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Modulation of enhancer of zeste homolog 2 (EZH2) pharmacodynamic markers and tumor gene expression by mevrometostat plus enzalutamide in patients with castration-resistant prostate cancer (CRPC)
Michael Thomas Schweizer, MD1, Li Liu, PhD
2, Szu-Yu Tang, PhD
2, Whijae Roh, PhD
2, Vinicius Bonato, PhD
2, Joan Carles, MD, PhD
3, Benjamin Garmezy, MD
4, Curtis J. Dunshee, MD, FACS
5, Guillermo de Velasco, MD, PhD
6, Konstantin Penkov, MD
7, Claudia Andreu-Vieyra, PhD
8, Neelesh Soman, MD, PhD
9, Begoña Mellado, MD, PhD
10.
1Division of Medical Oncology, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA,
2Pfizer Inc., San Diego, CA, USA,
3Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain,
4Sarah Cannon Research Institute, Nashville, TN, USA,
5Arizona Urology Specialists, Tucson, AZ, USA,
6Hospital Universitario 12 de Octubre, Madrid, Spain,
7General Department, Private Medical Institution "Euromedservice", St Petersburg, Russian Federation,
8Pfizer Inc., Collegeville, PA, USA,
9Pfizer Inc., Los Angeles, CA, USA,
10Hospital Clínic i Provincial de Barcelona, Barcelona, Spain.
Introduction: We report pharmacodynamic effects of EZH2 inhibition and tumor gene expression changes by mevrometostat+enzalutamide in patients with CRPC from a phase 1 study (NCT03460977).
Methods: Serial whole blood and paired tumor biopsy samples were collected during dose escalation of mevrometostat (150-1250mg BID, empty stomach) +enzalutamide (160mg QD). Paired tumor biopsy samples were collected before the study and after 21 days of treatment. H3K27Me3, a pharmacodynamic marker, was evaluated in peripheral granulocytes by flow cytometry and in biopsy samples by immunohistochemistry. Tumor gene expression was profiled by whole transcriptomic RNA sequencing.
Results: Mevrometostat+enzalutamide resulted in a dose-dependent reduction of H3K27Me3 in both peripheral granulocytes and paired tumor biopsies from patients with CRPC. Strong H3K27Me3 reduction (≥75%) in granulocytes was achieved at mevrometostat ≥375mg +enzalutamide. Tumor H3K27Me3 levels were reduced from baseline in 6 patients who received mevrometostat 1250mg +enzalutamide with a geometric mean change of -67% (95% CI: -86%, -23%;
P=0.020) by H scores and -75% (95% CI: -93%, -11%;
P=0.038) by H3K27Me3 staining; no significant changes were observed in 4 patients who received mevrometostat 500mg +enzalutamide. Mevrometostat 1250mg +enzalutamide increased expression of genes repressed by the PRC2/EZH2 complex and decreased expression of EZH2 and genes involved in the E2F pathway, G2M checkpoint, Myc-responsive genes, and/or cell cycle progression.
Conclusion: Mevrometostat+enzalutamide effectively inhibited EZH2 in a dose-dependent manner and may overcome drug resistance. Pivotal phase 3 studies of mevrometostat+enzalutamide in patients with metastatic CRPC are ongoing.
©2025 American Society of Clinical Oncology, Inc. Adapted and reused with permission. This abstract was accepted and previously presented at the 2025 Genitourinary Cancers Symposium. All rights reserved.
Funding: Pfizer Inc. Enzalutamide was provided by Astellas Pharma Inc. Editorial support was provided by Onyx (a division of Prime, London, UK).
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