Validation of surrogate endpoint biomarkers in prostate cancer chemoprevention trials

Phase 2 cancer chemoprevention trials are designed to provide estimates of the efficacy of an agent at a specified dose, and the expected size of the risk reduction that may be achieved in a subsequent phase 3 randomized tria l. To allow these trials to be rapid and efficient, the study outcome is mo dulation of a surrogate endpoint biomarker (SEB), that is, a molecular even t assumed to be on the causal pathway between the chemopreventive agent and the desired reduction in cancer incidence. However, SEBs commonly used in prostate cancer chemoprevention studies, such as prostate-specific antigen, high grade prostatic intraepithelial neoplasia, proliferation, and apoptos is, have not been Validated by documenting that changes in the SEBs ultimat ely translate to decreased prostate cancer risk. Because of uncertainty in the pathway from SEBs to cancer, additional considerations are necessary to permit valid inferences from phase 2 trial data. This article considers th e framework underlying validation and use of SEBs in specific chemopreventi on models and methodologic issues in quantifying the effect of an agent. in particular, inferences depend on whether a single pathway involving the SE Bs is assumed to mediate the effect of the agent on cancer incidence. If th ere are competing pathways of equal or greater importance than the one invo lving the candidate SEE, then the estimate of chemopreventive efficacy will be biased and may greatly underestimate the magnitude of the achievable ri sk reduction. Strategies for validating biomarkers and minimizing the degre e of bias in the risk reduction estimate are discussed. Finally, problems a ssociated with phase 2 study designs commonly used for prostate cancer chem oprevention are discussed, along with possible solutions.