(UroToday.com) The 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 13th and 15th 2025, was host to the Trials in Progress Poster Session A: Prostate Cancer. Dr. Michael Schweizer presented the trial in progress poster 287: 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.
Dr. Schweizer began his presentation by introducing Mevrometostat (PF-06821497), a potent, selective inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2). EZH2 is canonically involved in the epigenetic repression of target genes, particularly those related to cell cycle regulation, such as the Ink4b/Arf/Ink4a locus. Inhibition of EZH2 impedes cell cycle arrest, thereby helping to preserve the proliferative potential of cells.(1)
Specifically in prostate cancer, EZH2 overexpression has been found to be associated with poor prognosis, contributing to disease progression through the transcriptional repression of tumor suppressor genes and androgen receptor (AR) co-activation. Moreover, EZH2 also co-regulates AR-mediated transcriptional programs and causes cell cycle deregulation by methylating nonhistone targets. (2) Considering this known associations between EZH2 and the AR, the addition of an EZH2 inhibitor to an androgen receptor pathway inhibitor (ARPI) is hypothesized to extend the duration of clinical response and delay or prevent castration resistant prostate cancer compared with an ARPI alone.(1)
Enzalutamide is a potent ARPI approved for the treatment of patients with mCRPC, nonmetastatic CRPC, metastatic castration-sensitive prostate cancer (CSPC), and nonmetastatic CSPC with biochemical recurrence at high risk for metastasis (3). In the MEVPRO-1 phase 1/2 dose-escalation study (NCT03460977), the combination of Mevrometostat with enzalutamide showed promising activity and a manageable adverse event profile in patients with CRPC who had received prior treatment with abiraterone or enzalutamide. In this presentation, Dr. Schweizer described the design of MEVPRO-2, a global, randomized, double-blind, placebo-controlled phase 3 trial exploring whether the addition of Mevrometostat to enzalutamide can delay or prevent antiandrogen resistance, thereby increasing the duration of clinical benefit of enzalutamide in patients with ARPI-naïve mCRPC.
The key inclusion and exclusion criteria are detailed in the table below:
Approximately 900 patients will be randomized 1:1 to receive mevrometostat (875 mg twice daily with food) in combination with enzalutamide (160 mg once daily), or placebo (twice daily) with enzalutamide (160 mg once daily). Notably, the sample size estimation is based on the number of events needed to observe protocol-defined statistical differences between the treatment groups. The study schema is shown in the figure below:
Randomization will be stratified by:
- Previous docetaxel in the mCSPC setting
- Presence of hepatic metastases
The primary efficacy endpoint is radiographic progression-free survival (rPFS), per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3, bone) assessed by blinded central radiology review.
The key secondary endpoints were:
- Overall survival
- Measures of antitumor activity by overall response rate and duration of response
- Patient-reported outcomes
- Pharmacokinetics
- Circulating tumor DNA burden.
Safety will be assessed through adverse event monitoring, physical examinations, vital signs and clinical laboratory tests. Detailed information on the primary, secondary, and exploratory endpoints is summarized below.
The planned statistical analysis will include time-to-event endpoints, comparing treatment arms using a stratified log-rank test. Hazard ratios and 95% confidence intervals (CIs) will be estimated using a stratified Cox proportional hazards model. Kaplan–Meier analysis will summarize time-to-event endpoints, including the median and 95% CIs, based on the Brookmeyer–Crowley method.
The first patient in MEVPRO-2 was enrolled on October 22, 2024. The study is currently enrolling in three countries (USA, China, and Japan), with additional sites planned in North America, Europe, Asia, and South America. The study is estimated to be completed in November 2028.
Presented by: Michael T. Schweizer, MD, Medical Oncologist at Fred Hutch Cancer Centre and Associate Professor, Medical Oncology Division University of Washington School of Medicine. Seattle, WA.
Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:
- Kung PP, Bingham P, Brooun A, Collins M, Deng YL, Dinh D, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania R, Kephart SE, Krivacic C, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter D, Rollins RA, Sach N, Sharma S, Sherrill J, Spangler J, Stewart AE, Sutton S, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, Edwards M. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497). J Med Chem. 2018 Feb 8;61(3):650-665. doi: 10.1021/acs.jmedchem.7b01375. Epub 2017 Dec 27. PMID: 29211475.
- Park SH, Fong KW, Kim J, Wang F, Lu X, Lee Y, Brea LT, Wadosky K, Guo C, Abdulkadir SA, Crispino JD, Fang D, Ntziachristos P, Liu X, Li X, Wan Y, Goodrich DW, Zhao JC, Yu J. Posttranslational regulation of FOXA1 by Polycomb and BUB3/USP7 deubiquitin complex in prostate cancer. Sci Adv. 2021 Apr 7;7(15):eabe2261. doi: 10.1126/sciadv.abe2261. PMID: 33827814; PMCID: PMC8026124.
- Astellas Pharma US Inc. Full prescribing information: XTANDI® (enzalutamide) for oral use. https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf. Published 2023. Accessed November 6, 2024.