Event-free survival and complete response rate as surrogate endpoints for overall survival in high-risk non-muscle-invasive bladder cancer: A meta-analysis of bacillus Calmette-Guérin-naive or -remote cases.

Abstract

Event-free survival (EFS) and complete response rate (CRR) are recommended as primary endpoints in bladder cancer trials to enable timely assessment of therapeutic benefit. However, their surrogacy relationship with overall survival (OS) in high-risk non-muscle-invasive bladder cancer (HR NMIBC) remains unclear. This meta-analysis evaluated EFS and CRR as surrogate endpoints for OS in bacillus Calmette-Guérin (BCG)-naive or -remote HR NMIBC. A systematic literature review identified trials enrolling BCG-naive or -remote HR NMIBC patients and reporting EFS, CRR, and OS. Weighted linear regression models estimated trial-level associations between the hazard ratio (HR) for EFS and HR for OS, odds ratio for CRR and HR for OS, and arm-level association between median EFS and median OS. Strength of association was quantified using the correlation coefficient (R) and coefficient of determination (R²). Sensitivity analyses evaluated consistency across EFS definitions, publication year, and BCG treatment history. Ten eligible trials were identified for surrogacy analyses of EFS and CRR. Strong correlations were observed between EFS and OS at the trial level (R = 0.85; R² = 0.72) and arm level (R = 0.90; R² = 0.82). Trial-level associations between CRR and OS were weaker (R² = 0.36 for 3-month CRR; R² = 0.30 for 6-month CRR). Sensitivity analyses confirmed robustness of the primary results. In BCG-naive or -remote HR NMIBC, EFS shows strong correlation with OS at the trial and arm levels, supporting its potential as a surrogate endpoint. Further validation incorporating additional trials across varied therapeutic modalities is warranted.