Dr Schweizer on the Background of the MEVPRO-1 and MEVPRO-2 Trials in mCRPC

“[Mevrometostat] was initially developed because there are a lot of data looking at mechanisms that mediate prostate cancer drug resistance and some of the factors that can push later-stage prostate cancers towards dedifferentiated, neuroendocrine lineages. This is a phenomenon that's been described as lineage plasticity, and it's becoming increasingly recognized as one of the drivers of aggressive late-stage prostate cancer biology. That's how the initial target, EZH2, was identified.”

Michael Schweizer, MD, a professor in the Clinical Research Division, an affiliate investigator in the Translational Science and Therapeutics Division, and a member of the Immunotherapy Integrated Research Center at Fred Hutch Cancer Center, discussed prior data with mevrometostat (PF-06821497) in metastatic castration-resistant prostate cancer (mCRPC) that led to the initiation of the phase 3 MEVPRO-1 (NCT06551324) and MEVPRO-2 (NCT06629779) trials.

Mevrometostat is a novel EZH2 inhibitor that has displayed preclinical efficacy in mCRPC, Schweizer said. EZH2 has been shown to play a role in mechanisms that mediate drug resistance in prostate cancer and push prostate cancer tumors towards differentiated, neuroendocrine lineages, he continued. “Lineage plasticity” has since been recognized as a driver of aggressive, late-stage prostate cancer biology and led to the exploration of EZH2 as a potential treatment target in the space, he added.

Findings from a phase 1 trial (NCT03460977) that were presented during the 2025 Genitourinary Cancers Symposium demonstrated that patients who received mevrometostat in combination with enzalutamide (Xtandi; n = 41) experienced a median radiographic progression-free survival of 14.3 months (95% CI, 7.5-not estimable [NE]) compared with 6.2 months (95% CI, 4.1-13.9) among those treated with enzalutamide monotherapy (n = 40), Schweizer said. These data translated to a 49% reduction in the risk of radiographic disease progression in favor of the investigational arm (HR, 0.51; 90% CI, 0.28-0.95), he noted. These data paved the way for mevrometostat plus enzalutamide to be evaluated in MEVPRO-1 and MEVPRO-2.