least one positive biomarker can [2] Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000
benefit from ICI. Therefore, testing only for MMR/MSI might human cancer genomes reveals the landscape of tumor mutational
burden. Genome Med 2017;9:34.
mean that some patients with non-MSI-H but TMB-H status
[3] Campbell BB, Light N, Fabrizio D, et al. Comprehensive analysis of
could miss out on the opportunity for immunotherapy. Sim- hypermutation in human cancer. Cell 2017;171:1042–1056.e10.
ilarly, Abida et al [4] reported that nine patients had inde- [4] Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of
terminate MSI scores with evidence of dMMR. This microsatellite instability in prostate cancer and response to immune
reminds us that testing for MSI just might overlook some checkpoint blockade. JAMA Oncol 2019;5:471–8.
[5] Moore C, Naraine I, Zhang T. Complete remission following
dMMR patients who could potentially benefit from ICI. pembrolizumab in a man with mCRPC with both microsatellite
Abida et al [4] mentioned that 384 tumors (24.8%) were instability and BRCA2 mutation. Oncologist. In press. https://doi.org/
excluded from their MSIsensor analysis because of low 10.1093/oncolo/oyae156.

https://doi.org/10.1016/j.eururo.2024.08.037
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
e16 EUROPEAN UROLOGY 87 (2025) e15–e16

Feng Qi *

Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of

Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University,
Nanjing, China
E-mail address: [email protected] (F. Qi).

