Background: Metastatic CRPC is a leading cause of cancer death worldwide. Although abiraterone (abi) + prednisone in either castration-sensitive or castration-resistant disease 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 function and is upregulated in prostate cancer following androgen-deprivation therapy (ADT). Onvansertib is an oral and highly-selective PLK1 inhibitor that demonstrated safety and tolerability as a single agent in a Ph1 trial. Preclinical studies showed that PLK1 inhibition enhanced abi anti-tumor effect in cell line models and in patient-derived tumor xenografts via an AR-independent mechanism. Transcriptomic analyses revealed that abi induced mitosis-related gene sets in cells synergistic for abi + onvansertib, and identified an abi-onvansertib synergy gene signature. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib + abi 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 are enrolled at time of PSA progression while on standard abi. Prior treatment with enzalutamide or apalutamide is not permitted. Three onvansertib dosing schedules are tested in noncomparative arms: arm A (24 mg/m² on days 1-5 of a 21-day cycle), arm B (18 mg/m² on days 1-5 of a 14-day cycle), and arm C (12 mg/m² on days 1-14 of a 21-day cycle). To-date, 24 patients were enrolled in Arm A, and 20 patients each in Arms B and C. 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 in each arm achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) in circulating tumor cells and targeted genomic profiling of circulating tumor DNA to assess associations between genomic alterations and response to treatment. Additionally, transcriptomic analysis of archived tumor tissue will be performed to identify gene expression signatures associated with clinical responses. Clinical trial information: NCT03414034.