C2321008: A PHASE 3, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY OF MEVROMETOSTAT (PF-06821497) WITH ENZALUTAMIDE IN METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER (MEVPRO-3)
- Trial ID
- 2024-519369-24-00
- Protocol
- C2321008
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
This phase 3, randomized, double-blind, placebo-controlled study evaluates mevrometostat (PF-06821497) in combination with enzalutamide in patients with metastatic castration-sensitive prostate cancer. The primary objective is to demonstrate that mevrometostat in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging blinded independent central review (BICR)-assessed radiologic progression-free survival (rPFS). This endpoint is clinically relevant as it provides an objective measure of disease control and treatment efficacy in delaying cancer progression in this patient population who have not received prior novel hormonal therapy or chemotherapy for metastatic disease.
The secondary objectives include:
• To demonstrate that mevrometostat in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging overall survival (OS).
• To compare anti-tumor activity between mevrometostat in combination with enzalutamide and placebo in combination with enzalutamide.
• To compare safety and tolerability between mevrometostat in combination with enzalutamide and placebo in combination with enzalutamide.
• To evaluate the pharmacokinetics (PK) of mevrometostat when dosed in combination with enzalutamide.
• To compare patient-reported outcomes (PROs) between mevrometostat in combination with enzalutamide and placebo in combination with enzalutamide.
• To assess the relationship between circulating tumor DNA (ctDNA) burden and outcome.
Participants
This clinical trial enrolled a total of **907 male participants** aged **18 years or older** diagnosed with **metastatic castration-sensitive prostate cancer**. The study population consisted of individuals with histologically or cytologically confirmed **adenocarcinoma of the prostate** without small cell features, with metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI scan. Participants were required to have an **ECOG performance status** of 0 or 1, indicating good functional capacity. Key selection criteria included participants who had not received prior cytotoxic chemotherapy or androgen receptor pathway inhibitors for metastatic castration-sensitive prostate cancer, with limited exceptions for androgen deprivation therapy initiated prior to randomization, which was required to continue throughout the study. Prior palliative radiation or surgery for symptomatic control was permitted if completed at least 2 weeks before randomization. The trial population excluded female subjects and did not include vulnerable populations.
Plans and Procedures
This is a Phase 3, **randomized**, **double-blind**, **placebo-controlled** clinical trial evaluating the efficacy and safety of **mevrometostat** (PF-06821497) in combination with **enzalutamide** compared to placebo in combination with enzalutamide in participants with **metastatic castration-sensitive prostate cancer**. The trial is designed to demonstrate superiority of the investigational treatment regimen in prolonging **radiologic progression-free survival** as assessed by blinded independent central review according to RECIST 1.1 criteria for soft tissue disease and PCWG3 criteria for bone disease. Participants will be male individuals aged 18 years or older with histologically or cytologically confirmed **adenocarcinoma of the prostate** without small cell features and documented metastatic disease by positive bone scan or metastatic lesions on CT or MRI scan. Eligible participants must not have received prior cytotoxic **chemotherapy**, androgen receptor pathway inhibitors, or other systemic anticancer therapies for metastatic castration-sensitive prostate cancer, with limited exceptions for **androgen deprivation therapy**, first-generation antiandrogens, and one course of palliative radiation or surgery. Participants must have an ECOG performance status of 0 or 1 at screening.
The investigational medicinal products include mevrometostat (PF-06821497) administered as oral tablets, enzalutamide provided as 40 mg soft capsules, and matching placebo tablets for mevrometostat. The maximum daily dose of mevrometostat is 1750 mg, and the maximum daily dose of enzalutamide is 160 mg, both administered via the **oral route**. The maximum treatment period is 29 days per cycle. Androgen deprivation therapy must be initiated prior to randomization and continued throughout the study duration. The trial is expected to commence recruitment in August 2025 and is estimated to conclude in February 2035, representing an overall trial duration of approximately 10 years.
The primary endpoint is blinded independent central review-assessed radiologic progression-free survival per RECIST 1.1 for soft tissue disease and PCWG3 for bone disease. Secondary endpoints include **overall survival**, objective response rate in participants with measurable soft tissue disease at baseline, duration of soft tissue response, proportion of participants with **prostate-specific antigen** response of 50% or greater, time to PSA progression, time to initiation of antineoplastic therapy, time to first symptomatic skeletal event, and time from randomization to **castration-resistant prostate cancer**. Additional secondary endpoints encompass safety assessments including type, incidence, severity, seriousness, and relationship to study medications of **adverse events** and laboratory abnormalities graded according to NCI CTCAE version 5.0. **Pharmacokinetic** parameters will be characterized by pre-dose trough and post-dose plasma concentrations of mevrometostat at selected visits. Patient-reported outcomes will be evaluated through changes from baseline and time to deterioration in pain symptoms, health-related quality of life, functioning, fatigue symptoms, and general health status using validated instruments. Exploratory endpoints include assessment of **circulating tumor DNA** burden at baseline and during the study.
