Results from an open-label, randomized Phase 2 study (NCT03460977) show that combining the EZH2 inhibitor mevrometostat with enzalutamide and androgen deprivation therapy (ADT) significantly improves outcomes compared to enzalutamide alone.

Mevrometostat is a potent and selective inhibitor of EZH2. Earlier dose exploration had indicated that the combination of mevrometostat plus enzalutamide and ADT was generally safe and showed early signs of effectiveness, including effects on EZH2 activity, observable tumor shrinkage (objective response), and significant drops in PSA levels.
The latest report comes from the dose expansion portion of the study, which enrolled 81 patients with mCRPC who had previously used abiraterone and had received no more than one prior chemotherapy treatment. Patients were randomly assigned to receive either the combination therapy (mevrometostat 1250 mg twice daily on an empty stomach plus enzalutamide 160 mg daily) or enzalutamide 160 mg daily alone, while continuing ADT.
The central finding of the study focused on the primary endpoint: radiographic progression-free survival (rPFS), which measures how long patients live without their cancer growing or spreading as seen on scans. The results demonstrated a significant improvement for those receiving the combination therapy. The median rPFS was a notable 14.3  (7.5, not estimable) and 6.2 (4.1, 13.9) months for those receiving enzalutamide alone. This represents a statistically significant benefit, with a hazard ratio of 0.51.
Beyond the primary measure, the combination therapy also showed benefits in secondary endpoints. Among patients whose cancer could be measured at the start of the trial, the objective response rate was 26.7% with the combination, versus 14.3% with enzalutamide alone. Additionally, a confirmed decline of 50% or more in prostate-specific antigen (PSA50) was observed in a significantly higher proportion of patients in the combination group (34.1%) compared to the enzalutamide-alone group (15.4%).

Regarding safety, the mevrometostat and enzalutamide combination had a manageable adverse event profile. However, as is common with combination treatments, the occurrence of severe (Grade ≥3) treatment-emergent adverse events was higher in the combination arm (53.7%) compared to the enzalutamide-alone arm (42.5%).

In conclusion, the study authors determined that the combination of mevrometostat and enzalutamide improved outcomes for patients with mCRPC compared to enzalutamide alone, with a manageable side effect profile. Given these positive results, further investigation into this combination therapy for mCRPC patients is considered warranted.

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