PROJECT SUMMARY/ABSTRACT Over the past 20 years, the SPORE in Prostate Cancer at Memorial Sloan Kettering Cancer Center has made significant advances in prostate cancer research and treatment, using the evolving mechanistic understanding of the drivers of tumor growth to improve patient management across the clinical spectrum of the disease. Applying a biomarker- based, risk-adapted approach, our work has led to the development of new diagnostic blood tests and prognostic models to distinguish indolent from clinically significant cancers, the discovery of new therapeutic targets, their validation in preclinical models, and the successful development of drugs directed to them in trials designed according to the recommendations of the Prostate Cancer Working Group 3. Our efforts have impacted clinical practice worldwide. The overall objectives of our SPORE are: 1) to interrogate the genomics and molecular pathways relevant to prostate cancer progression, 2) to identify and validate clinically relevant biomarkers, and 3) to develop novel agents and therapeutic strategies. In the next 5 years, we propose 3 research projects to address new clinical challenges that have emerged in the context of the evolving landscape of prostate cancer. For localized disease, the challenges are to identify patients at high risk for metastasis and death and to determine optimal upfront treatment to improve cure. To address this, RP-1 will determine germline and somatic genomic features associated with disease progression in high-risk localized disease and RP-2 will determine the role of signaling from the prostate microenvironment in resistance to androgen-deprivation therapy and determine the efficacy of targeting these signals. For patients with metastatic disease, the widespread adoption of potent next-generation androgen receptor (AR) signaling inhibitors has changed the landscape of prostate cancer, highlighting the need for therapeutic strategies for cancers that develop AR independence. Previously our SPORE characterized the AR-independent “lineage plasticity” disease state as driven by TP53 and RB1 loss. RP-3 now seeks to better define the genomic heterogeneity inherent in this disease state and evaluate novel therapeutic strategies. PARP inhibitors were recently approved for metastatic cancers with DNA damage repair mutations, but the response rate is only ~50%. RP-1 will define the genomic context that predicts for PARP inhibitor response.