August 7, 2024
 EUROPEAN UROLOGY 87 (2025) e17–e18

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Letter to the Editor

Reply to Feng Qi’s Letter to the Editor re: Niklas Klümper, [5]; thus, no conclusions can be drawn regarding the role
Viktor Grünwald, Arndt Hartmann, et al. The Role of of high TMB status in predicting the immunotherapy
Microsatellite Instability/DNA Mismatch Repair Deficiency response in PC patients in KEYNOTE-158 [4,5].
and Tumor Mutational Burden as Biomarkers in A critical issue in determining MSI-H status is the appro-
Predicting Response to Immunotherapy in Castration- priate choice of assay. MMR deficiency can be directly iden-
resistant Prostate Cancer. Eur Urol. 2024;86:388–390 tified via immunohistochemistry (demonstrating the loss of
one of the four major MMR enzymes PMS2, MLH1, MSH2,
We read with great interest Dr. Qi’s letter on our recently and MSH6) or detection of pathogenic inactivating muta-
published Platinum Opinion editorial regarding the role of tions in one of these four enzymes. There are also indirect
microsatellite instability (MSI) in predicting the surrogates of genetic instability caused by MMR deficiency,
immunotherapy response in patients with metastatic pros- commonly known as MSI. Microsatellites are repetitive
tate cancer (PC) [1]. Systematic studies have documented DNA elements that are typically stable within an organism,
the prevalence of microsatellite instability-high (MSI-H) in but genetic instability in tumor (and germline) DNA can lead
PC because of deficiencies in DNA mismatch repair (MMR) to alterations in these microsatellites, resulting in MSI. MSI
enzymes. For example, a comprehensive investigation by can be detected using classical sequencing approaches or
Abida et al [2] identified 32 MSI-H cases out of 1000 next-generation sequencing (NGS) [6].
patients with PC treated at the Memorial Sloan Kettering Dr. Qi raises the point that NGS might be better suited
Cancer Center, highlighting the rarity of this genetic alter- for MSI/MMR deficiency testing than other methods, ref-
ation in PC. erencing observations by Abida et al [2] that their MSI
In this context, Dr. Qi referred to a pan-cancer study sensor algorithm appeared to fail in reliably identifying
involving approximately 100 000 human cancer samples a specific subset of PC patients with MSI-H/MMR defi-
that broadly addressed mechanisms of hypermutation in ciency status. However, Dr. Qi’s argument is inconsistent
human cancers [3]. This study effectively demonstrated var- because the MSI sensor used by Abida et al is a software
ious hypermutation mechanisms, including genetic alter- algorithm reliant on NGS results. Therefore, it is unclear
ations in POLE/POLD1 and mismatch repair (MMR) why an NGS approach should be considered superior in
deficiency, along with other factors contributing to a high this context.
tumor mutational burden (TMB). However, Dr. Qi’s inter- As outlined in our editorial, selection of appropriate
pretation of this study should be approached with caution, modalities for testing MSI or MMR is challenging, particu-
as no direct cancer-specific conclusions can be drawn from larly because the Bethesda consensus microsatellite panel
the work by Campbell et al [3]. Furthermore, it is well estab- that is commonly used is primarily suited for colorectal can-
lished that tumors can exhibit a TMB >10 mutations/Mb cer and has shown lower sensitivity for detection of MSI-H
despite being MMR-proficient and wild-type for POLE/ status in other cancer types [1]. In summary, there is an
POLD1. In the specific context of PC, Abida et al [2] demon- unmet need for reliable pan-cancer methods to type MSI-
strated that high TMB status predominantly occurred in the H/MMR deficiency status in cancers other than colorectal
subset of MMR-deficient PCs, while other alterations, such adenocarcinoma, which undoubtedly should be a focus of
as POLE/POLD1 mutations leading to hypermutation, were intensified research in the coming years.
exceedingly rare (only 1 case in their study had a POLE
mutation leading to high TMB status). Conflicts of interest: Niklas Klümper reports honoraria and travel
While Abida et al [2] reported that PC patients with MSI- expenses from BicycleTX, Astellas, Novartis, Ipsen, Photocure, and
H tumors can significantly benefit from immunotherapy, Dr. MSD; and research funding from BicycleTX. Markus Eckstein reports
Qi’s interpretation of the KEYNOTE-158 trial [4,5], which honoraria and travel expenses from BicycleTX, Eisai, MSD, AstraZeneca,
enrolled a small number of PC patients, but only in the Janssen-Cilag, Cepheid, Roche, Astellas, Diaceutics, Owkin, and BMS;
MSI-H/MMR-deficient arm [4], is inconsistent. The trial research funding from BicycleTX, AstraZeneca, Janssen-Cilag, STRA-
arm in which PC patients were enrolled only included TIFYER, Cepheid, Roche, Gilead, Owkin, and QUIP GmbH; and advisory
patients with confirmed MSI-H/MMR-deficient status [4], fees from BicycleTX, Diaceutics, MSD, AstraZeneca, Janssen-Cilag, Geno-
while no PC patients were enrolled in the TMB-high arm mic Health, Owkin, and BMS.

https://doi.org/10.1016/j.eururo.2024.09.019
0302-2838/Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data
mining, AI training, and similar technologies.
e18 EUROPEAN UROLOGY 87 (2025) e17–e18

References Niklas Klümper a,b,c

Markus Eckstein d,e,f,*
[1] Klumper N, Grunwald V, Hartmann A, Holzel M, Eckstein M. The role
of microsatellite instability/DNA mismatch repair deficiency and a
Department of Urology, University Hospital Bonn, Bonn, Germany
tumor mutational burden as biomarkers in predicting response to b
Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf, Bonn,
immunotherapy in castration-resistant prostate cancer. Eur Urol
Germany
2024;86:388–90. c
Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
[2] Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of d
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-
microsatellite instability in prostate cancer and response to immune
checkpoint blockade. JAMA Oncol 2019;5:471–8. Universität Erlangen-Nürnberg, Erlangen, Germany
e
[3] Campbell BB, Light N, Fabrizio D, et al. Comprehensive analysis of EMN Comprehensive Cancer Center, University Hospital Erlangen, Friedrich-
hypermutation in human cancer. Cell 2017;171:1042–1056.e10. Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
f
[4] Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in Bavarian Center for Cancer Research, Munich, Germany
patients with noncolorectal high microsatellite instability/mismatch
repair-deficient cancer: results from the phase II KEYNOTE-158 *Corresponding author. Institute of Pathology, University Hospital
study. J Clin Oncol 2020;38:1–10. Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg,
[5] Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational Krankenhausstraße 8–10, 91054 Erlangen, Germany.
burden with outcomes in patients with advanced solid tumours E-mail address: [email protected] (M. Eckstein).
treated with pembrolizumab: prospective biomarker analysis of the
multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol September 10, 2024
2020;21:1353–65.
[6] Vikas P, Messersmith H, Compton C, et al. Mismatch repair and
microsatellite instability testing for immune checkpoint inhibitor
therapy: ASCO endorsement of College of American Pathologists
guideline. J Clin Oncol 2023;41:1943–8.
 EUROPEAN UROLOGY 87 (2025) e19

