Background: 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 a Phase 1b/2 study to explore the safety and efficacy of two regimens of CPI-1205 in combination with either E or A/P. Key eligibility criteria include progressive mCRPC in patients previously treated with a second generation androgen inhibitor, ECOG 0-1 and measurable or non- measurable disease. Key exclusion criteria include > 1 second generation androgen inhibitor. During the phase 1b, sequentially enrolled cohorts will receive CPI-1205 at continuous – 28-day cycles combined with either standard dose of E (160mg PO once daily) or A/P (1000mg PO once daily/ 5 mg BID). The primary objective is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of each regimen. Secondary objectives include safety, pharmacokinetic, pharmacodynamics profiles and activity (PSA, circulating tumor cells, imaging) in mCRPC. Once RP2D is established, we will start a Phase 2 trial of a 2^nd generation androgen inhibitor combined with CPI-1205.