Abstract CT161: A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

Abstract Background: mCRPC remains a leading cause of cancer-related deaths worldwide. Although abi increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. PLK1, a serine/threonine kinase, is a master regulator of cell-cycle progression and is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In Phase I testing, onvansertib demonstrated a manageable safety profile, with transient hematologic effects as its most prominent, yet reversible, toxicity. Methods: The goal of this Phase II 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 are enrolled at time of PSA progression while on standard abi and treated with onvansertib (24 mg/m2 orally on days 1-5 of a 21-day cycle) plus abi (administered orally and continuously once daily with prednisone) until time of radiographic or symptomatic progression. The safety lead-in of 3 subjects showed no dose-limiting toxicities or new toxicities from the combination of onvansertib with abi. A 29-patient expansion phase is ongoing, with 11 patients enrolled as of January 2019. With 32 patients, 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. Toxicity and PSA levels are monitored during treatment. Exploratory analyses include quantification of circulating tumor cells, evaluation of PLK1 inhibition in vivo and evaluation of predictive genomic biomarkers in circulating tumor DNA, such as alterations in oncogenes and tumor suppressors. Citation Format: David J. Einstein, Atish Choudhury, Philip Saylor, Lillian Werner, Mark Erlander, Maya Ridinger, Glenn Bubley. A Phase II study of the polo-like kinase (PLK1) inhibitor onvansertib in combination with abiraterone (abi) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT161.