Background: Radium-223, an α-emitting radioisotope inducing DNA double-stranded breaks leading to cell death has demonstrated improvement in overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors prevent the repair of DNA single-stranded breaks and have demonstrated clinical efficacy as monotherapy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway and in combination with androgen receptor signaling inhibitors irrespective of DNA repair mutation status. In preclinical models, PARP inhibitors have shown efficacy as radio sensitizing agents. We designed a phase 1/2 trial to identify the recommended phase 2 dose (RPD2) of olaparib and radium-223 and test the hypothesis that radium-223 + olaparib will demonstrate anti-tumor activity in mCRPC irrespective of homologous recombination repair deficiency (HRD) status (NCT03317392). Methods: This open-label, multicenter, phase 1/2 study evaluates the dosing, safety and efficacy of olaparib with radium-223 in men with mCRPC with bone metastases. The phase 1 component used a 3+3 dose escalation design to determine the olaparib recommended phase 2 dose (RP2D) + fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). The phase 1 portion has completed accrual (n = 12) and demonstrated that the RP2D of olaparib is 200 mg by mouth twice daily when combined with standard dose radium-223. The phase 2 component of the study which was activated in 1/2021 is an open-label, randomized trial (1:1) evaluating olaparib + radium-223 compared to radium-223 alone. The inclusion criteria include patients with mCRPC with any number of prior therapy lines for mCRPC and ≥2 bone metastases by imaging and at least 1 lesion which has not been treated with prior radiation. Patients with visceral metastases or malignant lymphadenopathy ( > 4 cm in short diameter) are excluded. The primary endpoint for phase 2 is radiographic progression-free survival (rPFS) per PCWG3 guidelines for bone metastases and RECIST v1.1 for non-bone disease. The integrated biomarker is Oncopanel assay to determine HRR status. A key secondary endpoint will evaluate rPFS in biomarker positive and negative patients. Other secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, and OS. Exploratory endpoints include WES/WTS of baseline biopsy tissue, assessment of RAD51 IHC and correlation with outcomes, ctDNA assessment and correlation with responses, evaluation of changes in the tumor immune microenvironment, and quality of life assessment. Target accrual is 133 patients. Clinical trial information: NCT03317392.