A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration resistant prostate cancer (mCRPC).

TPS398Background: EZH2 is frequently mutated and overexpressed in human cancer. High levels of expression are correlated with disease stage, aggressiveness, and poor outcome in patients with prostate cancer (Varambally, 2002). EZH2 inhibition restores androgen receptor expression and sensitivity to antiandrogen therapy in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as an approach to overcome resistance to antiandrogen therapy (Ku, 2017). CPI-1205 is a potent, selective and cofactor-competitive EZH2 inhibitor, that inhibits both wild-type and mutant EZH2 catalytic activity in a reversible manner. Preclinical studies have shown profound anti-proliferative effects of CPI-1205 in treating both lymphoma and prostate cancer cell models. Antitumor activity of EZH2 methyltransferase inhibitors has been observed in patients with non-Hodgkin’s lymphoma. These observations support the clinical evaluation of CPI-1205 with standard doses of A/P or E in mCRPC. Methods: We present...