Phase 3 MEVPRO-1 and MEVPRO-2 Trials Set to Evaluate EZH2 Inhibition Plus Enzalutamide in mCRPC

After displaying early efficacy in a phase 1 trial (NCT03460977), the EZH2 inhibitor mevrometostat (PF-06821497) in combination with enzalutamide (Xtandi) will be examined in the phase 3 MEVPRO-1 (NCT06551324) and MEVPRO-2 (NCT06629779) trials for patients with metastatic castration-resistant prostate cancer (mCRPC), according to Joshua Lang, MD, MS.^1,2

Data from the phase 1 study showed that the median radiographic progression-free survival among patients who received mevrometostat plus enzalutamide (n = 41) was 14.3 months (95% CI, 7.5-not estimable) compared with 6.2 months (95% CI, 4.1-13.9) in the enzalutamide monotherapy arm (n = 40; HR, 0.51; 90% CI, 0.28-0.95).³ 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%).

“If a patient is progressing on an androgen receptor pathway inhibitor [ARPI], can we potentially come in and rescue that response with a combination that could be incredibly impactful for men fighting metastatic prostate cancer,” Lang said in an interview with OncLive®. “It also provides an opportunity to delay the initiation of chemotherapy. That's a clinically meaningful benefit, with the goal of improving survival and fighting metastatic prostate cancer.”

Lang is a faculty member in the Division of Hematology, Medical Oncology and Palliative Care in the Department of Medicine, the co-director of the internal medicine residency’s Physician-Scientist Training Program at the University of Wisconsin (UW) School of Medicine and Public Health in Madison. He is also the director of the UW Carbone Cancer Center’s circulating biomarker core and liquid biospecimen team, the co-leader of its tumor microenvironment program, and the clinical co-chair of its precision medicine molecular tumor board.

In the interview, Lang discussed how EZH2 inhibition with mevrometostat can be used to enhance the activity of ARPIs, prior data with mevrometostat in mCRPC, and the key design features of the MEVPRO-1 and MEVPRO-2 trials.

OncLive: What is EZH2 and how can agents like mevrometostat target it?

Lang: EZH2 has been identified as a potential therapeutic target and one that can be altered in the development of more aggressive prostate cancers. This includes not only the development of neuroendocrine prostate cancer but also treatment resistance, particularly to commonly used ARPIS such as abiraterone acetate [Zytiga], enzalutamide, darolutamide [Nubeqa], and apalutamide [Erleada].

As we’ve come to better understand EZH2 as an epigenetic modulator, we recognize that it appears to be active in a subset of patients and can drive more aggressive disease. This is not present in all patients, but in a significant portion, EZH2 activity plays a role. That has led to growing interest in therapeutically targeting this pathway. Mevrometostat has been evaluated in phase 1 trials and has shown early evidence of efficacy, including responses and durability of response in a subset of patients with metastatic castration-resistant prostate cancer. Ongoing studies like MEVPRO-1 and MEVPRO-2 are now evaluating whether this approach can better target patients with treatment-resistant or aggressive disease.

What is the clinical rationale for combining EZH2 inhibition with an ARPI?

Resistance to ARPIs can be driven by multiple mechanisms, including genomic alterations in the AR. However, we’ve also identified acquired epigenetic changes that can contribute to resistance, particularly in patients who transition to a neuroendocrine phenotype.

EZH2 plays a significant role in these epigenetic alterations, and mevrometostat has been developed to target and potentially reverse them. The hope is that this approach can resensitize patients to androgen receptor pathway inhibition. For patients who have progressed on first-line ARPIs in the hormone-sensitive setting, this may offer an opportunity to reintroduce a generally well-tolerated class of agents.

What were the notable safety data with mevrometostat that preceded these phase 3 trials?

Epigenetic therapies have been under development for many years, targeting different molecules and proteins, each with distinct toxicity profiles. Some earlier agents in this class were associated with significant toxicities. Mevrometostat appears to be better tolerated compared with prior epigenetic therapies.

That said, there are still notable adverse effects, including diarrhea, asthenia, taste changes, and anemia. These need to be monitored and managed proactively. Bone marrow suppression, including anemia and thrombocytopenia, can occur but is generally manageable with dose modifications.

With appropriate monitoring and supportive care, the goal is to maintain patients on a tolerable dose that allows for durable treatment over time.

What are the key design features of MEVPRO-1?

MEVPRO-1 is a global, open-label phase 3 trial evaluating mevrometostat in combination with enzalutamide in men with mCRPC who have progressed on prior abiraterone.

This study is addressing an important clinical question, as enzalutamide has limited efficacy in this setting, with response rates of approximately 5% and poor durability. MEVPRO-1 is evaluating whether the addition of mevrometostat can improve outcomes in this population, where patients would otherwise typically receive chemotherapy, prostate-specific maturation agent [PSMA]–targeted radioligand therapy, immunotherapy, or enroll in clinical trials.

How is MEVPRO-2 designed?

MEVPRO-2 is a global, randomized, double-blind phase 3 trial evaluating whether the addition of mevrometostat to standard enzalutamide improves outcomes in patients who have not previously received an ARPI.

The study is assessing whether this combination can delay treatment resistance, improve survival, and maintain quality of life, which is especially important when adding a novel agent to an otherwise well-tolerated therapy.

What role in the prostate cancer treatment landscape could mevrometostat potentially fill?

There remain significant unmet needs for men with metastatic prostate cancer, particularly as our most effective therapies, such as ARPIs, are now used earlier in the disease course in the metastatic hormone-sensitive setting.

When patients progress to metastatic castration-resistant disease, treatment options become more limited. Although we have approved therapies such as PSMA-targeted radioligand therapy, docetaxel, and cabazitaxel, there is still a need for additional strategies.

Mevrometostat has the potential to fill an important role by targeting epigenetic mechanisms of resistance and potentially resensitizing patients to existing therapies, offering another option in a setting where treatment choices are limited.

References

1. A study to learn about the investigational medicine called PF-06821497 (mevrometostat) in men with mCRPC who were previously treated with abiraterone acetate for prostate cancer (MEVPRO-1). (MEVPRO-1). ClinicalTrials.gov. Updated March 4, 2026. Accessed April 15, 2026. https://clinicaltrials.gov/study/NCT06551324
2. A study to learn how PF-06821497 (Mevrometostat) works in men with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated March 25, 2026. Accessed April 15, 2026. https://clinicaltrials.gov/study/NCT06629779
3. Schweizer MT, Calvo M, Moreno V, et al. Mevrometostat (PF-06821497), an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): a randomized dose-expansion study. J Clin Oncol. 2025;43(suppl 5):LBA138. doi:10.1200/JCO.2025.43.5_suppl.LBA138