Although intermediate clinical endpoints (ICEs) may expedite completion of randomized controlled trials (RCTs) evaluating perioperative systemic treatments for localized muscle-invasive bladder cancer (MIBC), no validated surrogate for overall survival (OS) has been established. We aimed to assess the surrogacy of pathologic complete response (pCR), pathologic objective response (pOR), and disease-free survival (DFS) for OS.
We analyzed 4,828 patients with MIBC (cT2-T4N0M0) who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) across 29 European centers (2001-2024). The inverse probability of treatment weighting (IPTW) approach was used to adjust for confounding between NAC and RC-only groups. Surrogacy was evaluated using: (1) adapted Prentice criteria to test whether each ICE remained a significant predictor of OS while the treatment effect disappeared in IPTW-adjusted multivariable Cox models; (2) the proportion of treatment effect explained (PTE); and (3) an emulated 2-stage meta-analytic framework to estimate the pseudo-trial-level R2 between treatment effects on each ICE and OS across 1,000 replicates of 5 random clusters. The surrogate threshold effect (STE) was calculated for ICEs demonstrating strong surrogacy (R2≥0.7).
Overall, 1,288 (26.7%) patients received NAC followed by RC and 3,540 (73.3%) underwent RC alone. In IPTW-adjusted Cox regression analyses including NAC and each ICE separately, pCR (hazard ratio [HR], 0.32; 95% CI, 0.24-0.41; P<.001), pOR (HR, 0.26; 95% CI, 0.21-0.31; P<.001), and DFS (HR, 5.17; 95% CI, 4.56-5.86; P<.001) were independent predictors of OS. The PTE was 0.42 (95% CI, 0.22-0.54), 0.48 (95% CI, 0.24-0.58), and 0.84 (95% CI, 0.66-0.96) for pCR, pOR, and DFS, respectively. At the pseudo-trial level, the R2 was 0.22 (95% CI, 0.20-0.25), 0.33 (95% CI, 0.31-0.36), and 0.83 (95% CI, 0.81-0.84) for the correlation between treatment effects on pCR, pOR, and DFS and OS, respectively. The STE was 0.82 (95% CI, 0.81-0.84) for DFS.
We observed uncertainty regarding the surrogacy of pCR and pOR in patients undergoing RC with or without NAC for localized MIBC. Only DFS consistently mediated the treatment effect on OS, supporting its use as a surrogate for RCT dimensioning when a recurrence or death risk reduction of ≥18% is expected.
Journal of the National Comprehensive Cancer Network : JNCCN. 2026 Jun 16 [Epub ahead of print]
Pietro Scilipoti, Mario de Angelis, Constance Thibault, Aleksander Ślusarczyk, Francesco Del Giudice, Roberto Contieri, Rodolfo Hurle, José Daniel Subiela, Giuseppe Simone, Flavia Proietti, Keiichiro Mori, Shahrokh Shariat, David D'Andrea, Stefania Zamboni, Nazareno Suardi, Hajime Tanaka, Shunya Matsumoto, Yasuhisa Fujii, Riccardo Bertolo, Alessandro Antonelli, Elliott Diamant, Dimitri Vordos, Pierre-Etienne Gabriel, Théo Harber, Marc Colombel, Paul Hanquiez, Vera Chatain, Igor Duquesne, Mihnea Bogdan Borz, Gregory Verhoest, Anne Mauger De Varennes, Louis Surlemont, Marion Ghenassia, Alexandra Masson-Lecomte, Arthur Peyrottes, Cédric Lebacle, Peter Beniac, Priscilla Léon, Stéphane Larré, Fayek Taha, Gautier Marcq, Aleksandra Szostek, Benjamin Pradere, Giorgio Calleris, François Audenet, Evanguelos Xylinas, Yves Allory, Anne-Sophie Bajeot, Doriane Prost, Elisabeth Grobet-Jeandin, Francesco Montorsi, Andrea Necchi, Alberto Briganti, Marco Moschini, Mathieu Roumiguié, Morgan Rouprêt, Thomas Seisen
1Department of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy., 4Department of Medical Oncology, Hopital Européen Georges Pompidou, APHP Centre, Institut du Cancer Paris CARPEM, Paris, France., 5Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland., 6Department of Maternal Infant and Urologic Sciences, "Sapienza" University of Rome, Policlinico Umberto I Hospital, Rome, Italy., 7Department of Urology, Humanitas Clinical and Research Institute IRCCS, Rozzano, Italy., 8Departament of Urology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de Alcala, Madrid, Spain., 9Department of Urology, "Regina Elena" National Cancer Institute, IRCCS, Rome, Italy., 10Department of Urology, The Jikei University School of Medicine, Tokyo, Japan., 11Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., 15Department of Urology, Spedali Civili of Brescia, Brescia, Italy., 16Institute of Science Tokyo, Tokyo, Japan., 17Department of Urology, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy., 18Department of Urology, Henri Mondor Hospital, University of Paris Est Créteil, Créteil, France., 3GRC 5 Predictive Onco-Uro Group, Department of Urology, Pitie-Salpetriere Hospital, AP-HP, Sorbonne University, Paris, France Paris, France., 19Department of Urology, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France., 20Department of Urology, Lyon Sud Hospital, Lyon, France., 21Department of Urology, Cochin Hospital, APHP, Université Paris Cité, Paris, France., 22Department of Urology, University Hospital of Rennes, Rennes, France., 23Department of Urology, Rouen University Hospital, Rouen, France., 24Department of Urology, Saint Louis Hospital, APHP, Université Paris Cité, Paris, France., 25Department of Urology, University Hospital of Bicêtre-Paris Sud-Saclay University, Le Kremlin Bicêtre, Paris, France., 26Department of Urology, Clinique Pasteur, Royan, France., 27Department of Urology, Reims University Hospital, Reims, France., 28Department of Urology, Claude Huriez Hospital, Lille, France., 29Department of Urology, La Croix Du Sud Hospital, Quint-Fonsegrives, Toulouse, France., 30Department of Urology, Hôpital Européen Georges Pompidou, APHP, Université Paris Cité, Paris, France., 31Department of Urology, Bichat-Claude Bernard Hospital, APHP, Université Paris Cité, Paris, France., 32UMR 144 CNRS, Institut Curie, Paris, France., 33Department of Urology, Toulouse University Hospital, University of Toulouse Ut3, Toulouse, France., 34Department of Urology, Paris Saint-Joseph Hospital, Paris, France., 35Division of Urology, Geneva University Hospitals, Geneva, Switzerland., 36Department of Urology, Clinique Pasteur Toulouse, Toulouse, France.