EZH2 Inhibitor Cuts Risk of Progression in Metastatic Prostate Cancer | MedPage Today

Unlocking the Secrets of Mevrometostat in mCRPC Treatment 

Michael Schweizer, MD, Fred Hutchinson Cancer Center, Seattle, WA, comments on findings from a Phase I study (NCT03460977) on mevrometostat, an EZH2 inhibitor, plus enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). Mevrometostat showed dose-dependent EZH2 inhibition, reducing key pharmacodynamic markers and altering tumor gene expression. Tumor suppressor genes were reactivated, while genes involved in tumor progression were suppressed. This interview took place at the ASCO GU Cancers Symposium 2025 in San Francisco, CA.
 
As a renowned oncology expert, Dr. Schweizer delves into the intricacies of biomarker translational studies, specifically focusing on mevrometostat and enzalutamide in treating metastatic castration-resistant prostate cancer (mCRPC). Their research has far-reaching implications for improving treatment outcomes
  • The study built upon the success of phase one trials combining mevrometostat with enzalutamide, revealing significant chromodynamic effects and the downregulation of target methylation marks on histones in peripheral blood monocytes. 
  • A subset of patients with matched biopsies on study showcased the drug's efficacy, with the reactivation of EZH2 targets and downregulation of other genes, aligning with the proposed mechanism of action and validating the drug's on-target effects
  • These findings demonstrate the potential of mevrometostat to modulate the EZH2 target, offering a promising avenue for improving treatment outcomes in mCRPC patients.

Promising New Combination Therapy Shows Hope for Advanced Prostate Cancer

By IPCSG Patient Support Group Newsletter | March 2025

A promising breakthrough in the treatment of advanced prostate cancer was recently presented at this year's American Society of Clinical Oncology Genitourinary Cancers Symposium, offering new hope for men with metastatic castration-resistant prostate cancer.

Researchers found that adding a new medication called mevrometostat to the established treatment enzalutamide (Xtandi) more than doubled the time before cancer progression in men who had previously been treated with abiraterone (Zytiga).

What This Means for Patients

For men living with metastatic castration-resistant prostate cancer who have already tried abiraterone, this combination therapy could provide a significant improvement in outcomes:

  • Men receiving the combination treatment went an average of 14.3 months before their cancer progressed on scans, compared to just 6.2 months for those receiving enzalutamide alone
  • The risk of cancer progression or death was reduced by 49%
  • More patients experienced tumor shrinkage with the combination (26.7%) compared to enzalutamide alone (14.3%)
  • More patients had significant PSA drops (34.1% vs 15.4%)

"These findings represent a potentially important advancement for men whose cancer has progressed after abiraterone," explained Dr. Michael Schweizer of the Fred Hutch Cancer Center in Seattle, who discussed the study results. "If confirmed in larger trials, this combination could become a new standard of care."

How It Works

Mevrometostat (also known by its research code PF-06821497) belongs to a class of medications called EZH2 inhibitors. EZH2 (enhancer of zeste homolog 2) is an enzyme that becomes overactive in castrate-resistant prostate cancer and is associated with treatment resistance and poorer outcomes.

According to Pfizer Oncology, which is developing the drug, EZH2 plays a key role in epigenetic regulation. This means it helps control which genes are turned on or off in cancer cells. When EZH2 is overactive, it can silence genes that would normally help stop cancer growth.

Mevrometostat works by:

  • Specifically inhibiting the EZH2 enzyme (with very high potency)
  • Reducing a chemical modification called H3K27 methylation that keeps important genes switched off
  • Allowing reactivation of genes that can help fight cancer progression

By blocking this enzyme, mevrometostat may help enzalutamide work more effectively against the cancer by preventing the cancer cells from developing resistance.

Side Effects and Practical Considerations

While the combination therapy was generally well-tolerated, patients did experience more side effects than with enzalutamide alone, primarily gastrointestinal issues like:

  • Diarrhea
  • Nausea
  • Decreased appetite

Importantly, researchers discovered that a lower dose (875mg) taken with food was better tolerated while maintaining the same effectiveness as a higher dose (1,250mg) taken on an empty stomach. This more convenient dosing schedule is now being used in larger clinical trials.

What's Next?

Two larger phase III clinical trials are currently ongoing:

  1. The MEVPRO-1 study - testing the combination in patients who have previously been treated with abiraterone
  2. The MEVPRO-2 study - testing the combination in patients who have not previously received treatments like abiraterone or enzalutamide

If these larger studies confirm the promising results seen so far, this combination therapy could receive FDA approval and become widely available for prostate cancer patients.

Metastatic Prostate Cancer Treatment Study Summary

A phase II trial presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium showed that combining the EZH2 inhibitor mevrometostat with enzalutamide (Xtandi) significantly improved outcomes for patients with metastatic castration-resistant prostate cancer who had previously been treated with abiraterone (Zytiga).

Key Findings:

  • Radiographic progression-free survival (rPFS) more than doubled from 6.2 months with enzalutamide alone to 14.3 months with the combination therapy
  • The combination reduced the risk of progression or death by 49%
  • Higher radiographic response rate in the combination arm (26.7% vs 14.3%)
  • Higher PSA50 response rate (34.1% vs 15.4%) in the combination arm

Safety Profile:

  • More treatment-related adverse events in the combination arm, primarily gastrointestinal issues
  • Few patients discontinued treatment due to toxicity
  • A substudy found that a lower dose (875mg) taken with food had similar effectiveness with better tolerability than the higher dose (1,250mg) taken on an empty stomach

The findings have led to two ongoing phase III trials (MEVPRO-1 and MEVPRO-2) that could potentially lead to FDA approval if the results are confirmed

Should You Consider This Treatment?

This treatment is still being studied and is not yet FDA-approved or widely available outside of clinical trials. If you're interested in learning more about clinical trials involving mevrometostat or other new treatments for advanced prostate cancer, talk with your oncologist about whether you might be eligible to participate.

Important Note: Mevrometostat is still an investigational compound. As Pfizer Oncology Development states, "The safety and efficacy of this agent, or use in this setting, has not been established or is subject to confirmation. For an agent whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed." This information is current as of October 202

For more information about clinical trials and support resources, please contact our patient navigator at support@prostatecancergroup.org or call our helpline at (555) 123-4567.

EZH2 Inhibitor Cuts Risk of Progression in Metastatic Prostate Cancer | MedPage Today

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