Treatment with mevrometostat (MEV), an enhancer of zeste homolog 2 inhibitor, in combination with enzalutamide (ENZ) results in better survival outcomes and response than ENZ alone among patients with metastatic castration-resistant prostate cancer (mCRPC), reports a study presented at ASCO GU 2025. The combined therapy also demonstrates a favourable safety profile.

In addition, among patients who received MEV plus ENZ, MEV 875 mg with food exhibits a comparable plasma exposure as MEV 1,250 mg on an empty stomach.

“MEV plus ENZ improved outcomes versus ENZ [alone] in patients with mCRPC, with a manageable adverse event (AE) profile,” said lead study author Dr Michael Thomas Schweizer from the Division of Medical Oncology, University of Washington; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, US.

Schweizer and his team identified mCRPC patients who received prior abiraterone, ≤1 prior chemotherapy in any setting, and had evidence of progression per modified Prostate Cancer Working Group 3 criteria. Those on androgen deprivation therapy (ADT) were randomized to receive MEV (orally, 1,250 mg BID on empty stomach) plus ENZ (160 mg QD) or ENZ alone, stratified by prior chemotherapy.

Radiographic progression-free survival (rPFS) per investigator assessment and safety served as the primary endpoint of this randomized dose-expansion study. Other endpoints included objective response (OR) by RECIST 1.1 (for patients with measurable disease at baseline), prostate-specific antigen of ≥50 percent from baseline (PSA50), and pharmacokinetics.

Improved outcomes

Eighty-one patients met the eligibility criteria, of whom 41 received MEV plus ENZ and 40 ENZ alone. The median age was 70 years for the MEV plus ENZ arm and 71.5 years for the ENZ alone arm. The median follow-up was 9.6 months. Overall, 43.9 percent and 45.0 percent of patients in the combination and monotherapy groups received prior taxane therapy, respectively. [ASCO GU 2025, abstract LBA138]

The primary endpoint was significantly higher in the MEV plus ENZ arm than the ENZ alone arm (median rPFS, 14.3 vs 6.2 months; hazard ratio, 0.51 90 percent confidence interval [CI], 0.28?0.95).

Among patients with measurable disease at baseline (n=15 with MEV plus ENZ; n=14 with ENZ alone), OR rate was 26.7 percent (95 percent CI, 7.8?55.1) for MEV plus ENZ (four partial responses) and 14.3 percent (95 percent CI, 1.8?42.8) for ENZ alone (two partial responses). Confirmed PSA50 was noted in 34.1 percent (95 percent CI, 20.1?50.6) and 15.4 percent (95 percent CI, 6.0?31.1) of patients, respectively.

Safety profile

Schweizer and colleagues observed several treatment-emergent AEs (TEAEs). The most common TEAEs were diarrhoea (78.0 percent), reduced appetite (58.5 percent), and dysgeusia (58.5 percent) in the combination arm and asthenic conditions (42.5 percent), nausea (25.0 percent), and anaemia (22.5 percent) in the monotherapy arm.

More than half of patients treated with MEV plus ENZ (eg, diarrhoea, neutropenia, and sepsis) and about one in four of those on ENZ alone had grade ≥3 TEAEs (53.7 percent vs 42.5 percent). No treatment-related deaths occurred during the study period.

Notably, the geometric mean plasma exposures of MEV following multiple doses combined with ENZ were similar between MEV 1,250 mg on an empty stomach and MEV 875 mg with food (AUCtau [h*ng/mL]: 1250 mg, 8,733; 875 mg, 9,631; Cmax [ng/mL]: 1250 mg, 2,371; 875 mg, 1,868]). However, MEV 875 with food showed a better safety profile versus MEV 1,250 without food.

“Further investigation of MEV plus ENZ in patients with mCRPC is warranted,” said Schweizer.