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Mevrometostat, an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): A randomized dose-expansion study
Michael Thomas Schweizer, MD1, Mariona Calvo, MD
2, Victor Moreno, MD, PhD
3, Begoña Mellado, MD, PhD
4, Daniel Castellano, MD
5, Alexander I. Spira, MD
6, Qiang Wei, MD
7, Joan Carles, MD, PhD
8, Benjamin Garmezy, MD
9, Cheol Kwak, MD, PhD
10, Iwona Ługowska, MD, PhD
11, Konstantin Penkov, MD
12, Neal D. Shore, MD
13, Li Liu, PhD
14, Rajendar K. Mittapalli, PhD
14, Jessica Tougias, PhD
15, Claudia Andreu-Vieyra, PhD
16, Neelesh Soman, MD, PhD
17, Teresa Alonso Gordoa, MD
18.
1Division of Medical Oncology, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA,
2Medical Oncology Department, Catalan Institute of Oncology, L’Hospitalet del Llobregat, Barcelona, Spain,
3START Madrid-FJD, Fundación Jiménez Díaz University Hospital, Madrid, Spain,
4Hospital Clínic i Provincial de Barcelona, Barcelona, Spain,
5Hospital Universitario 12 de Octubre, Madrid, Spain,
6Virginia Cancer Specialists PC, Fairfax, VA, USA,
7Department of Urology, West China Hospital of Sichuan University, Chengdu, China,
8Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain,
9Sarah Cannon Research Institute, Nashville, TN, USA,
10Department of Urology, Seoul National University Hospital, Seoul, Korea, Republic of,
11Early Phase Clinical Trials Department, Maria Skłodowska Curie National Research Institute of Oncology, Warsaw, Poland,
12General Department, Private Medical Institution "Euromedservice", St Petersburg, Russian Federation,
13Carolina Urologic Research Center, Myrtle Beach, SC, USA,
14Pfizer Inc., San Diego, CA, USA,
15Pfizer Inc., New York, NY, USA,
16Pfizer Inc., Collegeville, PA, USA,
17Pfizer Inc., Los Angeles, CA, USA,
18Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Introduction: Mevrometostat is an EZH2 inhibitor. We report outcomes from the open-label, randomized, dose-expansion part of a mevrometostat phase 1 study (NCT03460977).
Methods: Patients with mCRPC who received prior abiraterone, ≤1 prior chemotherapy (any setting), and progression per modified PCWG3 criteria were randomized 1:1 to mevrometostat (1250mg BID, empty stomach) +enzalutamide (160mg QD) or enzalutamide. Primary endpoints were radiographic progression-free survival (rPFS) and safety. Secondary endpoints included objective response, decline in prostate-specific antigen ≥50% from baseline, and pharmacokinetics.
Results: As of September 2, 2024, 81 patients were included. Median (range) age was 70 years (48-86) for mevrometostat+enzalutamide and 71.5 years (50-86) for enzalutamide. Median (95% CI) rPFS was 14.3 months (7.5, not estimable) for mevrometostat+enzalutamide and 6.2 months (4.1, 13.9) for enzalutamide (HR 0.51; 90% CI: 0.28, 0.95). Secondary endpoints and safety are shown in the
Table. Geometric mean plasma exposures were comparable for mevrometostat 1250mg (empty stomach) and 875mg (with food) (AUC
tau [h*ng/mL]: 8733 vs 9631; C
max [ng/mL]: 2371 vs 1868, respectively). Safety was improved with mevrometostat 875mg (with food) versus 1250mg (empty stomach).
Conclusions: Mevrometostat+enzalutamide improved outcomes versus enzalutamide in patients with mCRPC, with a manageable safety profile.
©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.
Disclosure: A genAI tool (10/24/24; Pfizer; GPT-4) developed the 1st draft; authors assume content responsibility.
Funding: Pfizer Inc. Enzalutamide was provided by Astellas Pharma Inc. Medical writing support was provided by Onyx (a division of Prime, London, UK).
Table. Secondary efficacy endpoints and safety | | | | | | | | | |
| | | Mevrometostat (1250mg BID, empty stomach)+enzalutamide (n=41) | | Enzalutamide (n=40) |
| Secondary endpoints | | | | |
| Patients with measurable disease at baseline, n | | 15 | | 14 |
| OR rate (95% CI), % | | 26.7 (7.8, 55.1)† | | 14.3 (1.8, 42.8)† |
| Confirmed PSA50 (95% CI), % | | 34.1 (20.1, 50.6) | | 15.4 (6.0, 31.3) |
| Safety, n (%) | | Any grade | | Grade ≥3 | | Any grade | | Grade ≥3 |
| Any TEAE | | 40 (97.6) | | 22 (53.7)‡ | | 37 (92.5) | | 17 (42.5)‡ |
| Most common TEAEs (>30% of patients in either treatment group) |
| Diarrhea | | 32 (78.0) | | 7 (17.1) | | 6 (15.0) | | 0 |
| Decreased appetite | | 24 (58.5) | | 0 | | 6 (15.0) | | 0 |
| Dysgeusia | | 24 (58.5) | | 0 | | 3 (7.5) | | 0 |
| Asthenic conditions | | 23 (56.1) | | 2 (4.9) | | 17 (42.5) | | 1 (2.5) |
| Anemia | | 20 (48.8) | | 2 (4.9) | | 9 (22.5) | | 1 (2.5) |
| Nausea | | 17 (41.5) | | 0 | | 10 (25.0) | | 0 |
| Alopecia | | 16 (39.0) | | 0 | | 0 | | 0 |
| Median (IQR) duration of follow-up for rPFS was 9.6 (3.1-14.5) months.
†Four partial responses for mevrometostat+enzalutamide and two partial responses for enzalutamide.
‡There were no treatment-related deaths.
BID, twice daily; CI, confidence interval; IQR, interquartile range; OR, objective response; PSA50, decline in prostate-specific antigen of ≥50% from baseline; rPFS, radiographic progression-free survival; TEAE, treatment-emergent adverse event. |
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