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Letter to the Editor

Re: Frédéric Panthier, Vineet Gauhar, Eugenio Ventimiglia, ous variables often provide more nuanced prediction than
Jia-Lun Kwok, Etienne Xavier, Olivier Traxer. Rethinking categorical variables. I would like to add a further recom-
Stone-free Rates and Surgical Outcomes in Endourology: A mendation that the computed tomography slice thickness
Point of View from PEARLS Members. Eur Urol. should be standardized and reported along with the
2024;86:198–199 methodology for determining stone volume. Advances in
kidney stone care, specifically in URS, are coming quickly,
In the future, we might envision that urologists will refer to and it is imperative that the quality of our clinical evidence
stones of 8 mm3, 27 mm3, and 64 mm3 rather than 2 mm, evolves as well.
3 mm, and 4 mm, as volume provides more valuable infor-
mation than single-dimension measurements in stone dis- Conflicts of interest: The author has nothing to disclose.
ease. As Panthier et al [1] recommend, use of the
maximum stone diameter defies logic, as this describes a References
three-dimensional object in only two dimensions. More-
over, this is not just a mathematical mischaracterization [1] Panthier F, Gauhar V, Ventimiglia E, Kwok JL, Keller EX, Traxer O.
but, more importantly, is also potentially a clinical problem, Rethinking stone-free rates and surgical outcomes in endourology: a
point of view from PEARLS members. Eur Urol 2024;86:198–9.
as we know that larger residual fragments predict down- [2] Raman JD, Bagrodia A, Gupta A, et al. Natural history of residual
stream stone events [2–4]. Data from a randomized con- fragments following percutaneous nephrostolithotomy. J Urol
trolled trial comparing an aspiration device to standard 2009;181:1163–8.
ureteroscopy (URS) demonstrated a lower rate of postoper- [3] Li X, He L, Li J, Duan Z, Gao Z, Liu L. Medium-term follow-up of
clinically insignificant residual fragments after minimal invasive
ative events including emergency department visits, hospi-
percutaneous nephrolithotomy: prognostic features and risk factors.
talization, and retreatment (4.3% vs 16.4%; p = 0.015; Int J Clin Exp Med 2015;8:21664–8.
unpublished data under peer review). This makes sense [4] Iremashvili V, Li S, Penniston KL, Best SL, Hedican SP, Nakada SY. Role
because the residual stone volume was lower with the aspi- of residual fragments on the risk of repeat surgery after flexible
ration device than with standard URS (11.7 ± 25.8 mm3 vs ureteroscopy and laser lithotripsy: single center study. J Urol
2019;201:358–63.
57.8 ± 124.6 mm3; p = 0.017). The implication is that leaving
more stones behind increases the risk of a postoperative Roger L. Sur *
event. Moreover, the suggestion by Panthier et al that the
volumetric stone-free rate (V-SFR) is a better measure of Department of Urology, University of California-San Diego, San Diego, CA, USA
stone surgery success than SFR is a paradigm shift that I E-mail address: [email protected] (R.L. Sur).
wholeheartedly agree with. SFR is a binary outcome (yes
vs no), while V-SFR is a continuous outcome, and continu- August 20, 2024

*
Department of Urology, University of California-San Diego, San Diego, CA, USA.

https://doi.org/10.1016/j.eururo.2024.08.039
0302-2838/[pdftagstart acctype=Ó 2024 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including
those for text and data mining, AI training, and similar technologies.
e20
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