PROJECT SUMMARY/ABSTRACT The frequency of germline (~12%) and somatic (~25%) alterations in BRCA2, ATM, and other DNA damage repair (DDR) genes in patients with castration-resistant prostate cancer (CRPC) has been described. DDR- altered PC has higher metastatic progression rates, and an attenuated response to androgen deprivation therapy (ADT). The frequency of DDR alterations in poor-risk non-castrate PC is approximately 10-15% (predominantly germline). We propose that exceptional responses or cure may be obtained with therapy targeted at further inhibition of the DDR pathway (PARP inhibition) together with ADT, radical prostatectomy (RP) and extended lymph node dissection (LND), and radiation to visible metastases. Our teams’ experience has demonstrated that aggressive, multimodality therapy in non-castrate, high-risk localized and oligometastatic PC can result in pathologic complete responses in the prostate, along with durable PSA remissions (undetectable PSA with non-castrate testosterone). Encouraged by this and the activity seen with olaparib in DDR-altered CRPC, Aim 1 of this project proposes a novel, flexible, randomized, multi-arm clinical trial platform (MetaCURE trial) to test the ability of targeted systemic therapy with a PARP inhibitor, together with ADT+abiraterone, RP and LND, and radiation to visible metastases, to eliminate PC in patients with and without DDR pathway alterations (as classified by alterations in single genes in the pathway). The protocol is supported by Janssen Pharmaceuticals and the trial opened Q2 2018. The novel structure allows new treatment arms to be added without writing a new protocol. Aims 2 and 3 are enabled by the MetaCURE platform’s prospectively embedded correlative science program in which tumor tissue samples (from diagnostic prostate biopsy, RP, lymph nodes, and metastatic sites) and blood samples for cell-free DNA analysis will be systematically collected before and after therapy. All patients will have paired tumor/germline sequencing using MSK-IMPACT to confirm the result of local tumor profiling and to assess for loss of heterozygosity of DDR pathway mutations. In-depth analyses with whole exome sequencing and RNA-Seq will be carried out on exceptional responders/nonresponders to identify potential biomarkers of response/resistance and in non-DDR altered tumors that respond, new genotypes that reflect DDR-altered status. Analysis of cell-free DNA in Aim 3 will complement Aim 2, by tracking levels of DDR alterations to assess for minimal residual disease and to identify potential mechanisms of drug resistance. The evaluation of actionable mutations associated with resistance to PARP inhibition and ADT, the evaluation of treatment effect on genomic mutation burden, and observations from other projects in this grant (Project 1 and Project 3) will inform the development of subsequent treatment cohorts in the MetaCURE trial.