Mechanistic rationale for combining EZH2 inhibition with enzalutamide

Dr. Agarwal asks Dr. Morgans about the mechanistic rationale for combining EZH2 inhibitors—such as mevrometostat—with enzalutamide. Dr. Morgans explains that this combination is designed to deliver synergy that can overcome resistance to androgen receptor pathway inhibitors (ARPIs). By reversing lineage plasticity and restoring or maintaining sensitivity to AR-targeted therapy, EZH2 inhibition complements androgen receptor (AR) blockade. She reiterates that EZH2 works with AR to silence tumor suppressors in its canonical role and acts as a co-activator for non-canonical AR-independent gene expression that drives neuroendocrine differentiation when resistance develops.

Dr. Morgans cites preclinical data showing synergistic inhibition of proliferation and colony formation, along with induction of apoptosis, when EZH2 inhibitors are combined with enzalutamide. Because ARPIs are used so widely across the prostate cancer disease spectrum, preventing resistance is a clinically meaningful goal.

Dr. Agarwal then provides a concise summary for clinicians: EZH2 has three key functions in prostate cancer. First, it silences tumor suppressor genes by chromatin compaction. Second, it collaborates with AR by co-activating AR splice variants. Third, it propels prostate cancer toward neuroendocrine differentiation, a state largely independent of AR signaling. Dr. Morgans confirms that this is a clear, digestible framework for understanding EZH2 biology.

In the next episode, "Biomarker selection and the MEVPRO patient population," the experts address whether EZH2 testing is required for trial enrollment and how the MEVPRO trials compare with other EZH2 inhibitor studies.