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Evaluating the Surrogacy of Pathological Complete Response at Radical Cystectomy in Neoadjuvant-based Muscle-invasive
Pietro Scilipoti1, Aleksander Ślusarczyk2, Constance Thibault3
1Department 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.
European Urology Oncology
|June 24, 2026
Summary
Pathological complete response (pCR) is not a validated surrogate for overall survival (OS) in muscle-invasive bladder cancer (MIBC) neoadjuvant trials. This study found pCR did not meet trial-level surrogacy criteria for OS, questioning its use in trial design.
Area of Science:
- Oncology
- Clinical Trials
- Biostatistics
Background:
- Overall survival (OS) is the gold standard for neoadjuvant trials in muscle-invasive bladder cancer (MIBC), but requires extensive follow-up.
- Pathological complete response (pCR) is a potential surrogate endpoint, but its validity at the trial level is uncertain.
Purpose of the Study:
- To evaluate if pathological complete response (pCR) can serve as a valid trial-level surrogate endpoint for overall survival (OS) in neoadjuvant trials for muscle-invasive bladder cancer (MIBC).
- To assess the strength of association between pCR rates and OS, and between treatment effects on pCR and OS.
Main Methods:
- Systematic review and meta-analysis of prospective nonrandomized and randomized controlled trials (RCTs) of neoadjuvant therapies for MIBC.
- Two-step trial-level surrogacy analysis assessing the association between pCR rates and landmark OS, and between treatment effects on pCR and OS.
- Kaplan-Meier curve analysis for survival reconstruction and inverse-variance-weighted linear regression.
Main Results:
- Twelve trials (3119 patients) were included. The association between pCR and 3-year OS was weak (R²=0.30), improving to moderate (R²=0.50) after excluding high-risk trials.
- In RCTs (2622 patients), the association between treatment effects on pCR and OS was poor (R²=0.06), improving to weak (R²=0.42) after excluding high-risk trials.
- Sensitivity analyses showed limited surrogacy performance for chemotherapy-only or immunotherapy-containing RCTs.
Conclusions:
- Pathological complete response (pCR) is prognostically informative but does not meet formal trial-level surrogacy criteria for overall survival (OS) in neoadjuvant MIBC trials.
- The findings do not support using pCR as a standalone surrogate endpoint for designing or powering registrational neoadjuvant-based MIBC trials.
- Further research may be needed to identify reliable surrogate endpoints that allow for shorter trial durations.