Evaluating the Surrogacy of Pathological Complete Response at Radical Cystectomy in Neoadjuvant-based Muscle-invasive Bladder Cancer Trials

: 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.