The MOMENT Trial: Mevrometostat Plus Enzalutamide in Post‑ARPI, Pre‑Abiraterone mCRPC

Mevrometostat is an oral EZH2 inhibitor being developed to overcome resistance to androgen‑receptor–targeted therapy in prostate cancer. In tumors, EZH2 helps switch off tumor‑suppressor genes and supports androgen‑independent growth and lineage plasticity, changes that are strongly linked to progression on drugs like enzalutamide. Adding an EZH2 inhibitor to continued AR blockade is meant to “re‑discipline” the epigenetic program so cancer cells stay dependent on androgen signaling instead of escaping it.

The MOMENT trial is a phase 2, open‑label, single‑arm study run by the Prostate Cancer Clinical Trials Consortium that takes this idea into a very specific, modern treatment niche. It enrolls about 60 men with metastatic castration‑resistant prostate cancer who have already received an AR pathway inhibitor (enzalutamide, darolutamide, or apalutamide) in the metastatic castration‑sensitive or non‑metastatic CRPC setting, have evidence of progression on that earlier ARPI, but have not progressed on abiraterone and have not received PARP or AKT inhibitors. All patients get mevrometostat 875 mg twice daily with food plus enzalutamide 160 mg once daily, continued until radiographic progression or unacceptable toxicity. The primary endpoint is radiographic progression‑free survival; key secondary endpoints include overall survival, PSA50 response, time to PSA progression, and safety.

What makes MOMENT different from the big phase 3 MEVPRO trials is exactly where it sits in the sequence. Other mevrometostat studies are testing the combination with enzalutamide in cleaner settings: first‑line ARPI‑naïve mCRPC, post‑abiraterone mCRPC, or metastatic castration‑sensitive disease. MOMENT instead targets the increasingly common real‑world scenario where a patient has already had an ARPI earlier (mCSPC or nmCRPC), then declares mCRPC, but has not yet “burned” abiraterone, PARP inhibitors, or AKT inhibitors. By excluding prior abiraterone progression and PARP/AKT use, the study keeps those standard options available later and asks a focused question: in this post‑early‑ARPI, pre‑abiraterone window, is it worth intensifying enzalutamide with an epigenetic agent to delay progression?

Clinical trial.