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

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.

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 (R²) and Pearson correlation coefficient (r) with 95% bootstrap confidence intervals (CIs).

Eighteen RCTs including 9617 patients were analyzed. The correlation between PFS2 and OS was strong (r = 0.714, 95% CI 0.204-0.893, R² = 0.509). Validation using long-term OS data showed a moderate but weaker correlation (r = 0.552, 95% CI -0.12 to 0.897, R² = 0.305). Surrogacy was stronger in trials with PFS2 maturity ≥55% (r = 0.93, R² = 0.864) versus <55% (r = -0.652, R² = 0.425), and in those with OS information fraction ≥75% (r = 0.931, R² = 0.866) versus <75% (r = 0.625, R² = 0.391). Correlation was similar across OS maturity subgroups (<40%: r = 0.677, 40%-60%: r = 0.702).

PFS2 demonstrated a context-dependent association with OS, with stronger correlations observed only at higher levels of PFS2 maturity and OS information fraction.