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

Area of Science:

• Urology
• Oncology
• Clinical Trials

Background:

• Intermediate clinical endpoints (ICEs) can accelerate randomized controlled trials (RCTs) for localized muscle-invasive bladder cancer (MIBC).
• No validated surrogate for overall survival (OS) has been established for perioperative systemic treatments in MIBC.
• This study evaluates pathologic complete response (pCR), pathologic objective response (pOR), and disease-free survival (DFS) as potential surrogates for OS.

Purpose of the Study:

• To assess the surrogacy of pCR, pOR, and DFS for OS in localized MIBC patients undergoing radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC).
• To determine if ICEs can reliably predict treatment effects on OS, potentially shortening trial durations.

Main Methods:

• Analysis of 4,828 MIBC patients from 29 European centers (2001-2024) undergoing RC with or without NAC.
• Utilized inverse probability of treatment weighting (IPTW) to adjust for confounding factors.
• Evaluated surrogacy using adapted Prentice criteria, proportion of treatment effect explained (PTE), and an emulated 2-stage meta-analytic framework (R2).

Main Results:

• pCR, pOR, and DFS were independent predictors of OS in IPTW-adjusted Cox models.
• PTE values were 0.42 for pCR, 0.48 for pOR, and 0.84 for DFS.
• Pseudo-trial level R2 values were 0.22 for pCR, 0.33 for pOR, and 0.83 for DFS, with DFS demonstrating strong surrogacy (STE=0.82).

Conclusions:

• Uncertainty exists regarding the surrogacy of pCR and pOR for OS in localized MIBC patients treated with RC +/- NAC.
• DFS consistently mediated the treatment effect on OS, supporting its use as a surrogate endpoint.
• DFS can be used for RCT sample size calculations when an 18% reduction in recurrence or death risk is anticipated.