Mevrometostat
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| Other names | PF-06821497 |
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| Formula | C22H24Cl2N2O5 |
| Molar mass | 467.34 g·mol−1 |
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Mevrometostat (development code PF-06821497) is an investigational anticancer drug that functions as a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2).[1][2] Currently under development by Pfizer, mevrometostat is being investigated primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in combination with enzalutamide.
Mevrometostat is a small molecule inhibitor that targets EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2).[1][3] EZH2 plays a crucial role in epigenetic regulation by modifying gene expression patterns that control cellular fate decisions, including differentiation and self-renewal.[1]
In prostate cancer, EZH2 dysregulation contributes to treatment resistance through multiple pathways, including:
- Silencing of tumor suppressor genes
- Activation of androgen receptor transcription factors
- Promotion of neuroendocrine transdifferentiation[4]
Mevrometostat demonstrates dose-dependent EZH2 inhibition, leading to reactivation of tumor suppressor genes while suppressing genes involved in tumor progression.[5]
Clinical development
Phase I/II trials
The primary clinical evaluation of mevrometostat is being conducted through a phase 1/2 dose-expansion study (NCT03460977) investigating the combination of mevrometostat with enzalutamide and androgen deprivation therapy in patients with mCRPC.[6]
The dose-expansion portion of this study enrolled patients with mCRPC who had previously received abiraterone, with evidence of disease progression per modified Prostate Cancer Working Group 3 criteria.[2]
Key efficacy results
In the randomized dose-expansion study, the combination of mevrometostat (1,250 mg twice daily on an empty stomach) plus enzalutamide demonstrated:
- 49% relative reduction in the rate of progression or death
- Approximately 8-month improvement in median radiographic progression-free survival (rPFS)
- Hazard ratio of 0.51 (90% CI: 0.28–0.95)[7]
The median radiographic progression-free survival was 14.3 months with the combination therapy compared to 6.2 months with enzalutamide alone.[8]
Phase III trials
Based on promising phase I/II results, Pfizer has initiated multiple phase 3 clinical trials:
MEVPRO-1 study
The MEVPRO-1 study (NCT06551324) is a randomized phase 3 trial evaluating mevrometostat in combination with enzalutamide versus physician's choice of therapy in patients with mCRPC previously treated with abiraterone acetate.[9][10]
- Study design: Randomized 1:1 to receive mevrometostat (875 mg twice daily with food) plus enzalutamide (160 mg daily) versus physician's choice of enzalutamide or docetaxel
- Target enrollment: Approximately 600 patients
- Primary endpoint: Blinded independent central review-assessed rPFS per RECIST 1.1 and PCWG3 criteria
- Key secondary endpoint: Overall survival
MEVPRO-2 study
The MEVPRO-2 study (NCT06629779) is evaluating mevrometostat plus enzalutamide in androgen receptor pathway inhibitor (ARPI)-naïve patients with mCRPC.[11][12]
Additional development
Pfizer has also initiated phase 3 trials evaluating mevrometostat plus enzalutamide in first-line metastatic castration-sensitive prostate cancer.[8][13]
Safety profile
The most common adverse events considered related to mevrometostat treatment include:
Dose optimization studies found that mevrometostat 875 mg twice daily with food showed similar efficacy and better safety compared to the 1,250 mg dose on an empty stomach.[15]
Pharmacokinetics
Based on safety and pharmacokinetic findings from phase 1 trials, mevrometostat 875 mg twice daily with food was selected as the recommended dose for phase 3 clinical development in combination with enzalutamide.[16]