Background: Despite multimodality txs such as surgery, radiotherapy, hormonal tx and chemo, metastatic CRPC (mCRPC) prognosis remains poor. Research suggests PARP-1 is a key regulator of androgen receptor (AR) signaling and transition to lethal CRPC. Nira is a safe, potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in CRPC, and Rad is an alpha particle emitter. Addition of PARP inhibition may further enhance the clinical benefit of Rad. Nira has a favorable safety profile however, data on safety, tolerability and efficacy of Nira plus radiotherapy is limited. We hypothesize that targeting the PARP-1/AR axis in combination with radiation is safe and will improve mCRPC management. Methods: This is a phase (ph) Ib dose finding study (NCT03076203) of pts with progressive mCRPC using Time-to-Event Continual Reassessment Method (TITE-CRM). The primary objective is to determine the optimum ph II dose of Nira plus Rad (55 kBq/kg of body weight) in pts with and without prior chemo. Secondary endpoints include PSA reduction at 12 weeks (wks) and radiographic progression-free survival at 6 months. Pts enrolled to one of three dose levels of Nira (100, 200, and 300 mg PO daily). After completing 6 cycles of Rad, pts continued on Nira alone until objective progression, tx intolerance or pt decision. TITE-CRM identifies the maximum tolerated dose (MTD) based on toxicities observed over 12 wks of tx. Results: Between Oct 2017 and Jan 2020, 30 pts were enrolled (15 per stratum). Median age was 70 years; ECOG performance status was 0. The MTD of Nira was 100 mg in the chemo-exposed arm and 200 mg in the chemo-naïve arm. 19 Grade ≥ 3 adverse events were possibly related to tx: lymphocyte count decrease (n = 4, 13%), neutrophil count decrease (n = 3, 10%), anemia (n = 3, 10%), hypertension (n = 3, 10%), platelet count decrease (n = 2, 7%), creatinine increase (n = 1, 3%), hydronephrosis (n = 1, 3%), nausea (n = 1, 3%), white blood cell count decrease (n = 1, 3%). Tx duration and PSA response are shown in the table. Conclusions: Nira plus Rad was determined to be safe and tolerable. The MTD of Nira was identified and is pending ph II investigation. Managed by: Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Scientific Affairs and Bayer Healthcare Pharmaceuticals, Inc Clinical trial information: NCT03076203.