Mevrometostat

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

Clinical data
Other names	PF-06821497
Identifiers
IUPAC name 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one
CAS Number	1844849-10-0
PubChem CID	118572065
IUPHAR/BPS	10516
DrugBank	DB14799
ChemSpider	65321668
UNII	S4L4MM20B6
KEGG	D12845
ChEMBL	ChEMBL4080228
PDB ligand	CJD (PDBe, RCSB PDB)
Chemical and physical data
Formula	C22H24Cl2N2O5
Molar mass	467.34 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1=CC(=C(C(=O)N1)CN2CCC3=C(C=C(C(=C3C2=O)Cl)[C@@H](C4COC4)OC)Cl)OC
InChI InChI=1S/C22H24Cl2N2O5/c1-11-6-17(29-2)15(21(27)25-11)8-26-5-4-13-16(23)7-14(19(24)18(13)22(26)28)20(30-3)12-9-31-10-12/h6-7,12,20H,4-5,8-10H2,1-3H3,(H,25,27)/t20-/m1/s1 Key:RXCVUHMIWHRLDF-HXUWFJFHSA-N

Mechanism of action

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:

• Diarrhea
• Dysgeusia (taste alteration)
• Anemia^[14]

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]

Regulatory status

As of 2025, mevrometostat remains an investigational agent under clinical development by Pfizer. The drug has not received regulatory approval from the Food and Drug Administration (FDA), European Medicines Agency (EMA), or other regulatory authorities.

See also

• Polycomb repressive complex 2
• Tazemetostat (approved EZH2 inhibitor)
• Prostate cancer
• Enzalutamide