What is Mevrometostat?
Mevrometostat, also known by its development code PF-06821497, is an orally administered, investigational anticancer drug developed by Pfizer. It belongs to a class of drugs known as EZH2 (enhancer of zeste homolog 2) inhibitors. The primary focus of its clinical development is for the treatment of metastatic castration-resistant prostate cancer (mCRPC), often in combination with existing therapies like enzalutamide.
Prostate cancer is a major health concern, with an estimated 300,000 men diagnosed in the US annually. Many patients are treated with androgen deprivation therapy (ADT), but the cancer can eventually become resistant and continue to grow, leading to mCRPC. Mevrometostat represents a novel approach to combat this resistance. It was also previously investigated for other cancers, including follicular lymphoma and small-cell lung cancer.
The Epigenetic Mechanism of Action
Mevrometostat functions as a small molecule inhibitor that targets EZH2, which is the catalytic subunit of the polycomb repressive complex 2 (PRC2). Here's a breakdown of how it works:
- The Role of EZH2: EZH2 is a histone methyltransferase enzyme. In simple terms, it plays a crucial role in epigenetics by modifying gene expression without changing the DNA sequence itself. It does this by adding a methyl group to histone H3 on lysine 27 (a process called H3K27 methylation). This methylation typically silences genes, including tumor suppressor genes.
- EZH2 in Prostate Cancer: In many cancers, particularly advanced prostate cancer, EZH2 is overexpressed or dysregulated. This overexpression is associated with a poor prognosis and contributes to the cancer's progression and resistance to treatment. It can silence tumor suppressor genes, activate androgen receptor signaling, and promote cell cycle deregulation.
- How Mevrometostat Intervenes: Mevrometostat selectively binds to and inhibits the activity of EZH2. By blocking EZH2, it prevents H3K27 methylation. This action effectively 'wakes up' the silenced tumor suppressor genes, altering the gene expression patterns that drive cancer growth and proliferation. The goal is to delay or prevent resistance to hormone therapies and slow the cancer's progression.
Clinical Development and Trials
Mevrometostat is the subject of a comprehensive clinical trial program named MEVPRO, conducted by Pfizer. The program includes several key Phase 3 trials designed to evaluate its safety and efficacy:
- MEVPRO-1 (NCT06551324): This is a randomized, open-label, Phase 3 trial for patients with mCRPC who have already been treated with abiraterone acetate. It compares the combination of mevrometostat plus enzalutamide against the physician's choice of either enzalutamide alone or docetaxel chemotherapy. The primary endpoint is radiographic progression-free survival (rPFS). The study is expected to complete in late 2028.
- MEVPRO-2 (NCT06629779): This global, double-blind, placebo-controlled Phase 3 trial enrolls patients with mCRPC who have not yet received an androgen receptor pathway inhibitor (ARPI-naïve). It evaluates mevrometostat plus enzalutamide versus a placebo plus enzalutamide. This trial aims to recruit approximately 900 patients, with the primary endpoint also being rPFS.
- MEVPRO-3: This Phase 3 trial, planned to start in August 2025, will test mevrometostat in the hormone-sensitive prostate cancer setting, which is an earlier stage of the disease. It will compare mevrometostat plus Xtandi (enzalutamide) against Xtandi alone.
Results from an earlier randomized dose-expansion study were promising, showing the combination of mevrometostat and enzalutamide led to a median rPFS of 14.3 months compared to 6.2 months for enzalutamide alone.
Safety and Side Effect Profile
Like all cancer therapies, mevrometostat is associated with treatment-emergent adverse events (TEAEs). Data from clinical studies have established a manageable safety profile.
In studies combining mevrometostat with enzalutamide, common TEAEs were:
- Diarrhea (78.0%)
- Decreased appetite (58.5%)
- Dysgeusia (taste disturbance) (58.5%)
Grade 3 or higher TEAEs were observed in 53.7% of patients on the combination therapy compared to 42.5% in the enzalutamide-only group. Researchers found that taking mevrometostat with food may provide better gastrointestinal tolerability.
Comparison of Investigational EZH2 Inhibitors
| Feature | Mevrometostat (PF-06821497) | Tazemetostat (Tazverik) | Other EZH2 Inhibitors |
|---|---|---|---|
| Developer | Pfizer | Ipsen (Originally Epizyme) | Various companies (e.g., GSK, Daiichi Sankyo) |
| Primary Indication | Metastatic Castration-Resistant Prostate Cancer (mCRPC) | Epithelioid Sarcoma, Follicular Lymphoma (FDA Approved) | Various hematological and solid tumors (largely investigational) |
| Mechanism | Selective EZH2 inhibitor | Selective EZH2 inhibitor | Selective EZH2 inhibitors |
| Status | Phase 3 Clinical Trials | Approved and marketed | Various stages of clinical development |
| Administration | Oral tablets | Oral tablets | Typically oral |
Conclusion
Mevrometostat is a promising, targeted epigenetic therapy that offers a new mechanism of action for treating advanced prostate cancer. By inhibiting the EZH2 enzyme, it aims to overcome treatment resistance and slow disease progression in patients with mCRPC. Ongoing Phase 3 trials like MEVPRO-1, MEVPRO-2, and MEVPRO-3 will provide more definitive evidence on its efficacy and safety, potentially establishing it as a new standard of care in the fight against prostate cancer. The exploration of how it is taken to improve tolerability while maintaining efficacy underscores a commitment to optimizing its clinical potential for patients.
For more information on the ongoing clinical trials, you can visit the Pfizer Clinical Trials website.
