ABSTRACT Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Although men with European ancestry (EA) still represent the largest population of PCa patients, men with African ancestry (AA) are disproportionately affected by PCa with higher prevalence and worse outcomes. Androgen receptor (AR), a ligand-dependent nuclear transcription factor, plays a pivotal role in PCa development, and there are well- established genetic differences in the AR gene and associated pathways between EA versus AA men. However, it remains unclear how these genetic differences alter AR interaction with associated proteins, and their potential role in PCa development and response to AR targeted therapies. In this study, we hypothesize that differences in AR signaling contribute to the biological differences between PCa in AA versus EA men, and that PCa in AA men may have distinct AR-dependencies and be vulnerable to therapies that combine AR-targeted therapies with other targeted agents. To test these hypotheses, Aim 1 will assess the effect of androgen stimulation on PCa cells from AA versus EA patients, and in isogenic cells reflecting the genetic difference of AR. Aim 2 will identify vulnerabilities generated in response to AR-targeted therapies in AA versus EA PCa models.