Overall survival (OS) remains the gold standard end point in neoadjuvant trials for muscle-invasive bladder cancer (MIBC), yet its assessment requires prolonged follow-up. Whether pathological complete response (pCR) at radical cystectomy (RC) can serve as a valid trial-level surrogate remains unclear. To test this hypothesis, we conducted a systematic review and meta-analytic surrogacy analysis (PROSPERO CRD420251050357) of prospective nonrandomized trials and randomized controlled trials (RCTs) evaluating neoadjuvant therapies followed by RC in nonmetastatic MIBC (2003-2026). Eligible trials reported pCR and provided 3- and/or 4-yr OS via Kaplan-Meier curves, enabling survival reconstruction. Analyses followed an intention-to-treat approach. Surrogacy was evaluated using a two-step trial-level framework: (1) association between trial-arm pCR rates and landmark 3- or 4-yr OS using inverse-variance-weighted linear regression and (2) association between treatment effects log(1/Odds ratio (OR)) on pCR and log(hazard ratio [HR]) for OS, with the coefficient of determination (R2) quantifying surrogacy strength. Twelve trials (n = 3119 patients) met the eligibility criteria. In first-step analyses, the association between pCR and 3-yr OS across all trials was weak (R2 = 0.30, 95% confidence interval [CI] = 0-0.70) and improved to moderate after excluding trials at high risk of bias (R2 = 0.50, 95% CI = 0.20-0.80). In second-step analyses across eight RCTs (n = 2622), the association between treatment effects on pCR and OS was poor (R2 = 0.06, 95% CI = 0-0.84) and improved to weak after excluding high-risk trials (R2 = 0.42). Sensitivity analyses restricted to chemotherapy-only or immunotherapy-containing RCTs yielded similarly limited surrogacy performance. To conclude, although pCR remains prognostically informative, it did not meet formal trial-level surrogacy criteria for OS. These findings do not support the use of pCR as a stand-alone surrogate end point for designing or powering registrational neoadjuvant-based MIBC trials.
European urology oncology. 2026 Jun 25 [Epub ahead of print]
Pietro Scilipoti, Aleksander Ślusarczyk, Constance Thibault, Piotr Domański, Andrea Necchi, Francesco Montorsi, Alberto Briganti, Marco Moschini, Alexandra Masson-Lecomte, Ashish M Kamat, Evanguelos Xylinas, Benjamin Pradere, Shahrokh Shariat, Quoc-Dien Trinh, Alison Birtle, Enrique Grande, Joaquim Bellmunt, Yohann Loriot, Morgan Rouprêt, Thomas Seisen
Department of Experimental Oncology/Unit of Urology, Urological Research Institute (URI), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: ., Department of General, Oncological and Functional Urology, Medical University of Warsaw, Warsaw, Poland., Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CAncer Research for PErsonalized Medicine (CARPEM), Assistance publique-hôpitaux de Paris (AP-HP) Centre, Université de Paris Cité, Paris, France., Department of Experimental Oncology/Unit of Urology, Urological Research Institute (URI), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy., Department of Urology, St. Louis Hospital, Assistance publique-hôpitaux de Paris (AP-HP), Université de Paris, Paris, France., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Department of Urology, Bichat Claude-Bernard Hospital, Assistance publique-hôpitaux de Paris (AP-HP), University Paris Cité, Paris, France., Department of Urology, UROSUD, La Croix du Sud Hospital, Quint Fonsegrives, France., Comprehensive Cancer Center, Department of Urology, Medical University of Vienna, Vienna, Austria; Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan; Department of Urology, University of Texas Southwestern Medical Center, Dallas, USA; Department of Urology, Weill Cornell Medical College, New York, New York, USA., Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Lancashire Teaching Hospitals National Health Service (NHS) Foundation Trust, Preston, UK; University of Manchester, Manchester, UK., Department of Medical Oncology, Quironsalud Madrid, Madrid, Spain; Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Department de Médecine Oncologique & Institut national de la santéet de la recherche médicale (INSERM) U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France., Sorbonne University, Groupes de Recherche Clinique (GRC) 5 Predictive Onco-Uro, Assistance publique-hôpitaux de Paris (AP-HP), Urology, Pitié-Salpêtrière Hospital, Paris, France.