Progression-free survival 2 (PFS2) as a surrogate endpoint for overall survival (OS) in breast cancer randomized controlled clinical trials

Background Overall survival (OS) is the gold-standard endpoint in oncology trials but often requires prolonged follow-up. Progression-free survival 2 (PFS2) has been proposed as an intermediate surrogate. While prior analyses report sufficient correlation of PFS2 with OS, no study has specifically evaluated its surrogacy in breast cancer. Materials and methods A systematic search of Medline, Web of Science, and Cochrane Library was conducted to identify randomized controlled trials (RCTs) in breast cancer reporting both PFS2 and OS. Trial-level associations between log-transformed hazard ratios for PFS2 and OS were examined using sample size-weighted linear regression. Surrogacy strength was quantified using the coefficient of determination ( R 2 ) and Pearson correlation coefficient ( r ) with 95% bootstrap confidence intervals (CIs). Results Eighteen RCTs including 9617 patients were analyzed. The correlation between PFS2 and OS was strong ( r = 0.714, 95% CI 0.204-0.893, R 2 = 0.509). Validation using long-term OS data showed a moderate but weaker correlation ( r = 0.552, 95% CI –0.12 to 0.897, R 2 = 0.305). Surrogacy was stronger in trials with PFS2 maturity ≥55% ( r = 0.93, R 2 = 0.864) versus