Mevrometostat With Enzalutamide: Better Outcomes Compared With Enzalutamide Monotherapy for mCRPC

Zeste homolog 2 (EZH2) inhibitors can aid in the treatment of cancer by catalyzing the methylation of H3 histone of H3K27Me3, which inhibits the transcription of target genes including tumor suppressors. Mevrometostat, a potent and selective inhibitor of EZH2, has been analyzed in combination with enzalutamide and androgen deprivation therapy (ADT) in a previous study.

The combination demonstrated a manageable safety profile with evidence of EZH2 pharmacodynamic inhibition, objective response (OR), and decline in prostate-specific antigen of more than 50% from baseline (PSA₅₀) in patients with metastatic castration-resistant prostate cancer (mCRPC).

New outcomes from the open-label, randomized, dose-expansion portion of this study have recently been reported and have provided insight into the continued efficacy of this combination.

The study included patients with mCRPC who had previously received abiraterone, had no more than one prior chemotherapy treatment in any setting, and had evidence of progression based on modified Prostate Cancer Working Group 3 criteria.

Patients who received ADT were randomized 1:1 to receive mevrometostat 1250 mg orally twice daily in combination with enzalutamide 150 mg once daily or enzalutamide monotherapy stratified by prior chemotherapy. The primary end points of the study were radiographic progression-free survival (rPFS) and safety. Secondary end points included OR based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for patients with measurable disease at baseline, PSA₅₀, and pharmacokinetics.

A total of 81 patients were involved in the study as of September 2024. Mevrometostat with enzalutamide was administered to 41 patients, and 40 patients received enzalutamide alone. The median follow-up was 9.6 months.

Taxane therapy had been previously administered to 43.9% of patients in the mevrometostat plus enzalutamide arm and 45.0% of patients in the enzalutamide arm. The median rPFS was 14.3 months (95% CI, 7.5-not estimable) for mevrometostat plus enzalutamide and 6.2 months (95% CI, 4.1-13.9) for enzalutamide monotherapy (hazard ratio, 0.51; 90% CI, 0.28-0.95).

Measurable disease at baseline was found in 15 patients in the mevrometostat plus enzalutamide arm and in 14 patients in the enzalutamide monotherapy arm; the OR rate was 26.7% (95% CI, 7.8%-55.1%) with 4 partial responses and 14.3% with 2 partial responses, respectively.

Confirmed PSA₅₀ was seen in 34.1% (95% CI, 20.1%-50.6%) of patients in the mevrometostat plus enzalutamide arm and in 15.4% (95% CI, 6.0%-31.3%) of patients in the enzalutamide monotherapy arm. The most common treatment-emergent adverse events were diarrhea (78.0%), decreased appetite (58.5%), and dysgeusia (58.5%) in the mevrometostat plus enzalutamide arm and asthenic conditions (42.5%), nausea (25.0%), and anemia (22.5%) in the enzalutamide monotherapy arm.

Treatment-emergent events of grade 3 or higher were observed in 53.7% of patients in the mevrometostat plus enzalutamide arm (diarrhea, neutropenia, and sepsis) and in 42.5% of patients in the enzalutamide monotherapy arm. No treatment-related deaths occurred. In patients who received mevrometostat plus enzalutamide, mevrometostat 875 mg with food had an improved safety profile compared with mevrometostat 1250 mg on an empty stomach.

Mevrometostat in combination with enzalutamide was shown to improve outcomes over enzalutamide alone in patients with mCRPC and had a manageable adverse event profile, warranting further investigation into this treatment combination.