OBJECTIVES: To assess the statistical validity of using progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in metastatic breast cancer (mBC) patients receiving 1st, 2nd and beyond 2nd line chemotherapy, alone or in combination with targeted therapies. METHODS: A systematic literature search of randomized controlled trials of mBC evaluating anthracyclines, taxanes and targeted therapies reported between January 1, 1990 and August 1, 2015 was performed. Non-parametric Spearman Rank Correlation Coefficient and Weighted Fixed Effects Regression Analysis were used to test the strength of the association between hazard ratios for PFS (HR_PFS) and OS (HR_OS) as well as ΔPFS and ΔOS. RESULTS: Seventy-two RCTs providing 84 comparative arms met the inclusion criteria. The Spearman Rank correlation coefficient suggested a modest association between HR_OS and HR_PFS (Spearman’s rho = 0.46; p < 0.001) as well as ΔPFS and ΔOS (Spearman’s rho = 0.52; p < 0.001). The weighted multivariable regression modelling indicated that HR_PFS was a significant predictor of HR_OS (model coefficient = 0.18, p = 0.04). However, only 31% (i.e. model R) of the variability between the PFS-OS association was accounted for. When trials were limited to ≥ 2^nd line setting, the strength of the association improved (α = 0.40, p < 0.001) and R increased to 55%. However, the HR_PFS - HR_OS association was no longer significant when only 1^stline trials were considered (α = 0.90). CONCLUSIONS: Improvements in PFS are correlated with increased OS. However, the effect appears to be driven by trials in the ≥ 2^nd line setting. Therefore, PFS can be a suitable surrogate for OS in mBC trials evaluating new treatments in the 2^nd setting and beyond. However, the findings do not support the use of PFS alone as a primary endpoint of trials evaluating new drugs in the 1^st line setting.