Surrogacy of Intermediate Clinical Endpoints for Overall Survival in Patients With Localized Muscle-Invasive Bladder Cancer

BACKGROUND: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

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Journal
Journal of the National Comprehensive Cancer Network
Published
2026-06-16
DOI
https://doi.org/10.6004/jnccn.2026.7014
Primary Topic
Bladder and Urothelial Cancer Treatments
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article
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article

Surrogacy of Intermediate Clinical Endpoints for Overall Survival in Patients With Localized Muscle-Invasive Bladder Cancer

P. Hanquiez, Peter Beniač, Marc COLOMBEL, Igor Duquesne et al.
Journal of the National Comprehensive Cancer Network
Bladder and Urothelial Cancer Treatments
article

Surrogacy of Intermediate Clinical Endpoints for Overall Survival in Patients With Localized Muscle-Invasive Bladder Cancer

P. Hanquiez, Peter Beniač, Marc COLOMBEL, Igor Duquesne, Pietro Scilipoti, S. Larré, Marion Ghenassia, Elliott Diamant, Flavia Proietti, Arthur Peyrottes, Shunya Matsumoto, Giorgio Calleris, Mihnea Bogdan Borz, Francesco Montorsi, Mario de Angelis, Doriane Prost, Alessandro Antonelli, Dimitri Vordos, Marco Moschini, Stefania Zamboni, Aleksandra Szostek, Louis Surlemont, A. Bajeot, V. Chatain, Cedric Lebacle, Nazareno Suardi, Théo Harber, Yasuhisa Fujii, Elisabeth Grobet-Jeandin, Riccardo Bertolo, Keiichiro Mori, Yves Allory, Hajime Tanaka, Evanguelos Xylinas, Alexandra Masson-Lecomte, José Daniel Subiela, Benjamin Pradere, Morgan Rouprêt, Thomas Seisen, Pierre-Etienne Gabriel, Andrea Necchi, Mathieu Roumiguié, Alberto Briganti, Giuseppe Simone, Rodolfo Hurle, David D’Andrea, Francesco del Giudice, Gautier Marcq, Shahrokh Shariat, Constance Thibault, François Audenet, Aleksander Ślusarczyk, Anne Mauger De Varennes, Roberto Contieri, Fayek Taha, Gregory Verhoest, Priscilla Léon
article en

Abstract

BACKGROUND: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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
Université Claude Bernard Lyon 1 (FR), Jikei University School of Medicine (JP), Centre National de la Recherche Scientifique (FR), Humanitas University (IT), Vita-Salute San Raffaele University (IT), Université Fédérale de Toulouse Midi-Pyrénées (FR), Universidad de Alcalá (ES), Université Paris-Est Créteil (FR), Université Paris Cité (FR), Cornell University (US), Charles University (CZ), Medical University of Warsaw (PL), Policlinico Umberto I (IT), Paris-Est Sup (FR), Saint Louis University Hospital (US), Sorbonne Université (FR), Sorbonne Paris Cité (FR), Comprehensive Cancer Center Vienna (AT), Hôpital Cochin (FR), Azienda Ospedaliera Universitaria Integrata Verona (IT), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), Hôpital Européen Georges-Pompidou (FR), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Centre Hospitalier Universitaire de Reims (FR), University Hospital of Geneva (CH), Hôpital Européen (FR), Hôpital Lyon Sud (FR), Pitié-Salpêtrière Hospital (FR), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Lyon Genou Centre Albert Trillat (FR), IRCCS Ospedale San Raffaele (IT), Hôpital Paris Saint-Joseph (FR), Clinique Pasteur (FR), Hôpital Saint-Louis (FR), Hôpital Bichat-Claude-Bernard (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hôpital Claude Huriez (FR), Centre Hospitalier Universitaire de Rennes (FR), Biologie cellulaire et Cancer (FR), Hospital Universitario Ramón y Cajal (ES), Bicêtre Hospital (FR), Onco-Urologie Prédictive (FR), Institute of Science Tokyo (JP), Université de Rouen Normandie (FR), Medical University of Vienna (AT), Institut Curie (FR), Sapienza University of Rome (IT), The University of Texas Southwestern Medical Center (US), Université de Reims Champagne-Ardenne (FR)
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Bladder and Urothelial Cancer Treatments
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