OBJECTIVES: Development of targeted and novel therapies in oncology necessitates identification of surrogate endpoints. Determining patient benefit in the absence of death or other complications is vital in drug development and patient care. Radiographic progression-free survival (rPFS) is used as a co-primary endpoint among men with metastatic castration-resistant prostate cancer (mCRPC) in randomized clinical trials (RCT). Overall survival (OS) is accepted as the gold standard clinical endpoint, but it requires long follow-up. Results of the current analysis will provide evidence on the relationship between rPFS and OS which can be used to extrapolate long-term OS for mCRPC subjects, especially in case OS is not mature at the time of HTA submission

METHODS: Proportional hazards (P-H) assumption was examined by the Schoenfeld residual test. Normality assumption was tested by the Shapiro-Wilk test. Spearman correlation, Daniels and Hughes (D&H) fixed effects meta-analysis, bivariate random effects meta-analysis (BRMA), and BRMA Product Normal Formulation (PNF) methods were used to demonstrate the association between rPFS and OS.

RESULTS: A systematic literature review of articles published on mCRPC trials from 2012 to 2022 yielded 109 studies. Further examination of available Kaplan-Meier curves and hazard ratios for OS and PFS provided 22 RCTs with requisite information for surrogacy analysis. Baseline characteristics of patient population in various studies have sufficient overlap. P-H assumption was followed by almost all the included studies. Normality assumption was not valid for OS. Unweighted Spearman correlation rho=0.62 and weighted Spearman correlation rho =0.65 were obtained for association between rPFS and OS, while standard BRMA and BRMA PNF yielded similar estimates of rho=0.69, showing medium correlation among the endpoints assessed.

CONCLUSIONS: The current study demonstrates significant association and medium correlation between rPFS and OS, among mCRPC patients. Hence, in instances where OS is immature, rPFS could potentially be used as a moderate level predictor for OS.