PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is notable for the expression and activity of a unique therapeutic target – the androgen receptor (AR). PC growth and survival is driven by AR, a nuclear transcription factor activated by androgens such as testosterone (T) and dihydrotestosterone (DHT). AR activity can be suppressed through ligand reduction in the form of androgen deprivation therapy (ADT). While ADT is initially effective in treating metastatic PC, disease progression, termed metastatic castration-resistant prostate cancer (mCRPC), inevitably occurs after several years. Additionally, long-term ADT is associated with significant mental and physical quality of life complications. Consequently, there has been a longstanding interest in the development of therapeutic modalities that can further exploit AR signaling to enhance treatment responses and also improve quality of life. In this proposal, our objective is to integrate and leverage two key aspects of PC biology: AR activity and DNA damage/repair. Integrating AR signaling and HDR has important treatment ramifications as a substantial body of preclinical and clinical work indicates that HDR deficiency (HDR-D) result in vulnerabilities to at least two drug classes: platinum (PLAT) chemotherapy and PARP inhibitors (PARPi) as well as radiation therapy. We propose three Specific Aims: Specific Aim 1. Conduct a Phase 2 clinical trial genotoxic therapeutics and supraphysiological androgen (SPA) in patients with mCRPC to determine response rates, identify resistance mechanisms, and establish biomarkers that associate with clinical responses. Specific Aim 2. Identify the mechanism(s) by which therapeutics overdriving AR activity induce DNA damage, regulate DNA repair processes, and enhance genotoxic chemotherapy. Specific Aim 3. Identify therapeutic drug combinations and dosing/administration strategies that optimize the therapeutic window resulting from AR expression and activity in mCRPC. The research plan is structured to drive bidirectional assessments of clinically-relevant mechanisms involving AR signaling and DNA repair in the context of treating advanced prostate cancer.