Progression-free Survival is Not a Valid Surrogate Endpoint for Overall Survival in First-Line Advanced Ovarian Cancer Treatment

The findings of a recent JAMA Network Open study indicate that overall survival (OS) is the preferred end point in trials of first-line treatment or maintenance treatment for advanced ovarian cancer, and progression-free survival (PFS) must be supported by additional end points if used as the primary end point.

“The Gynecologic Cancer InterGroup (GCIG) recommended that (PFS) can serve as a primary end point instead of (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types,” the researchers wrote in their abstract.

In this study, researchers performed a thorough search of publications in MEDLINE in September 2016. They searched for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. Eligibility criteria included studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available. They measured correlations between PFS and OS at the individual level using the Kendall τ model and assessed the association between-treatment effects on PFS and OS at the trial level using the Plackett copula bivariate (R2) model. The primary outcome was defined as overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. The researchers performed data from January 7 through March 20, 2019.

Overall, the study included 17 unique randomized trials with data from 11,029 unique patients, and the results showed a high correlation between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717 to 0.732), but a low association at the trial level (R2 = 0.24; 95% CI, 0-0.59). A subsequent subgroup analyses showed similar results. Overall, in the the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS.

“Progression-free survival cannot be validated as a strict surrogate of OS for assessing treatment effects in randomized clinical trials of first-line treatments of advanced ovarian cancers. Our findings support the GCIG Fifth Ovarian Cancer Consensus Conference statement that OS is the preferred primary end point for first-line clinical trials with or without a maintenance component, but we recognize the practical challenges and the potential for confounding factors such as crossover and long post-progression survival,” the researchers wrote in their conclusion.

They added that: “Progression-free survival is an alternative primary end point, but given that we have not been able to validate it as a surrogate of OS, following the US Food and Drug Administration and European Medicines Agency guidances, it should represent a favorable risk-benefit association with a large magnitude of the effect or it should contribute to delaying administration of more toxic therapies as second-line treatments; therefore, if PFS is chosen, OS must be measured as a secondary end point and PFS must be supported by additional end points, such as predefined patient-reported outcomes, especially for maintenance therapy.”