Relationship Between Progression-Free Survival and Overall Survival Benefit: A Simulation Study.

Unlabelled: This study evaluated the circumstances under which the observed progression-free survival (PFS) benefit may translate into an overall survival (OS) benefit.

Methods: A simulation study, based on PFS and OS joint model decomposition, was conducted to evaluate the impact of crossover rates, survival post progression (SPP) lengths, and magnitudes of difference in median PFS on OS. Under different simulation scenarios, the degree of impact was investigated based on the probability of observing a significant OS benefit given an observed PFS benefit.

Results: Using simulation parameters defined based on historical NDA datasets, the probability of detecting an OS benefit given the observed PFS benefit depends largely on crossover rate and SPP length (ie, SPP median times). Compared to no crossover, a crossover rate of ≤ 50% decreases the probability of detecting an OS benefit by at most 15% regardless of the SPP length. A crossover rate of > 50% decreases the probability of detecting an OS benefit much further, and the extent of decrease is proportional to the length of SPP.

Conclusion: Crossover rate and SPP length are important factors affecting the benefit translating from PFS to OS. This simulation study identified a threshold, of 50%, for crossover rate that is likely to confound OS effect. With a greater than 50% crossover rate, longer SPP further decreases the probability of translating a PFS benefit to OS.