Choosing a surrogate.

Top Line: Are PSA-based treatment outcomes a surrogate for overall survival in men receiving salvage treatment for prostate cancer?

The Study: The SPPORT trial was recently reported, and the addition of both 6 months of ADT and elective pelvic lymph node radiation to salvage post-prostatectomy radiation improved the primary endpoint of freedom from progression at 5 years (87.4% v 70.9%). The problem is that some experts question whether a PSA endpoint is the ideal endpoint when the randomized treatment suppresses PSA. In other words, does this positive PSA-based outcome translate to a positive survival outcome? Metastasis-free survival has been validated as a strong surrogate endpoint for men with localized prostate cancer, but it is not clear if that applies to the salvage treatment setting. This study used outcomes from RTOG 9601 to determine if the intermediate endpoints of biochemical failure (BF), distant metastasis (DM), and metastasis-free survival (MFS) were surrogates for overall survival (OS). As a reminder, 9601 showed that the addition of 2 years of bicalutamide to salvage radiation improved overall survival at 12 years. This study used three definitions of biochemical failure: nadir plus 0.3-0.5 (used in RTOG 9601), nadir plus 2.0         `    Z(the Phoenix definition, used in SPPORT), and the AUA definition (0.2) There was a strong correlation between MFS and OS, a moderate correlation between DM and OS, and a weak correlation between both BF definitions. Of note, the Phoenix definition (nadir+2) showed a stronger correlation with survival than the lower failure definitions. With respect to ADT, only the treatment effect on MFS was correlated with OS, not the effects on BF or DM. Do you recall if MFS was improved in SPPORT? While ADT and pelvic lymph node radiation reduced the rate of distant metastasis, a post-hoc analysis found no significant reduction in MFS (at least a 5 years). So, how should we apply the initial PSA-based outcomes of SPPORT? Should we wait for long-term survival outcomes? Such questions are even more complex in a new era where patients are re-staged with molecular imaging.

TBL: Metastasis-free survival (but not biochemical failure) is a strong surrogate for overall survival for men receiving salvage treatment for prostate cancer. | Jackson, J Clin Oncol 2022