To evaluate biochemical recurrence-free survival (BRFS) and metastasis-free survival (MFS) as potential intermediate clinical endpoints (ICEs) for overall survival (OS) in patients undergoing salvage radical prostatectomy (sRP).
Evaluable patients were selected from a retrospective dataset, resulting in a cohort of 879 patients with recurrent, non-metastatic, hormone-sensitive prostate cancer treated with sRP at 13 centres. ICE surrogacy was evaluated using a two-stage approach: (i) at the individual-patient level by fitting Clayton copula models and estimating Kendall's τ $$ \tau $$ ( τ $$ \tau $$ >0.7 indicating a strong association) and (ii) at the centre level, by fitting weighted linear regression of 5-year OS on 3-year BRFS and MFS.
The two-step analysis included 759 patients for BRFS (366 events) and 476 for MFS (137 events), with median follow-up of 37 months (95% confidence interval [CI] 36-42 months) and 34 months (95% CI 31-37 months), respectively. At the individual-patient level, MFS showed a strong association with OS (Kendall's τ $$ \tau $$ 0.85, 95% CI 0.82-0.88), which was not observed for BRFS (Kendall's τ $$ \tau $$ 0.63, 95% CI 0.56-0.69). At the centre level, neither 3-year BRFS (R2 = 0.15; slope = 0.34, P = 0.2) nor 3-year MFS (R2 = 0.21; slope = 0.26, P = 0.14) predicted 5-year OS with sufficient explanatory power. Limitations include the fact that centre-level analysis was based on single-arm associations rather than on treatment-effect surrogacy across arms, and retrospective data collection.
The BRFS should not be used as a surrogate endpoint in the sRP setting. MFS requires further validation in future prospective studies to confirm its association with OS. Patient-reported outcomes, such as quality-of-life and treatment-related toxicity, should be considered in parallel with OS.
BJU international. 2026 Jun 15 [Epub ahead of print]
Navid Roessler, Zuzanna Nowicka, Marcin Miszczyk, Giorgio Calleris, Alessandro Dematteis, Malte W Vetterlein, Simone Albisinni, Henk G Van Der Poel, Paul Cathcart, Giovanni E Cacciamani, Inderbir S Gill, Raj A Persad, Steven Joniau, Rafael Sanchez-Salas, Joseph A Smith, Robert Jeffrey Karnes, Mohamed E Ahmed, Pawel Rajwa, Derya Tilki, Shahrokh F Shariat, Paolo Gontero, Giancarlo Marra, Young Academic Urologists Prostate Cancer Working Party
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Department of Biostatistics and Translational Medicine, Medical University of Łódź, Łódź, Poland., Department of Urology, Città della Salute e della Scienza, University of Torino School of Medicine, Torino, Italy., Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Urology Department, University Clinics of Brussels, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium., Department of Urology, Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Department of Urology, Guy's & St Thomas' NHS Foundation Trust, London, UK., USC Institute of Urology and Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Department of Urology, Bristol Urological Institute, Bristol, UK., Department of Urology, University Hospitals, Leuven, Belgium., Department of Urology, Institut Mutualiste Montsouris, Paris, France., Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA., Department of Urology, Mayo Clinic, Rochester, Minnesota, USA.