Sponsor: Pfizer (industry)
Phase: 3
Start date: Oct. 21, 2024
Planned enrollment: 600
Mevrometostat (PF-06821497) is an investigational, orally bioavailable inhibitor of enhancer of zeste homolog 2 (EZH2), developed by Pfizer. It is currently under clinical evaluation for the treatment of various cancers, including metastatic castration-resistant prostate cancer (mCRPC), small-cell lung cancer (SCLC), and follicular lymphoma. (pfizeroncologydevelopment.com)
EZH2 is a histone methyltransferase that plays a critical role in epigenetic regulation by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to gene silencing. Overexpression or mutation of EZH2 has been implicated in the progression and treatment resistance of several cancers. Mevrometostat selectively inhibits EZH2, resulting in decreased H3K27me3 levels, reactivation of tumor suppressor genes, and inhibition of tumor cell proliferation. (pfizeroncologydevelopment.com)
In a Phase 1 study involving patients with mCRPC, the combination of mevrometostat and enzalutamide demonstrated promising efficacy:
Radiographic Progression-Free Survival (rPFS): Median rPFS was 17.0 months for all patients (n=47), 17.1 months for those with prior abiraterone treatment (n=12), and 11.7 months for those with prior enzalutamide treatment (n=35). (delta.larvol.com)
Prostate-Specific Antigen (PSA) Response: A confirmed ≥50% decline in PSA levels (PSA50) was observed in 14.9% of patients. (delta.larvol.com)
Objective Response Rate (ORR): Among 22 patients with measurable disease at baseline, the ORR was 27.3%, including one complete response and five partial responses. (delta.larvol.com)
The combination of mevrometostat and enzalutamide was reported to have a manageable safety profile in the Phase 1 study. Specific adverse events were not detailed in the available sources, but the overall tolerability supports further investigation in larger trials. (delta.larvol.com)
Note: Mevrometostat is an investigational drug and has not been approved by any health authority. Clinical trials are ongoing to evaluate its safety and efficacy.
Last updated: Apr 2025
Goal: Evaluate whether combining the EZH2 inhibitor mervometostat (PF-06821497) with enzalutamide improves radiographic progression-free survival versus physician’s choice of enzalutamide or docetaxel in men with mCRPC previously treated with abiraterone.
Patients: Adults with histologically or cytologically confirmed adenocarcinoma of the prostate (no small cell features), metastatic disease in bone and/or soft tissue, and progression on abiraterone in the mCSPC or first-line mCRPC setting. Patients must be castration-resistant, ECOG 0–2, with adequate organ function and life expectancy ≥6 months. Key exclusions include prior ARSI (enzalutamide/apalutamide/darolutamide), prior PARP monotherapy, prior chemotherapy except docetaxel for mCSPC without early progression, significant cardiovascular disease, active CNS metastases or seizures, significant GI conditions affecting absorption, recent/active suicidal ideation/behavior, and recent use of other investigational products.
Design: Phase 3, randomized, open-label, multicenter study with approximately 600 participants allocated to experimental combination therapy versus physician’s choice control. Randomization occurs after confirmation of eligibility; assessments include BICR for radiographic endpoints and serial PROs. Follow-up for efficacy up to ~4.5 years for OS.
Treatments: Arm A: Mervometostat (PF-06821497) 875 mg BID plus enzalutamide 160 mg QD. Mervometostat is a potent, selective EZH2 inhibitor that reduces H3K27 methylation and may reverse PRC2-mediated transcriptional repression; it shows high selectivity for EZH2 over EZH1. In early-phase mCRPC studies, mervometostat (alone and with enzalutamide) demonstrated manageable safety and signals of efficacy, including a median rPFS around 17 months and objective responses in measurable disease. Arm B: Physician’s choice of enzalutamide 160 mg QD or docetaxel 75 mg/m2 IV every 21 days, representing standard second-line AR-directed therapy or taxane chemotherapy after abiraterone progression.
Outcomes: Primary: rPFS by BICR using RECIST v1.1 for soft tissue and PCWG3 for bone. Secondary: overall survival; objective response rate and duration of response in measurable disease; PSA endpoints (time to PSA progression, PSA50 response); time to initiation of new antineoplastic therapy; time to first symptomatic skeletal event; safety and AE incidence per NCI CTCAE v5.0; patient-reported outcomes including pain (BPI-SF), HRQoL (FACT-P domains and total), EQ-5D-5L, PRO-CTCAE symptomatic toxicity, FACT-GP5 side-effect burden; time to confirmatory deterioration in pain and definitive deterioration in HRQoL/physical well-being; pharmacokinetics of mervometostat with enzalutamide; exploratory ctDNA burden at baseline and on treatment.
