 Prostate cancer PCa is the most common cancer among men in the U.S. One important strategy to address this public health concern is to prevent the disease. Two large randomized clinical trials, The Prostate Cancer Prevention Trial PCPT and The Reduction by Dutasteride of Prostate Cancer Events REDUCE, have demonstrated a 23-25 reduction in PCa risk with the use of 5 alpha reductase inhibitors 5ARIs: finasteride and dutasteride. However, 5ARIs have not been widely adopted due, in part, to poor cost-effectiveness. We hypothesize that targeted chemoprevention, based on 1 overall genetic risk family history FH and PCa risk-associated genetic variants, and 2 polymorphisms that interact with 5ARIs, may be more efficacious and cost-effective, and thus more likely to be employed by physicians and their patients. The effectiveness of this genomic-targeted approach needs to be systematically evaluated and compared to non-genomic approaches using evidence-based methods such as those recommended by the EGAPP Evaluation of Genomic Applications in Practice and Prevention working group. We have assembled a multidisciplinary research team to address an overarching question of whether a genomic-targeted approach improves outcomes related to chemoprevention of PCa using 5ARIs compared to a non-targeted approach. We will evaluate and compare the efficacy, perception, decision making, and cost-effectiveness of genomic and non-genomic approaches in two existing large randomized clinical trials REDUCE and PCPT, two new study populations of men at risk for PCa, and in a survey of physicians. The unique study design of REDUCE and PCPT, with end-of-study prostate biopsies, allows us to address two critical questions in this study: PSA detection-bias of PCa risk-associated SNPs and efficacy of genomic-targeted chemoprevention of PCa using 5ARIs. We have the following specific aims: 1 assess the clinical validity of PCa risk prediction models using a panel of non PSA detection biased PCa risk-associated SNPs. 2 identify and assess the clinical validity of novel polymorphisms that interact with 5ARIs in reducing PCa diagnosis using both genome-wide and candidate gene approaches, 3 assess the clinical utility of a genomic-targeted approach by comparing its reduction in rates of PCa with non-targeted chemoprevention, 4 compare perception and decision making of physicians and patients for genomic and non-genomic-targeted chemoprevention of PCa, and 5 Compare the cost-effectiveness of genomic and non-genomic-targeted chemoprevention of PCa. Results from this study will provide comprehensive data for evidence-based evaluation by the Center for Disease Controls EGAPP working group, provide a proof of principle study of comparative effectiveness research CER, and will help build a road map for future genomic and personalized medicine GPM in the 21st century. 