Alicia Morgans, MD, MPH, and Michael Schweizer, MD, discuss the phase 3 MEVPRO-1 and MEVPRO-2 trials of mevrometostat plus enzalutamide in mCRPC.
Mevrometostat (PF-06821497), which leverages EZH2 inhibition to improve the efficacy of androgen pathway receptor inhibitors (ARPIs) such as enzalutamide (Xtandi), has shown promising results in an early-phase study for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), leading to the initiation of 2 phase 3 trials: MEVPRO-1 (NCT06551324) and MEVPRO-2 (NCT06629779).1,2
“[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 toward dedifferentiated, neuroendocrine lineages,” Michael Schweizer, MD, said in an interview with OncLive. “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.”
Schweizer is 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 Hutchinson Cancer Center in Seattle, Washington. He is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.
During the 2025 American Society of Clinical Oncology (ASCO)
“Mevrometostat is typically used in combination with an ARPI like enzalutamide for a couple of different reasons,” Alicia Morgans, MD, MPH, explained in an interview with OncLive. “EZH2 is thought to be a mediator of lineage plasticity, and when it's [inhibited] in combination with an ARPI, [it] helps to limit the shift of prostate cancer cells that are trying to become resistant [and] prevents them from developing those neuroendocrine differentiation pathways that allow them to become resistant to an ARPI.”
Morgans is a genitourinary medical oncologist and director of the Survivorship Program at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.
Findings from the phase 1 trial revealed that the median rPFS in the combination arm (n = 41) was 14.3 months (95% CI, 7.5-not estimable [NE]) compared with 6.2 months (95% CI, 4.1-13.9) in the monotherapy arm (n = 40; HR, 0.51; 90% CI, 0.28-0.95). Additionally, the confirmed rate of patients who experienced at least a 50% reduction in prostate-specific antigen levels (PSA50) was 34.1% (95% CI, 20.1%-50.6%) in the combination arm. The confirmed PSA50 rate in the monotherapy arm was 15.4% (95% CI, 6.0%-31.3%).
“We presented results from a randomized expansion cohort that evaluated the efficacy of mevrometostat in combination with enzalutamide compared with enzalutamide alone in patients who had previously received abiraterone acetate [Zytiga],” Schweizer explained. “There was a fairly long duration of [rPFS] for patients who received the combination compared with enzalutamide that equated to a decrease of almost 50% risk for [disease] progression. This initial signal paved the way for the 2 phase 3 studies that are being launched.”
In terms of safety, any-grade treatment-emergent adverse effects (TEAEs) were reported at a rate of 97.6% in the combination arm. Patients also experienced treatment-related TEAEs (95.1%), serious adverse effects (SAEs; 34.1%), treatment-related serious TEAEs (24.4%), TEAEs leading to dose reduction (36.6%), and TEAEs leading to study discontinuation (2.4%). Comparatively, in the monotherapy arm, any-grade TEAEs, treatment-related TEAEs, SAEs, treatment-related serious TEAEs, TEAEs leading to dose reduction, and TEAEs leading to study discontinuation occurred at respective rates of 92.5%, 82.5%, 27.5%, 2.5%, 7.5%, and 5.0%.
Additional data from this phase 1 study, presented during the 2026 ASCO
Findings from the presentation revealed that patients in part 2A achieved a median rPFS of 14.3 months (95% CI, 2.0-NE), an objective response rate (ORR) of 25.0% (95% CI, 0.6%-80.6%), and a PSA50 rate of 40.0% (95% CI, 16.3%-67.7%) with mevrometostat at the 875 mg twice-daily dose. In part 2C, these respective values were NE (95% CI, 4.3-NE), 16.7% (95% CI, 0.4%-64.1%), and 42.9% (95% CI, 17.7%-71.1%).
In the total safety-evaluable population, comprising patients in both part 2A and 2B, (n = 29), any-grade TEAEs (41.4%), TEAEs related to mevrometostat (31.0%), serious TEAEs (27.6%), serious TEAEs related to mevrometostat (13.8%), and TEAEs leading to mevrometostat discontinuation (10.3%) were reported. The most common any-grade TEAEs included diarrhea (44.8%) and thrombocytopenia (44.8%).
“A key thing to know is that the initial adverse effect profile that we reported was using mevrometostat on an empty stomach, and the dosing strategy for the phase 3 trials is giving [it] with food,” Schweizer said. “This was based on some additional data that showed that when mevrometostat was given with food at a lower dose, [we saw] essentially the same pharmacokinetic exposure with a lower overall frequency of AEs. By giving [mevrometostat with] food, you can achieve a similar drug exposure with lower doses and a better safety profile.”
MEVPRO-1 is a randomized, open-label, multicenter trial that will examine mevrometostat in combination with enzalutamide compared with physician’s choice of second-line AR-directed therapy in patients with mCRPC following disease progression on abiraterone acetate (Figure 1).3 Patients are also required to have an ECOG performance status of 0 to 2 and a life expectancy of at least 6 months per investigator assessment to be eligible for the study.
Eligible patients will be randomly assigned to receive mevrometostat at 875 mg twice daily plus enzalutamide at 160 mg daily, or to the active comparator arm. In the active comparator arm, patients will receive physician’s choice of enzalutamide at 160 mg daily or intravenous docetaxel at 75 mg/m2 every 21 days.
The primary end point is rPFS per blinded independent central review per RECIST 1.1 and Prostate Cancer Clinical Trials Working Group 3 criteria. Secondary end points include overall survival (OS), ORR, duration of response (DOR) in measurable soft tissue disease, time to PSA progression, time to initiation of antineoplastic therapy, PSA response, safety, time to first symptomatic skeletal event, and quality of life (QOL) measures.
The global, multicenter, randomized MEVPRO-2 study is examining mevrometostat plus enzalutamide in patients with mCRPC who have not received systemic anticancer therapies after diagnosis except for androgen deprivation therapy and first-generation antiandrogen agents (Figure 2).4 Patients are required to have an ECOG performance status of 0 or 1, a life expectancy of at least 12 months, and progressive disease in the setting of medical or surgical castration.
Eligible patients will be randomly assigned 1:1 to receive mevrometostat at 875 mg twice daily or placebo, both in combination with enzalutamide at 160 mg daily.
The primary end point is rPFS. Secondary end points include OS, time to pain progression, ORR, DOR in measurable soft tissue disease, time to PSA progression, PSA response, time to initiation of antineoplastic therapy, time to first symptomatic skeletal event, PFS on next line of therapy, safety, tumor burden per circulating tumor DNA, pharmacokinetic measures, QOL measures, and safety.
“Everyone who treats [patients] with prostate cancer is excited to see the phase 3 MEVPRO-1 and MEVPRO-2 trials finish their data collection, and we are very excited to see what the ultimate outcomes [will be] for these studies,” Morgans said. “EZH2 inhibition in prostate cancer would give us another mechanism of attack against mCRPC.”