Burden on patient: Moderate. The experimental arm involves continuous oral therapy plus standard monitoring, with scheduled imaging for rPFS (typically every 8–12 weeks) similar to routine mCRPC care. Additional burdens include pharmacokinetic blood draws through Cycle 6 Day 1 and serial PRO questionnaires, along with optional or required ctDNA sampling, increasing visit time but not typically requiring invasive procedures. Patients randomized to docetaxel will have higher visit frequency for IV infusions every 3 weeks and chemotherapy-related monitoring. Overall, procedures are largely consistent with standard practice in mCRPC, with added PK and PRO assessments contributing modest extra time and blood draws.
Inclusion Criteria:
* Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features.
* Metastatic disease in bone documented on bone scan, or in soft tissue documented on CT/MRI scan.
* Progressive disease in the setting of surgical or medical castration with evidence of disease progression on treatment with abiraterone acetate in the mCSPC setting or first line mCRPC setting is required.
* Eastern Cooperate Oncology Group (ECOG) performance status 0 - 2, with life expectancy of at least 6 months as assessed by the investigator.
Exclusion Criteria:
* Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may make the participant inappropriate for the study.
* Know history of active inflammatory gastrointestinal disease, chronic diarrhea, or previous gastric resection or lap-band surgery.
* Clinically significant cardiovascular disease.
* Known or suspected brain metastasis or active leptomeningeal disease or clinically significant history of seizure.
* Prior treatment for prostate cancer at any stage with any cytotoxic chemotherapy, radioligand therapy (i.e. 177Lu-PSMA-617, radium 223), androgen receptor signaling inhibitors (ARSi) including enzalutamide, apalutamide, darolutamide, poly ADP-ribose polymerase (PARP) monotherapy or other systemic anti-cancer treatment, with the following exceptions:
1. Treatment with first-generation antiandrogen agents, if discontinued prior to first dose of study intervention.
2. Docetaxel treatment is allowed for mCSPC, as long as no signs of failure, or disease progression occurred during treatment or within 3 months of treatment completion.
* Previous administration with an investigational product within 30 days or 5 half-lives preceding the first dose of study intervention (whichever is shorter).
* Inadequate organ function.
CABA, Buenos Aires, C1120AAT, Argentina
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Capital Federal, Buenos Aires, C1419AHN, Argentina
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Ciudad Autónoma de Buenos Aires, Buenos Aires, C1426ANZ, Argentina
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Mar del Plata, Buenos Aires, 7600, Argentina
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Mar del Plata, Buenos Aires, B7600FZO, Argentina
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Capital, Córdoba Province, X5008HHW, Argentina
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Buenos Aires, C1120, Argentina
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Buenos Aires, C1419AHN, Argentina
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Buenos Aires, C1431FWO, Argentina
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Auchenflower, Queensland, 4066, Australia
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Clayton, Victoria, 3168, Australia
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Melbourne, Victoria, 3000, Australia
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Fortaleza, Ceará, 60135-237, Brazil
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Fortaleza, Ceará, 60336232, Brazil
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Porto Alegre, Rio Grande do Sul, 90610-000, Brazil
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Santo André, São Paulo, 09060-650, Brazil
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São José do Rio Preto, São Paulo, 15090-000, Brazil
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São José do Rio Preto, São Paulo, 15090000, Brazil
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São Paulo, São Paulo, 01327-001, Brazil
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São Paulo, 01221-020, Brazil
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São Paulo, 04014-002, Brazil
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Calgary, Alberta, T2N 5G2, Canada
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Vancouver, British Columbia, V5Z 4E6, Canada
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Toronto, Ontario, M4N 3M5, Canada
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Montreal, Quebec, H2X 3E4, Canada
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Wuhu, Anhui, 241001, China
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Beijing, Beijing Municipality, 100050, China
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Beijing, Beijing Municipality, 100191, China
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Chongqing, Chongqing Municipality, 400030, China
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Fuzhou, Fujian, 350001, China
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Fuzhou, Fujian, 350014, China
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Lanzhou, Gansu, 730030, China
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Guangzhou, Guangdong, 510180, China
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Guangzhou, Guangdong, 510515, China
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Guilin, Guangxi, 541199, China
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Wuhan, Hubei, 430022, China
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Changsha, Hunan, 410013, China
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Huai'an, Jiangsu, 223300, China
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Nanjing, Jiangsu, 210000, China
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Nantong, Jiangsu, 226361, China
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Suzhou, Jiangsu, 215004, China
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Shenyang, Liaoning, 110167, China
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Shenyang, Liaoning, China
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Xi'an, Shaanxi, 710061, China
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Xi'an, Shaanxi, 710068, China
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Yantai, Shandong, 264099, China
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Shanghai, Shanghai Municipality, 200065, China
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Chengdu, Sichuan, 610041, China
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Jiaxing, Zhejiang, 314001, China
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Hangzhou, Zhejiang, 310016, China
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Ningbo, Zhejiang, 315010, China
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Wenzhou, Zhejiang, 325000, China
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Olomouc, Olomoucký kraj, 779 00, Czechia
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Pardubice, Pardubický kraj, 53203, Czechia
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Prague, Praha 10, 10034, Czechia
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Prague, Praha 4, 14059, Czechia
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Pardubice, 53003, Czechia
