Safety profile and adverse event management with mevrometostat plus enzalutamide

Dr. Morgans asks Dr. Agarwal to describe adverse events observed with mevrometostat plus enzalutamide and how they are managed. Dr. Agarwal first contextualizes the available safety data: most reported toxicity comes from earlier studies that used a higher mevrometostat dose (1250 mg twice daily) under fasting conditions. The phase 3 trials use 875 mg twice daily with food, which improves tolerability while maintaining drug exposure, since food increases bioavailability.

The adverse event profile is predominantly gastrointestinal. In phase 1, the most common treatment-emergent adverse events (TEAEs) were diarrhea (40%), dysgeusia, and anemia (36%); anemia is a hallmark of castration-resistant prostate cancer and often present at baseline. In the randomized dose-expansion study, diarrhea occurred in 78% of patients, with decreased appetite and dysgeusia at 58%. Grade 3 or higher TEAEs occurred in approximately 53% of patients on the combination versus 42% on enzalutamide alone—roughly an 11% increase, driven largely by gastrointestinal events.

Dr. Agarwal stresses that dose modification is central to management. He starts patients at 875 mg twice daily with food and follows the protocol-defined dose reduction schedule when needed; side effects often improve with dose reduction in patients who are responding. He flags a class consideration: secondary myeloid malignancies—myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)—have been reported with another EZH2 inhibitor, tazemetostat, at 1.7% per the FDA label; no such signal has emerged with mevrometostat. He recommends monthly laboratory monitoring including liver enzymes and complete blood counts. Dr. Morgans reinforces that dose modifications help patients stay on treatment.

In the next episode, "Trial enrollment and referral pathways for community and rural clinicians," Dr. Agarwal outlines practical steps for identifying eligible patients and discussing trial participation.