Progression‐free survival: Does a correlation with survival justify its role as a surrogate clinical endpoint?

We thank Becker et al1 for their thoughtful editorial on our article2 describing progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in renal cancer clinical trials. We agree that our data do not necessarily support the use of PFS as a surrogate endpoint for OS across the entire renal cancer therapeutic spectrum.2 We further concur that additional work needs to be done to establish PFS as a pragmatic endpoint for regulatory purposes. However, we disagree with Becker et al that it is necessary to fulfill the Prentice criteria to establish surrogacy. More specifically, fulfilling Prentice's third criterion that the treatment effect on the surrogate (PFS) should capture the full effect of treatment on the clinical endpoint (OS) is an extremely high bar.3 Multiple authors have proposed and utilized different approaches to the validation of surrogate endpoints.4-8 Although a full discussion is beyond the scope of this correspondence, we would like to point out that one alternative approach is the adjusted association, θ.9 The adjusted association first estimates the dependency parameter within each treatment arm and then aggregates the information by a weighted average. As we demonstrated in our article,2 the adjusted association was a highly statistically significant measure that strongly suggests that PFS is a surrogate endpoint for OS, at least within the context of the trials analyzed. No specific funding was disclosed. The authors made no disclosures. Susan Halabi, PhD Department of Biostatistics and Bioinformatics Duke University; Alliance Statistical and Data Center Duke University Durham, North Carolina Brian I. Rini, MD Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio Bernard Escudier, MD Department of Cancer Medicine Institut Gustave Roussy Villejuif, France Walter M. Stadler, MD Department of Medicine University of Chicago Medical Center Chicago, Illinois Eric J. Small, MD Department of Urology University of California at San Francisco San Francisco, California