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Hradec Králové, 500 05, Czechia
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Nice, Alpes-maritimes, 06189, France
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Nice, Alpes-maritimes, 06189, France
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Strasbourg, Alsace, 67033, France
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Brest, Finistère, 29609, France
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Nîmes, GARD, 30029, France
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Toulouse, Haute-garonne, 31059, France
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Suresnes, Hauts-de-seine, 92151, France
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Saint-Grégoire, Ille-et-vilaine, 35760, France
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Reims, Marne, 51726, France
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Pierre-Bénite, Rhône, 69310, France
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Lyon Cedex08, Rhône-alpes, 69373, France
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Villejuif, Val-de-marne, 94800, France
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Clermont-Ferrand, 63011, France
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Tübingen, Baden-Wurttemberg, 72076, Germany
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Nürtingen, Baden-Wurttemberg, 72622, Germany
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Mettmann, North Rhine-Westphalia, 40822, Germany
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Münster, North Rhine-Westphalia, 48149, Germany
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Hamburg, 20246, Germany
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Athens, Attikí, 115 28, Greece
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Chaïdári, Attikí, 124 62, Greece
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Athens, Attikí, 155 62, Greece
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Athens, Attikí, 151 25, Greece
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Győr, Győr-Moson-Sopron, 9024, Hungary
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Budapest, Pest County, 1122, Hungary
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Meldola, Emilia-Romagna, 47014, Italy
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Rome, Lazio, 00144, Italy
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Milan, 20132, Italy
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Kashiwa, Chiba, 277-8577, Japan
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Chiba, Chiba, 260-8717, Japan
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Matsuyama, Ehime, 791-0280, Japan
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Sapporo, Hokkaido, 003-0804, Japan
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Sapporo, Hokkaido, 060-8648, Japan
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Kobe, Hyōgo, 650-0017, Japan
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Kanazawa, Ishikawa-ken, 920-8641, Japan
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Yokohama, Kanagawa, 232-0024, Japan
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Yokosuka, Kanagawa, 238-8558, Japan
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Suita, Osaka, 565-0871, Japan
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Shinjuku-ku, Tokyo, 1608582, Japan
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Yamagata, 990-9585, Japan
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Osaka, 541-8567, Japan
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Fukuoka, 811-1395, Japan
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Kumamoto, 860-0008, Japan
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Nijmegen, Gelderland, 6532 SZ, Netherlands
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Hilversum, North Holland, 1212 VG, Netherlands
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Leeuwarden, Provincie Friesland, 8934 AD, Netherlands
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Amersfoort, Utrecht, 3813 TZ, Netherlands
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Grudziądz, Kuyavian-Pomeranian Voivodeship, 86-300, Poland
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Torun, Kuyavian-Pomeranian Voivodeship, 87-100, Poland
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Krakow, Lesser Poland Voivodeship, 31-826, Poland
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Krakow, Lesser Poland Voivodeship, 30-348, Poland
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Wroclaw, Lower Silesian Voivodeship, 50-981, Poland
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Koszalin, West Pomeranian Voivodeship, 75-581, Poland
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Prešov, 08 001, Slovakia
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Trnava, 917 02, Slovakia
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Prešov, 080 01, Slovakia
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Bratislava, 833 10, Slovakia
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Košice, 041 91, Slovakia
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Martin, 036 59, Slovakia
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Port Elizabeth, Eastern Cape, 6045, South Africa
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Johannesburg, Gauteng, 2193, South Africa
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Pretoria, Gauteng, 0081, South Africa
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George, Western Cape, 6529, South Africa
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Hwasun, Jeonranamdo, 58128, South Korea
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Goyang-si, Kyǒnggi-do, 10408, South Korea
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Seoul, Seoul-teukbyeolsi [seoul], 06351, South Korea
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Seoul, Seoul-teukbyeolsi [seoul], 03080, South Korea
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Seoul, Seoul-teukbyeolsi [seoul], 03722, South Korea
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Seoul, Seoul-teukbyeolsi [seoul], 05505, South Korea
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Seoul, Seoul-teukbyeolsi [seoul], 07985, South Korea
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Daegu, Taegu-kwangyǒkshi, 41404, South Korea
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L'Hospitalet de Llobregat, Catalunya [cataluña], 08908, Spain
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Barcelona, Catalunya [cataluña], 08036, Spain
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Barcelona, Catalunya [cataluña], 08041, Spain
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Madrid, Madrid, Comunidad de, 28041, Spain
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Madrid, Madrid, Comunidad de, 28034, Spain
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Madrid, 28050, Spain
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Madrid, 28007, Spain
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Valencia, 46026, Spain
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Manresa, 8423, Spain
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Madrid, 28040, Spain
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Stockholm, Stockholms LÄN [se-01], 11883, Sweden
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Gothenburg, Västra Götalands LÄN [se-14], 413 45, Sweden
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Taichung, 407, Taiwan
