Background: Metastatic CRPC remains a leading cause of cancer-related deaths worldwide. Although abiraterone (abi) in either the castration-sensitive or castration-resistant setting increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic functions and progression, and it is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts via several mechanisms. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In phase 1 testing, onvansertib demonstrated a manageable safety profile, with transient and reversible hematologic effects. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients will be enrolled at time of PSA progression while on standard abi. A safety lead-in phase has been completed at one dosing schedule (24 mg/m² on days 1-5 of a 21-day cycle) and is ongoing at a second dosing schedule (18 mg/m² on days 1-5 of a 14-day cycle). Expansion phases are ongoing on both arms. In addition, a more continuous dosing schedule has been proposed (12 mg/m² on days 1-14 of a 21-day cycle). With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if <2 of the first 13 patients achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) and other genomic alterations in circulating tumor cells and circulating tumor DNA that may be associated with response to treatment. Clinical trial information: NCT03414034