Abstract African American (AA) men have a 1.5-fold higher incidence of prostate cancer (PCa) than non-Latino White (WH) men and are 2.5 times more likely to die from the disease. The biological determinants of aggressive PCa in AA men are still unclear and elucidating these remains a critical and unmet need in cancer health disparities research. Work by our groups and others demonstrates that somatic genomic alterations, transcriptomic signatures and immune tumor microenvironment (TME) components in PCa are significantly different in AA and WH men, suggesting that molecular biomarkers of lethal disease may be different in these two populations. Despite this progress, prognostic biomarkers developed specifically for AA PCa lack validation in independent datasets due to the relative scarcity of well-annotated AA PCa cohorts. Here, in collaborative research between Johns Hopkins University (JHU) and Howard University (HU), we will focus on genomic and epigenomic profiling of metastatic PCa in AA men for the purpose of molecular biomarker discovery. Novel and established in situ biomarker assays reflecting underlying tumor genomic and TME alterations will be tested in relation to PCa outcomes and racial ancestry. In Aim 1 we will establish a unique cohort of locally metastatic prostate cancer from AA men for genomic and epigenomic profiling to assess differences between primary and metastatic disease. In Aim 2 we will perform genomic and epigenomic profiling of distant metastatic disease in AA men to identify biomarkers of lethal disease. In Aim 3, we will validate in situ molecular biomarkers of tumor progression in the joint JHU-HU PCa tissue cohorts. The work in this proposal will identify biomarkers of aggressive PCa among AA patients so that we can begin to realize the promise of precision medicine in this population.