Abstract CT094: Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

Abstract Background: Increased expression and neomorphic mutations of the histone methyltransferase EZH2 are often observed in cancer, leading to repression of genes associated with apoptosis and differentiation. High EZH2 expression and low expression of EZH2 target genes in mCRPC correlate with poor prognosis. CPI-1205 is a potent, reversible, cofactor-competitive small molecule inhibitor of EZH2. Preclinical studies revealed that prostate cancer models dependent on androgen receptor signaling (ARS) are sensitive to EZH2 inhibition, and that CPI-1205, when combined with novel ARS inhibitors, results in synergistic cell growth inhibition (Bradley 2018). Here we report preliminary results from the Phase Ib component. Methods: In this multicenter Phase Ib/II study, patients (pts) with mCRPC previously treated with a novel ARS inhibitor were enrolled in different cohorts exploring two regimens of oral CPI-1205 on a continuous 28-day cycle: 800 mg TID or 400 mg BID with cobicistat, a CYP3A4 inhibitor, combined with the standard dose of E (160 mg QD) or standard dose of A/P (1000 mg QD/5 mg BID). Prior chemotherapy was allowed. The primary objective in Phase Ib is to determine safety, a recommended Phase II dose, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 11/16/2018, 35 pts were enrolled in four cohorts (two cohorts of CPI-1205 + E; two cohorts of CPI-1205 + A/P) and were treated for ≥1 cycle. Age ranged from 55 to 90 years (median 72). 63% were ECOG 0 and 37% ECOG 1. 13 pts (37%) tested positive for ARV7. 21 pts (60%) had unfavorable circulating tumor cells (CTC) counts at baseline. 6 pts (17%) had prior taxane-based chemotherapy for mCRPC. 16 pts received CPI-1205 + E and 19 pts received CPI-1205 + A/P. Only 1 DLT (asymptomatic reversible ALT increase, Grade 4) was reported in the CPI-1205 + A/P + cobicistat. No serious AE related to the study drug was reported in any cohort. Overall, the commonly reported drug-related treatment-emergent adverse events (TEAEs ≥10%) were low-grade diarrhea (n= 11, 31%), fatigue and nausea (n= 9, 26% each), and decreased appetite (n=5, 14%). Grade ≥3 TEAEs were fatigue and elevated ALT (n=2, 6% each), and nausea, pruritus, hypokalemia, and muscular weakness (n=1, 3% each). 16 pts remain on treatment. Cases of PSA >80% reduction, CTC ≥30% reduction, and RECIST response were observed. Both CPI-1205 regimens resulted in significant target engagement (reduced H3K27me3 in PBMCs and CTCs). Patient sample analysis to maximize biomarker identification is ongoing. PK data will be presented. Conclusions: Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing Citation Format: Mary-Ellen Taplin, Arif Hussain, Satish Shah, Neal D. Shore, William Jeffery Edenfield, Oliver A. Sartor, Luke T. Nordquist, Manish Agrawal, William Clark, David R. Wise, William K. Oh, Mark T. Fleming, James E. Butrynski, Gurkamal S. Chatta, Manojkumar Bupathi, Claudia Lebedinsky, Adrian Senderowicz, Jian Li, Gozde Colak, David Nash, Patrick Trojer, William D. Bradley, Jessica Piel, Emmanuel S. Antonarakis. Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) 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 CT094.