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Is prostate-specific antigen progression a surrogate for objective clinical progression in early prostate cancer?

4652 Background: It is a common misconception that a correlation between endpoints is enough to demonstrate surrogacy. To show true surrogacy, the effect of an intervention on an intermediate endpoint relative to a control treatment needs to reliably predict the effect of the intervention on the clinical outcome of interest. Valid surrogate endpoints are needed to accelerate availability of information about new therapies for early prostate cancer where clinical progression and survival times are prolonged. The usefulness of prostate-specific antigen (PSA) progression as a surrogate for objective clinical progression has therefore been assessed in the bicalutamide ('Casodex') Early Prostate Cancer (EPC) Program, the world's largest prostate cancer treatment program.


METHODS
Individual data from all 8113 patients across 21 countries in the EPC Program were examined. Time to PSA progression and time to objective clinical progression were the endpoints evaluated. The effect of treatment on time to PSA progression was compared with the effect of treatment on time to objective clinical progression.


RESULTS
Analyses suggest that time to PSA progression is a modest surrogate endpoint for the effect of a hormonal intervention on objectively confirmed progression in patients with early prostate cancer (r2 = 0.52-0.65, p<0.001). An intervention that produces around a 50% reduction in the risk of PSA progression would likely result in around a 20% reduction in the risk of objective clinical progression.


CONCLUSIONS
The effect of treatment on PSA progression is moderately predictive for the effect of hormonal treatment on objective clinical progression. A large effect on PSA progression predicts for a smaller, but nonetheless clinically important effect on objective clinical progression. These data suggest that a large positive treatment effect on time to PSA progression is reasonably likely to reflect a clinically important delay in objective clinical progression, making PSA progression a valid endpoint for the evaluation of hormonal medicines in early prostate cancer. 'Casodex' is a trademark of the AstraZeneca group of companies. [Table: see text].