Progression-free survival as a surrogate endpoint for overall survival in antibody-drug conjugate trials for advanced breast cancer: a systematic review and meta-analysis

Abstract

Objective: To evaluate the validity of progression-free survival (PFS) as a surrogate endpoint for overall survival (OS)
in randomized controlled trials assessing antibody-drug conjugates in advanced breast cancer. Methods: A systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic reviews and MetaAnalyses (PRISMA) guidelines. Searches were conducted on PubMed, Embase, and Cochrane databases, including conference proceedings up to February 2024. Linear regression models weighted by trial size assessed trial-level correlation
between hazard ratios for PFS and OS. Surrogacy strength was classified based on the coefficient of determination (R²):
strong (≥0.7), moderate (0.5–0.69), or weak (<0.5). Results: Fifteen randomized controlled trials involving 7,360 patients
were included. Overall, a moderate correlation between PFS and OS was identified (R²=0.61; 95% confidence interval [CI]
0.29–0.94). Subgroup analyses revealed variability, with a notably weak correlation in human epidermal growth factor
receptor-type 2 (HER2)-positive breast cancer (R²=0.31; 95%CI 0.00–1.00). Trials with fewer participants (≤529) exhibited
stronger correlations (R²=0.74; 95%CI 0.35–1.00) compared to larger studies (>529 participants; R²=0.36; 95%CI 0.00–1.00).
The surrogate threshold effect for meaningful OS prediction was identified as a 25% reduction in the hazard ratio for PFS
across trials. Conclusion: PFS showed moderate surrogacy for OS in antibody-drug conjugate trials for advanced breast
cancer, with substantial variation across subgroups. Given the weak correlation in HER2-positive disease, reliance solely
on PFS might misrepresent true clinical benefit. OS should remain the primary endpoint in trials evaluating antibodydrug conjugate efficacy.