Background: Metastatic CRPC remains a leading cause of cancer-related deaths worldwide. Although abiraterone + prednisone (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. Onvansertib is an oral and highly-selective PLK1 inhibitor that demonstrated safety and tolerability in a Phase 1 trial. Preclinical studies showed that PLK1 inhibition enhanced abi efficacy 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 in combination with 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. Patients with prior treatment with enzalutamide or apalutamide are excluded. 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). The 3 arms have completed their safety-lead phases and expansion phases are ongoing. 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 determine whether enrichment for gene expression signatures, such as the abi-onv synergy signature identified in preclinical models, could be used to predict clinical response. Clinical trial information: NCT03414034