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EZH2 Inhibition for Prostate Cancer; It’s Taken Awhile, but We Just May Be onto Something Here

The polycomb group protein enhancer of zeste homolog 2 (EZH2) has been a potentially promising target for prostate cancer dating back to an early Nature publication from the Chinnaiyan lab in 2002.1 In that manuscript, they showed that EZH2 is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). Inhibition through genetic methods, in cell lines, decreased cell proliferation in vitro, and EZH2 expression correlated with worse prognosis, implicating a significant role of dysregulated EZH2 expression in prostate cancer progression.

Alterations in epigenetic programs, which include changes in DNA methylation and upregulation of EZH2, are now recognized to have a role in prostate cancer lineage plasticity.2,3 It is felt that EZH2 may have a role in the development of the neuroendocrine phenotype. Yet, beyond prostate cancer, genetic alterations and amplification of EZH2 have been observed in many different malignancies, such as melanoma, small cell lung cancer, esophageal cancer, and others. This is further supported by the fact that tazemetostat is already a FDA-approved EZH2 inhibitor for treatment of follicular lymphoma and epithelioid sarcoma.4,5

For prostate cancer, there have been many therapeutic attempts to inhibit EZH2. Approximately 4.5 years ago, I highlighted the ongoing trials in a Urotoday Clinical Trials Portal article.6 Since then, we have unfortunately seen multiple discouraging results with various EZH2 inhibitors. The phase 2 PROSTAR trial enrolled patients who progressed on either abiraterone or enzalutamide.7 The EZH2 inhibitor, CPI-1205, was added to either enzalutamide or abiraterone, respectively, and the former group was compared to enzalutamide alone. The trial was stopped early due to a lack of a strong enough signal of activity to continue. Tulmimetostat was tested in a phase 2 trial and it unfortunately yielded zero responses in prostate cancer.8 A phase 1/2 trial of SHR2554 monotherapy or in combination with androgen receptor inhibition was terminated without any presented results. Most recently, the Cello-1 study, a randomized phase 2 trial of tazemetostat plus enzalutamide vs. enzalutamide alone for patients with mCRPC was unsuccessful at demonstrating improvement in radiographic progression free (rPFS).9 In that report, median PFS was 16.6 and 13.8 months (p=0.37), for tazemetostat plus enzalutamide vs. enzalutamide, respectively.

Recent data with mevrometostat is much more promising. An open-label, phase 1/2 study of mevrometostat plus enzalutamide in patients with mCRPC who had previously progressed on abiraterone and/or enzalutamide, revealed a median rPFS rate of 17.0 months, which is impressive, considering almost half of the patient was also previously exposed to docetaxel.10 At the 2025 Genitourinary Cancers Symposium, additional data from the randomized dose expansion trial was presented.11 The primary endpoint of rPFS was superior for the mevrometostat 1250 mg po bid plus enzalutamide combination vs. enzalutamide alone with a median of 14.3 vs. 6.2 months (HR 0.51, 90% CI 0.28-0.95). Also in favor of the combination arm was objective response rate at 26.7% vs. 14.3%, respectively. PSA decline of 50% or greater, was also in favor of the combination arm, with a 34.1% vs. 15.4% PSA50 decline rate, respectively. Although gastrointestinal symptoms of anorexia, dysgeusia, nausea, and diarrhea, were common, a food-effect cohort of mevrometostat 875 mg po bid taken with food showed similar pharmacokinetic plasma exposure, with improved gastrointestinal tolerability, compared with 1250 mg bid on an empty stomach. Therefore, 875 mg po bid with food is the dose that will be explored in ongoing phase 3 trials.

The ongoing MEVPRO-1 phase 3, randomized trial (NCT06551324) will randomize 600 patients (1:1) with mCRPC who previously were treated with abiraterone to mevrometostat plus enzalutamide vs. physicians pre-specified choice of enzalutamide or docetaxel alone. The primary endpoint will be rPFS. The MEVPRO-2 phase 3, randomized trial (NCT06629779) will randomize 900 patients (1:1) with mCRPC, who are androgen receptor pathway inhibitor naïve, to enzalutamide with or without mevrometostat.

Below, are select ongoing trials using EZH2 inhibitors that are actively accruing patients. This includes both monotherapy and combination treatment trials.

Highlighted trials that include prostate cancer patients using an EZH2 inhibitor

  • Phase 1 trial of mevrometastat for castration resistant prostate cancer, small cell lung cancer or follicular lymphoma (NCT03460977)
  • CPI-0209 – Phase 1/2 trial with focus on advanced solid tumors and lymphomas (NCT04104776)
  • Alliance Group PREDICT - Phase 2 trial of metastatic prostate cancer that includes Valemetostat tosylate (NCT06632977)
  • MEVPRO-1 – Randomized phase 3 trial of previously abiraterone-treated patients to enzalutamide or docetaxel versus mevrometostat plus enzalutamide (NCT06551324)
  • MEVPRO-2 – Randomized phase 3 trial of enzalutamide with or without mevrometostat (NCT06629779)
  • KEYNOTE F19 – Phase 1/2 trial of XNW504 plus pembrolizumab (NCT06022757) – also includes a cohort with urothelial bladder cancer
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Varambally S, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002; 419:624-9.
  2. Beltran H, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016; 22:298-305.
  3. Ku SY, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017; 355:78-83.
  4. https://www.fda.gov/drugs/fda-granted-accelerated-approval-tazemetostat-follicular-lymphoma
  5. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tazemetostat-advanced-epithelioid-sarcoma
  6. https://www.urotoday.com/clinical-trials/from-the-editor/114198-from-the-desk-of-evan-yu-polycomb-complex-enhancer-of-zeste-2-ezh2-a-regulator-of-lineage-reprogramming-and-a-new-drug-target.html
  7. Taplin ME, et al. ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2019; 37 no. 7_suppl:TPS335.
  8. Drescher C, et al. EZH2/EZH1 inhibitor tulmimetostat (CPI-0209) in patients with advanced solid tumors or hematologic malignancies: Preliminary phase II results. J Clin Oncol 2023; 41 no. 16_suppl:3094.
  9. Abida W, et al. Updated safety and efficacy of tazemetostat (TAZ) plus enzalutamide (ENZ) in patients with metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol 2024; 35 (suppl 2, S967):1603P.
  10. Schweizer MT, et al. Mevrometostat (PF-06821497) in combination with enzalutamide for androgen receptor pathway inhibitor (ARPI)-naïve patients with metastatic castration-resistant prostate cancer (mCRPC): The phase 3, randomized MEVPRO-2 trial. J Clin Oncol 2024; 42 no. 16_suppl:5061.
  11. Schweizer MT, et al. PSMA-Directed Targeted Alpha Therapy Shows Activity in Heavily Pretreated Metastatic CRPC. J Clin Oncol 43, 2025 (suppl 5; abstr LBA138).