Mevrometostat, an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): A randomized dose-expansion study.

e17029 Background: Mevrometostat (M) is a potent and selective inhibitor of EZH2. Dose exploration of M + enzalutamide (E) + androgen deprivation therapy (ADT) showed a manageable safety profile with evidence of EZH2 pharmacodynamic inhibition, objective response (OR), and decline in prostate-specific antigen of ≥50% from baseline (PSA 50 ) in patients (pts) with mCRPC (NCT03460977). We report outcomes from the open-label, randomized, dose expansion part of this study. Methods: Pts with mCRPC who received prior abiraterone, ≤1 prior chemotherapy in any setting, with evidence of progression per modified Prostate Cancer Working Group 3 criteria were included. Pts receiving ADT were randomized 1:1 to M (orally, 1250 mg BID on an empty stomach) + E (160 mg QD) or E, stratified by prior chemotherapy. Primary endpoints were radiographic progression-free survival (rPFS) per investigator assessment and safety. Secondary endpoints included OR by RECIST 1.1 (for pts with measurable disease at baseline), PSA 50 , and pharmacokinetics. Results: As of September 2, 2024, 81 pts were included (M + E, n=41; E, n=40). Median (IQR) follow-up was 9.6 (3.1-14.5) months (mo). Median (range) age (years) was 70 (48-86) for M + E and 71.5 (50-86) for E. Overall, 43.9% of pts in the M + E group and 45.0% in the E group received prior taxane therapy. Median (95% CI) rPFS was 14.3 (7.5, not estimable) mo for M + E and 6.2 (4.1, 13.9) mo for E (hazard ratio 0.51; 90% CI 0.28, 0.95). In pts with measurable disease at baseline (M + E, n=15; E, n=14), OR rate (95% CI) was 26.7% (7.8, 55.1) for M + E (4 partial responses [PRs]) and 14.3% (1.8, 42.8) for E (2 PRs). Confirmed PSA 50 (95% CI) was observed in 34.1% (20.1, 50.6) of pts for M + E and 15.4% (6.0, 31.3) for E. Most common treatment-emergent adverse events (TEAEs) were diarrhea (78.0%), decreased appetite (58.5%), and dysgeusia (58.5%) for M + E, and asthenic conditions (42.5%), nausea (25.0%), and anemia (22.5%) for E. Grade ≥3 TEAEs were observed in 53.7% of pts in M + E (most common diarrhea, neutropenia, and sepsis) and 42.5% in E. There were no treatment-related deaths. Geometric mean plasma exposures of M after multiple doses in combination with E were comparable for M 1250 mg on an empty stomach and M 875 mg with food (AUC tau [h*ng/mL]: 1250 mg, 8733; 875 mg, 9631; C max [ng/mL]: 1250 mg, 2371; 875 mg, 1868). In M + E combination, M 875 mg with food had an improved safety profile compared with M 1250 mg on an empty stomach. Conclusions: M + E shows improved outcomes vs E in pts with mCRPC, with a manageable AE profile. In M + E combination, M 875 mg with food has similar plasma exposure as M 1250 mg on an empty stomach. Further investigation of M + E in pts with mCRPC is warranted. Disclosure: A genAI tool (10/24/24; Pfizer; GPT-4) developed the 1st draft; authors assume content responsibility. Clinical trial information: NCT03460977 .