Participant involvement begins with a screening visit to assess eligibility criteria and confirm diagnosis. Following successful screening and randomization, participants will attend regular follow-up visits for administration of study medications, safety assessments, efficacy evaluations including radiologic imaging, collection of blood samples for pharmacokinetic analysis and biomarker assessments, and completion of patient-reported outcome questionnaires. The frequency and timing of follow-up visits will be specified in the study protocol to ensure comprehensive monitoring of disease status, treatment response, and safety parameters. An end-of-study visit will be conducted to perform final assessments and ensure appropriate transition of care. The expected length of participant involvement extends throughout the treatment period until disease progression, unacceptable toxicity, withdrawal of consent, or study completion.
Conditions that may lead to early termination from the study include disease progression as determined by radiologic assessment or clinical criteria, development of unacceptable toxicity or adverse events requiring discontinuation of study treatment, participant decision to withdraw consent, initiation of alternative anticancer therapy, loss to follow-up, investigator decision that continued participation is not in the participant's best interest, pregnancy, or administrative reasons including sponsor decision to terminate the study. Participants who discontinue study treatment will be followed for survival and subsequent anticancer therapies unless consent is withdrawn for all study procedures.
Treatment
The experimental medication **PF-06821497** is administered as an oral tablet containing the active substance 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one. This small molecule drug is supplied in tablet form and administered via the **oral route**. The maximum daily dose is 1750 mg and the maximum total dose is 1750 mg. The maximum treatment period is 29 days. PF-06821497 is classified as an investigational medicinal product with test role in the trial.
**Enzalutamide** is administered as a commercially authorized medicinal product under the trade name Xtandi, supplied as 40 mg soft capsules. Enzalutamide is a chemical medicinal product administered via the oral route. The maximum daily dose is 160 mg and the maximum total dose is 160 mg. The maximum treatment period is 29 days. Enzalutamide provided by Pfizer utilizes commercially manufactured bulk enzalutamide capsules that are packaged as clinical supply. This product holds marketing authorization in the European Union under the number EU/1/13/846/001.
**Placebo** tablets are provided to match PF-06821497 in two strengths: tablets to match placebo for PF-06821497 125 mg and tablets to match placebo for PF-06821497 250 mg. These placebo formulations are designed to maintain blinding in this double-blind, placebo-controlled study. The placebo tablets contain no active substance and serve as the comparator treatment in the control arm of the trial.
Efficacy
The primary efficacy endpoint is radiologic progression-free survival assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease and Prostate Cancer Working Group 3 criteria for bone disease. Secondary efficacy endpoints include overall survival, the proportion of participants with measurable soft tissue disease at baseline achieving an objective response per Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by blinded independent central review and investigator, duration of soft tissue response per Response Evaluation Criteria in Solid Tumors version 1.1 assessed by blinded independent central review and investigator, proportion of participants with prostate-specific antigen response of 50% or greater in participants with detectable prostate-specific antigen values at baseline, time to prostate-specific antigen progression, time to initiation of antineoplastic therapy, time to first symptomatic skeletal event, and time from randomization to castration-resistant prostate cancer. Additional secondary endpoints include change from baseline and time to confirmed deterioration in participant-reported worst pain symptoms per Brief Pain Inventory Short Form, change from baseline in health-related quality of life, functioning, and symptoms and time to definitive deterioration per Functional Assessment of Cancer Therapy Prostate, change from baseline and time to definitive deterioration in participant-reported prostate cancer specific functioning and symptoms per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Cancer 25, change from baseline and time to confirmed deterioration in participant-reported fatigue symptoms per Brief Fatigue Inventory, change from baseline in participant-reported general health status per European Quality of Life 5-Dimensions 5-Level, and circulating tumor DNA burden at baseline and on study. Pharmacokinetic characterization will be performed through assessment of pre-dose trough and post-dose plasma concentrations of mevrometostat at selected visits.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male participants aged 18 years of age or older (or the minimum age of consent in accordance with local regulations) at screening.
- Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell features (neuroendocrine differentiation and other histologic components are permitted if adenocarcinoma is the primary histology). For participants without a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis.
- Metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesion(s) on CT or MRI scan (for soft tissue/visceral disease).
- Resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≤1 (except for AEs which do not constitute a safety risk in the investigator’s judgement).
- Participants cannot have received any cytotoxic chemotherapy, ARPIs (eg, enzalutamide, apalutamide, abiraterone acetate, or darolutamide), any other systemic anticancer therapies for mCSPC, with the following exceptions: a.ADT (chemical or surgical) must be started prior to randomization and must continue throughout the study. Prior therapy with up to 3 months of ADT (with or without antiandrogens) is allowed with no radiographic evidence of disease progression or rising PSA levels indicative of disease progression prior to Day 1.; b. Treatment with estrogens, cyproterone acetate or first-generation antiandrogens is allowed until randomization, but must be discontinued prior to randomization.; c. Participants may have received 1 course of palliative radiation or surgery for symptomatic control secondary to prostate cancer, which should be completed at least 2 weeks prior to randomization.
