According to results from a dose-expansion study, the addition of mevrometostat, a selective and potent EZH2 inhibitor, to enzalutamide improved outcomes compared to enzalutamide alone among patients with metastatic castration-resistant prostate cancer (mCRPC). 

These results were presented by Michael Schweizer, MD, Fred Hutchinson Cancer Center, Seattle, Washington, at the 2025 ASCO Genitourinary Cancers Symposium in San Francisco, California.

In this open-label study, 81 patients with mCRPC who experienced disease progression on or after abiraterone and ≤ 1 prior line of chemotherapy were randomized on a 1-to-1 basis to receive either 1250 mg of mevrometostat twice daily without food plus 160 mg of enzalutamide once daily (n = 41) or enzalutamide alone (n = 40). Randomization was stratified by prior chemotherapy administration. Primary end points included investigator-assessed radiographic progression-free survival (rPFS) and safety. Key secondary end points included objective response among patients with measurable disease at baseline (mevrometostat, n = 15; enzalutamide, n = 14) and PSA50. 

At a median follow-up of 9.6 months, the median rPFS was 14.3 months in the mevrometostat plus enzalutamide arm and 6.2 months in the enzalutamide arm. The OR rate was 26.7% in the mevrometostat plus enzalutamide arm and 14.3% in the enzalutamide arm. Confirmed PSA50 was observed in 34.1% and 15.4% of patients, respectively. 

The most common treatment-emergent adverse events reported in the mevrometostat plus enzalutamide arm included diarrhea (78%), decreased appetite (58.5%), and dysgeusia (58.5%). The most common treatment-emergent adverse events reported in the enzalutamide arm included asthenic conditions (42.5%), nausea (25%), and anemia (22.5%). Grade ≥3 treatment-emergent adverse events occurred in 53.7% of patients in the mevrometostat plus enzalutamide arm (most frequently including diarrhea, neutropenia, and sepsis) and 42.5% of patients in the enzalutamide arm. No treatment-related deaths were reported. 

Mevrometostat plus enzalutamide “shows improved outcomes vs [enzalutamide] in pts with mCRPC, with a manageable AE profile,” concluded Dr Schweizer et al. “Further investigation of [mevrometostat plus enzalutamide] in pts with mCRPC is warranted.”

Source: 

Schweizer MT, Calvo M, Moreno V, et al. 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. Presented at the 2025 ASCO Genitourinary Cancers Symposium. San Francisco, California. February 13-15, 2025. Abstract LBA138