Using PSA progression to predict survival in clinical trials


Because it takes so long for men with even advanced prostate cancer to progress through to death from any cause, there has been extensive effort over the years to define “surrogate” endpoints for prostate cancer-specific and overall survival in prostate cancer clinical trials.

At this point in time, neither the US Food & Drug Administration (FDA) nor the European Medicines Agency (EMEA) accepts any surrogate endpoint for survival in prostate cancer trials, although they have accepted certain complex types endpoints as ways to assess time to disease progression. A surrogate endpoint for survival would be an endpoint that predicts the probability of such survival in one or more well-defined patient populations with a high degree of accuracy.

PSA progression is known to be a marker for actual disease progression in patients with both hormone-sensitive and castration-resistant prostate cancer (HSPC and CRPC). Hussain et al. have therefore reanalyzed data from two older trials to see if they can establish criteria for the appropriate use of PSA progression under specific circumstances as a surrogate endpoint for overall survival.

The authors were able to demonstrate that:

  • 1,078 patients with HSPC receiving hormone therapy in SWOG 9346 and 597 patients with CRPC receiving chemotherapy in SWOG 9916 were eligible for this analysis.
  • PSA Working Group and Prostate Cancer Working Group definitions of PSA progression were strongly associated with overall survival (P < 0.001) in both study settings.
  • In SWOG 9346, both definitions predicted a 2.4-fold increased risk of death and a greater than fourfold increased risk of death if PSA progression occurred in the first 7 months of treatment.
  • In SWOG 9916, both definitions predicted a 40 percent increase in risk of death and a twofold increase in risk of death if PSA progression occurred at 3 months.
  • Using the Prostate Cancer Working Group 2008 definition of PSA progression
    • In SWOG 9346, median subsequent overall survival was 10 months versus 44 months in patients who did or did not have PSA progression by 7 months, respectively.
    • In SWOG 9916, median subsequent overall survival was 11 months versus 18 months for patients who did or did not have PSA progression by 3 months, respectively.

Hussain and her colleagues have therefore proposed that PSA progression, when defined as an increase of ≥ 25 percent above the nadir PSA value and an absolute increase of at least 2 or 5 ng/ml, is predictive of overall survival in HSPC and CRPC and may be a suitable endpoint (initially) for phase II clinical trials. We assume that this will need to be validated prospectively in further studies in order to establish whether this endpoint might be acceptable to regulatory agencies. The use of this enpoint in pivotal Phase II trials leading to new drug approval may be more complex and require additional validation.

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