Trial-level analysis of progression-free survival and response rate as end points of trials of first-line chemotherapy in advanced ovarian cancer.

Progression-free survival (PFS) has been reported as surrogate end point of overall survival (OS) in trials of advanced ovarian cancer (AOC). However, there is not a trial-level evaluation of surrogacy. The aim of this study is to perform an analysis of randomized trials enrolling patients with AOC receiving a first-line systemic chemotherapy, in order to evaluate the results of PFS, the other intermediate end points and their relationship with OS. A literature search of phase 3 randomized trials was performed by a predefined protocol. For each trial, the differences between arms of the results of OS and of other end points were calculated. These differences were compared by Spearman's rho coefficient to find out the potential correlation between every end point and OS. For the end points with the higher relationships with OS, the proportion of variability explained (R 2) was calculated by regression analysis. Thirty-eight studies have been included. PFS appears to be the end point more closely related to OS (R 2 = 0.506; p < 0.001), and this correlation is higher among studies published before 2003. ORR is correlated with OS only in the trials published after 2003 (R 2 = 0.344; p 0.027; 14 trials). In conclusion, in more recent trials ORR shows a level of correlation with OS similar to that of PFS. Though PFS should no longer be considered a surrogate end points of OS in trials of patients receiving a first-line chemotherapy for AOC, a prospective evaluation of new response-related end points is strongly recommended.