(UroToday.com) The 2025 SESAUA annual meeting featured a prostate cancer session and a presentation by Dr. Benjamin Garmezy discussing a phase 1 trial of mevrometostat (PF-06821497), a potent and selective inhibitor of EZH2, in CRPC. The proposed mechanism of action for mevrometostat is as follows:
Previously, dose exploration of mevrometostat with enzalutamide plus ADT showed a manageable safety profile and evidence of objective response, decline in PSA of ≥50% from baseline (PSA50), and pharmacodynamic modulation in patients with CRPC in part 2A of a phase 1 study (NCT03460977). At the 2025 SESAUA annual meeting, Dr. Garmezy reported longer term follow-up from the dose-escalation cohort.
This open-label, phase 1 study evaluated mevrometostat (orally, 150-1250 mg BID) plus enzalutamide (160 mg QD) in adults with CRPC who had evidence of cancer progression per PCWG3 and received prior abiraterone and/or enzalutamide. The primary endpoint was safety. Pharmacokinetics, radiographic progression-free survival, PSA50, and objective response were also assessed. The dose/response relationship of mevrometostat on-target H3K27Me3 pharmacodynamic modulation and circulating tumor DNA mutational profiling were exploratory endpoints.
As of November 2, 2023, 47 patients received ≥1 dose of study treatment, with a median follow up of 9.7 (IQR 2.0–22.8) months, and a median age of 70 (range 53–87) years. Overall, 57.4% of patients received prior abiraterone, 74.5% received prior enzalutamide, and 48.9% received prior taxane therapy. At data cut-off, 18 events were observed (14 progressions and 4 deaths). Median radiographic progression-free survival was 17.0 (95% CI 6.3, NE) months in all patients (n = 47), 17.1 (95% CI 6.2, NE) months for patients with prior abiraterone (without enzalutamide; n = 12), and 11.7 (95% CI 4.2, NE) months for patients with prior enzalutamide (± abiraterone; n = 35). Confirmed PSA50 was observed in 14.9% (95% CI 7.0, 31.4) of patients. In 22 patients with baseline measurable disease, objective response rate was 27.3% (95% CI 10.7, 50.2; 1 complete response, 5 partial responses). Geometric mean H3K27Me3 reduction was −75% (95% CI −93, −11) for mevrometostat plus enzalutamide (at mevrometostat 1250 mg BID) in tumor-paired biopsies (n = 6). Durable antitumor activity was observed in both post-abiraterone (without enzalutamide) and post-enzalutamide (± abiraterone) patients with and without androgen receptor and/or TP53 mutations. A summary of the adverse events is noted in the following table, highlighting that the most common adverse events were diarrhea and dysgeusia:
Dr. Garmezy concluded his presentation by discussing a phase 1 trial of mevrometostat (PF-06821497) in CRPC with the following take-home points:
- Mevrometostat plus enzalutamide shows activity in both post-abiraterone without enzalutamide and post-enzalutamide (± abiraterone) patients with CRPC, with evidence of tumor pharmacodynamic modulation and a manageable safety profile
- Further investigation is warranted in phase 2/3 trials
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Urological Association (SESAUA) 2025 Annual Meeting, Nashville, TN, Wed, Mar 12 – Sat, Mar 15, 2025.