- Participants must have ECOG PS 0 or 1.
Exclusion Criteria
- Any medical or psychiatric condition including any active suicidal ideation in the past year or suicidal behavior in the past 5 years or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
- Current use of any prohibited concomitant medication(s) or unwillingness or inability to use a required concomitant medication(s).
- Prior treatment with: a.ADT in the adjuvant/neoadjuvant setting, where the completion of ADT was <12 months prior to randomization and the total duration of ADT was >36 months; b. ARPI’s such as abiraterone, apalutamide, darolutamide, enzalutamide or other investigational ARPI’s; c.Cytochrome P17 enzyme inhibitors such as oral ketoconazole as anticancer treatments for prostate cancer; d. Chemotherapy including docetaxel or immunotherapy for prostate cancer.; e. Radiopharmaceuticals (ie, 177Lu-PSMA-617, radium-223); f. CDK4/6 inhibitors; g. Any other anticancer treatment for metastatic prostate cancer, excluding palliative radiotherapy/surgery and ADT as discussed above.
- Previous administration of an investigational product (drug or vaccine) which does not meet exclusion criterion 7 within 30 days or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during participation in this study.
- Inadequate renal function defined by an eGFR <45 mL/min/1.73 m2. Based upon participant age at screening, eGFR is calculated using the recommended formulas in Appendix 7 Section 10.7.2 to determine eligibility and to provide a baseline to quantify any subsequent kidney safety events. For eligibility assessment based upon estimated renal function, the higher of the screening and baseline eGFR values may be used.
- Major surgery (as defined by investigator) from which the participant has not fully recovered at least 28 days prior to randomization.
- Hepatic dysfunction defined as having any 1 of the following, which may be confirmed by a single repeat test, if necessary: a. Total bilirubin ≥1.5 x ULN (≥3 x ULN for participants with documented Gilbert’s syndrome, direct bilirubin >ULN is exclusionary) b. AST >2.5 x ULN c. ALT >2.5 x ULN
- Hematologic abnormalities defined as having any 1 of the following, which may be confirmed by a single repeat test, if necessary: a. ANC <1500/mm3; b. Platelets <100,000/mm3, independent of transfusion within 14 days of randomization; c. Hemoglobin <9 g/dL, independent of transfusion within 14 days of randomization
- Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
- Inability to swallow oral medications.
- Clinically significant cardiovascular disease, defined as: Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, or symptomatic pulmonary embolism or other clinically significant episode of thromboembolic disease, congenital long QT syndrome, Torsade de Pointes, clinically important arrhythmias, left anterior hemiblock (bifascicular block), ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, or other clinically significant cardiovascular disease as assessed by the investigator. If a participant has a cardiac rhythm device/pacemaker placed and QTcF >470 ms, the participant may be considered eligible. QTcF >480 ms on screening ECG.
- CNS pathology/neurological findings: a.Known or suspected brain metastasis or active leptomeningeal disease; b.Symptomatic or impending spinal cord compression or cauda equina syndrome; c.Participants with epidural disease, canal disease and prior cord involvement are NOT excluded if those areas have been treated, are stable and not neurologically impaired; d. Clinically significant history of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Also history of unexplained loss of consciousness or transient ischemic attack within 12 months of randomization.
- Any history of myelodysplastic syndrome, acute myeloid leukemia, or any other prior malignancy except for any of the following: a.Carcinoma in situ or nonmelanoma skin cancer.; b.Any prior malignancies ≥3 years before randomization with no subsequent evidence of recurrence or progression regardless of the stage; c. Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence or progression in the opinion of the investigator.
- In the opinion of the investigator, any clinically significant gastrointestinal disorder affecting absorption.
- Known allergic or hypersensitivity reactions to mevrometostat or its excipients or to enzalutamide or its excipients.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 30 Aug 2025 | 40 |
 Bulgaria | Not Recruiting | 30 Aug 2025 | 8 |
 Czechia | Not Recruiting | 30 Aug 2025 | 27 |
 Finland | Not Recruiting | 30 Aug 2025 | 34 |
 France | Not Recruiting | 30 Aug 2025 | 60 |
 Germany | Not Recruiting | 30 Aug 2025 | 54 |
 Greece | Not Recruiting | 30 Aug 2025 | 23 |
 Italy | Not Recruiting | 30 Aug 2025 | 52 |
 The Netherlands | Not Recruiting | 30 Aug 2025 | — |
 Poland | Not Recruiting | 30 Aug 2025 | 38 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Xtandi - 40 mg soft capsules | Test | SOFT CAPSULES | ORAL | 160 | 29 | PRD894075 |
PF-06821497 | Test | TABLET | ORAL | 1750 | 29 | PRD10984724 |
PF-06821497 | Test | TABLET | ORAL | 1750 | 29 | PRD10984711 |
Tablet to match placebo for pf-06821497 125mg | Placebo | N/A | — | — | — | N/A |
Tablet to match placebo for pf-06821497 250mg | Placebo | N/A | — | — | — | N/A |