Mevrometostat (PF-06821497), 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.
Authors: Michael Thomas Schweizer, Mariona Calvo, Victor Moreno, Begoña Mellado, Daniel Castellano, Alexander I. Spira, Qiang Wei, Joan Carles, Benjamin Garmezy, Cheol Kwak, Iwona Lugowska, Konstantin Penkov, Neal D. Shore, Li Liu, Rajendar K. Mittapalli, Jessica Tougias, Claudia Andreu-Vieyra, Neelesh Soman, Teresa Alonso Gordoa
Journal: Journal of Clinical Oncology (2025)

LBA138 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 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 Sept 2, 2024,81 pts were included (M+E, n=41; E, n=40). Median (IQR) follow-up was 9.6 (3.1-14.5) mo. Median (range) age (yrs) 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 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 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 empty stomach. Further investigation of M+E in pts with mCRPC is warranted. Disclosure: Pfizer's generative AI tool, MAIA, was used to draft this abstract (accessed: 2024-10-24); authors reviewed, edited, and take full responsibility for the content. Clinical trial information: NCT03460977 .