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Taoyuan District, 333, Taiwan
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Kaohsiung City, 807, Taiwan
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Taipei, 10002, Taiwan
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Taipei, 11217, Taiwan
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Tainan City, 704, Taiwan
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Istanbul, İ̇stanbul, 34899, Turkey (Türkiye)
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Istanbul, İ̇stanbul, 34668, Turkey (Türkiye)
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Istanbul, İ̇stanbul, 34010, Turkey (Türkiye)
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Istanbul, İ̇stanbul, 34722, Turkey (Türkiye)
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Ankara, 06620, Turkey (Türkiye)
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Ankara, 06560, Turkey (Türkiye)
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Ankara, 06520, Turkey (Türkiye)
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Ankara, 06010, Turkey (Türkiye)
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Blackburn, Blackburn WITH Darwen, BB2 3HH, United Kingdom
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London, London, CITY of, NW1 2PG, United Kingdom
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Edinburgh, Midlothian, EH4 2XU, United Kingdom
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Swansea, SA2 8QA, United Kingdom
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Glasgow, G12 0YN, United Kingdom
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Homewood, Alabama, 35209, United States
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Glendale, Arizona, 85306, United States
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Mesa, Arizona, 85202, United States
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Mesa, Arizona, 85206, United States
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Phoenix, Arizona, 85028, United States
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Gilbert, Arizona, 85297, United States
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Scottsdale, Arizona, 85260, United States
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Chandler, Arizona, 85224, United States
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Tucson, Arizona, 85741, United States
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Glendale, California, 91204, United States
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Stanford, California, 94305, United States
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Santa Rosa, California, 95403, United States
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San Mateo, California, 94402, United States
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San Francisco, California, 94158, United States
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San Francisco, California, 94158, United States
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Palo Alto, California, 94305, United States
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Los Angeles, California, 90067, United States
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Los Angeles, California, 90017, United States
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Glendale, California, 91206, United States
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Fountain Valley, California, 92708, United States
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Burlingame, California, 94010, United States
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Berkeley, California, 94702, United States
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Anaheim, California, 92801, United States
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Lakewood, Colorado, 80228, United States
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Bonita Springs, Florida, 34135, United States
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Bradenton, Florida, 34211, United States
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Cape Coral, Florida, 33909, United States
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Fort Myers, Florida, 33905, United States
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Fort Myers, Florida, 33908, United States
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N. Venice, Florida, 34275, United States
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Sarasota, Florida, 34236, United States
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Naples, Florida, 34102, United States
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Orlando, Florida, 32804, United States
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Orlando, Florida, 32804, United States
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Port Charlotte, Florida, 33980, United States
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Westmont, Illinois, 60559, United States
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Hinsdale, Illinois, 60521, United States
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Lisle, Illinois, 60532, United States
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Lisle, Illinois, 60532, United States
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Louisville, Kentucky, 40202, United States
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Louisville, Kentucky, 40245, United States
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Louisville, Kentucky, 40202, United States
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Westbrook, Maine, 04092, United States
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Topsham, Maine, 04086, United States
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St Louis, Missouri, 63106, United States
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Egg Harbor, New Jersey, 08234, United States
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Monroe, New York, 10950, United States
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Middletown, New York, 10941, United States
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Middletown, New York, 10941, United States
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The Bronx, New York, 10468, United States
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Salisbury, North Carolina, 28144, United States
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Lancaster, Pennsylvania, 17604, United States
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Myrtle Beach, South Carolina, 29572, United States
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Myrtle Beach, South Carolina, 29572, United States
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Myrtle Beach, South Carolina, 29572, United States
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Myrtle Beach, South Carolina, 29572, United States
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Nashville, Tennessee, 37203, United States
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San Antonio, Texas, 78229, United States
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Salt Lake City, Utah, 84112, United States
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Seattle, Washington, 98109, United States
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Seattle, Washington, 98195, United States
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Seattle, Washington, 98104, United States
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