Prostate-specific antigen kinetics as a surrogate endpoint in clinical trials of metastatic castration-resistant prostate cancer: a review.

Prostate cancer is the most common cancer in men. Overall survival is considered the best endpoint for clinical trials, but it is difficult to use in phase-2 studies. Although the reduction of PSA after cytotoxic chemotherapy has been identified as a valid surrogate for overall survival, it has not proven reliable for the evaluation of many biologics. Moreover, the PSA progression-free survival at 3 months was validated only for cytotoxic drugs, and the various measures of progression/delay have not been confirmed by large studies. Ultimately, outside of overall survival, no measure has been validated as a surrogate endpoint after treatment with targeted therapies and vaccine therapy. The PSA levels have a great variability and, theoretically, the use of measures of cell kinetics and PSA may be the most reliable approach to estimate the behavior of metastatic disease. Some measures of PSA kinetics have been well developed in the clinical castration-resistant prostate cancer, the PSA doubling time and the growth rate constant. The studies about the kinetics of PSA measures are reviewed and discussed. To date, studies that consider the measures of PSA kinetics as surrogate endpoints are still very few. However in the near future, the drug evaluation can not proceed separately, with distinct endpoints between cytotoxic and non-cytotoxic agents. Therefore, extensive analysis and validation of measures of kinetics derived from PSA, and candidates for a role for surrogate endpoint, will be needed in phase-3 studies, in order to test their effectiveness in different disease scenarios.