Prostate Cancer Chemoprevention Targeting High Risk Populations: Model for Trial Design and Outcome Measures.

Inspite of the large number of promising nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in high-risk cohorts are required to inform design of phase II clinical trials. Additionally, a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must be utilized to evaluate effectiveness in these trials. The goal of this paper is to provide a model, using a systematic approach for evaluating the safety, effectiveness and mechanism of action of a well characterized nutrient-derived agent-isoflavones - in a phase II clinical trial for prostate cancer (CaP) chemoprevention, targeting a population of African American (AA) and Caucasian men. Based on our previous observations, we hypothesize that the effects of isoflavones on prostate carcinogenesis are mainly mediated through the down regulation of androgen receptor (AR) and AR activity in AA men is higher due to its shorter length of Glutamine repeats in its N-terminus. We thus believe that isoflavones will exert a stronger protective effect for CaP in AA men and cause a higher activation of FOXO factors and their target genes. The aim of the study is to evaluate the comparative effectiveness of the study agent and placebo, in addition to a comparison of the effectiveness and safety in African American men compared to Caucasian men treated with this agent.