Background: PARP1 is a multi-functional enzyme implicated in DNA repair and transcription factor regulation. It regulates AR association with chromatin required for transcription, and in preclinical models, PARP1 inhibition delays castration-resistance. Germline and acquired defects of homologous DNA repair predict for sensitivity to PARP1-inhibitors in CRPC, and long-term responses have been observed. Enzalutamide is an AR antagonist that prolongs survival in metastatic CRPC. Goal: Combined targeting of AR by enzalutamide and the PARP-inhibitor niraparib may lead to synergistic benefit in CRPC. This study aims to assess the feasibility of this combination. Methods: Eligible participants must have progressive metastatic CRPC and ECOG PS 0-1. Prior docetaxel, Ra-223, or Sipileucel-T are permitted, but previous enzalutamide or other next-generation AR antagonists are not. A limited number of participants are allowed prior abiraterone. The study features a modular Phase I design beginning with a 4 week lead-in of standard dose enzalutamide 160mg daily. Participants who tolerate enzalutamide without dose-limiting toxicity (DLT) during lead-in then proceed to combination with niraparib. Up to 3 cohorts of 6 patients are planned with niraparib doses of 100 (dose level 0), 200 (+1), and 300 mg (+2). Dose escalation is permitted if the DLT rate during the first cycle (4 weeks) of combination therapy is < 33%. The primary objective is to determine the maximum tolerated dose of the combination. Secondary objectives include PSA kinetics, objective response, progression free survival, description of toxicity, and quality of life. Exploratory biomarker studies will be conducted to correlate with outcomes. Circulating tumor cells (CTCs) and plasma will be archived at baseline, post- enzalutamide, post-combination therapy with niraparib, and progression (Epic Sciences). Assays include CTC quantitation and morphology, nuclear AR expression, AR N:C terminal ratio to assess AR splice variants, and pilot studies assessing homologous repair deficiency phenotype. Enrollment opened February 2016. Clinical trial information: NCT02500901