PROJECT SUMMARY Despite the advancement of risk stratification tools on disease management for men with prostate cancer (PCa), there is still a paucity of prognostic tools aimed at identifying African American men (AAM) at increased risk for lethal prostate cancer in the setting of radiation therapy (RT) and androgen deprivation hormone therapy (ADT). Prognostic biomarker panels, such as Decipher, which have been developed and validated in surgical cohorts, have not been systematically validated for prognostic performance after RT+ADT. Furthermore, the cohorts used to derive and validate these prognostic tools have been, on the whole, made up of European-descendent patients. This has limited the prognostic ability in patients of African-descent, who have been shown to have worse prostate cancer-specific outcomes based on clinicopathologic factors including prostate-specific antigen (PSA), Gleason score, and tumor stage. Prognostic tools have not been developed with a racial equity lens, and the role of race and ancestry have only been an afterthought in the treatment recommendation guidelines resulting from Eurocentrically derived clinical studies. As of yet, race has remained on the sidelines without contributing in a clinically meaningful way to the identification, prognosis, treatment recommendations, and cost- effectiveness analysis for men of African-descent. This has limited our ability to identify non-white men at increased risk for lethal PCa, making treatment intensification less precise, limiting the effectiveness of more intense treatment interventions, and contributing to the widening of existing disparities. To address the lack of routine use of molecular biomarkers for therapeutic decision making in men with high-risk PCa, treated with definitive RT, the parent grant proposes to “develop and validate clinically useful and cost-effective prognostic and predictive biomarkers for high-risk PCa patients treated with RT.” This supplement seeks to expand the parent grant, by utilizing principles of health equity, to extend the reach of the findings beyond the traditional Eurocentric population, and in doing so improve the generalizability of the R01 findings to include AAM. This will be accomplished by: (1) comparing the clinical performance of the best prognostic signature and subsequent best prognostic tool, derived from integration of the genomic and clinicopathologic data, from parent grant Aim 1, between AAM and White men (WM) with PCa treated with RT, and (2) determine whether biomarker-based assignment to short-term ADT (STADT) vs. long-term ADT (LTADT) vs. LTADT+intensification, is cost-effective in AAM compared to WM with high-risk PCa, from parent grant Aim 3. Successful completion of this supplement will expand the findings of the parent R01 grant to focus specifically at AAM. Extending the reach of the findings beyond the traditional Eurocentric population.