Phase 3 Randomized Double-Blind Study of PF-06821497 and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2024-511652-40-00
- Protocol
- C2321003
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that **PF-06821497** in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer. This is clinically relevant as rPFS is a critical endpoint in assessing the efficacy of treatments for this condition, providing insights into the potential of PF-06821497 to delay disease progression.
Secondary objectives include:
- To demonstrate that PF-06821497 in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging overall survival (OS).
- To demonstrate that PF-06821497 in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging time to pain progression (TTPP).
- To evaluate anti-tumor activity.
- To compare safety and tolerability between the treatment arm and the control arm.
- To assess the relationship between circulating tumor DNA (ctDNA) burden and outcome.
- To evaluate the pharmacokinetics (PK) of PF-06821497 in combination with enzalutamide.
- To compare patient-reported outcomes (PROs) between the treatment arm and the control arm.
Participants
The clinical trial involves a total of **572 male participants** diagnosed with **metastatic castration-resistant prostate cancer**. The study population consists of males aged 18 years and older, with a confirmed histological or cytological diagnosis of adenocarcinoma of the prostate. Participants must have metastatic disease documented in bone or soft tissue and must be surgically or medically castrated, with serum testosterone levels at or below 50 ng/dL. The trial population was selected based on specific inclusion criteria, including progressive disease under castration conditions and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with a life expectancy of at least 12 months. The study does not include female subjects or vulnerable populations. Participants' general health status is assessed to ensure the resolution of acute effects from any prior therapy to baseline severity or CTCAE Grade 1, except for certain adverse events deemed not to pose a safety risk. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of PF-06821497 in combination with **enzalutamide** in patients with metastatic castration-resistant prostate cancer. The primary objective is to demonstrate the superiority of this combination over placebo with enzalutamide in prolonging radiographic progression-free survival (rPFS). The trial is expected to commence recruitment on January 10, 2025, and conclude by February 3, 2031.
Participants will be randomly assigned to receive either the investigational drug PF-06821497 with enzalutamide or a placebo with enzalutamide. The study will be conducted over a maximum treatment period of 28 days, with the possibility of continuation based on the participant's response and the absence of adverse effects. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess overall outcomes.
The inclusion criteria require male participants aged 18 years or older with histologically confirmed adenocarcinoma of the prostate, evidence of metastatic disease, and a castrated state with serum testosterone levels ≤50 ng/dL. Participants must also demonstrate progressive disease under medical or surgical castration. Exclusion criteria are not specified in the provided data.
Participants are expected to be involved in the study for the duration of the treatment period, with regular assessments to ensure compliance and monitor for any adverse events. Conditions that may lead to early termination from the study include significant adverse reactions, non-compliance with study protocols, or withdrawal of consent. The study aims to provide comprehensive data on the efficacy and safety of the investigational treatment, contributing valuable insights into the management of metastatic castration-resistant prostate cancer.
Treatment
The clinical trial involves the administration of **ENZALUTAMIDE**, a chemical medicinal product provided in capsule form. The active substance, enzalutamide, is administered orally with a maximum daily dose of 160 mg. The treatment period for enzalutamide is set at 28 days. The capsules are commercially manufactured and packaged as clinical supply by Pfizer. Participant compliance with the dosing schedule will be monitored throughout the trial.
**PF-06821497** is another investigational product used in this study. It is a small molecule drug provided in tablet form, with the active substance being 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. The tablets are administered orally with a maximum daily dose of 1750 mg, and the treatment period is also 28 days. The product is manufactured by Pfizer Inc., and participant adherence to the dosing regimen will be closely monitored.
The study also includes a **placebo** component, consisting of tablets designed to match the appearance of PF-06821497 at dosages of 125 mg and 250 mg. These placebo tablets are used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. The placebo tablets are administered orally, and compliance with the placebo regimen is monitored in the same manner as the active treatments.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of radiographic progression-free survival (**rPFS**), as determined by blinded independent central review (BICR) using RECIST 1.1 criteria for soft tissue disease and PCWG3 criteria for bone disease. Secondary endpoints include overall survival (OS), time to pain progression (TTPP), and the proportion of participants with measurable soft tissue disease at baseline achieving an objective response per RECIST 1.1, also assessed by BICR. Additional secondary endpoints involve the duration of soft tissue response, proportion of participants with a prostate-specific antigen (PSA) response of at least 50%, time to PSA progression, and time to initiation of new antineoplastic therapy or cytotoxic chemotherapy.
Further assessments will include time to the first symptomatic skeletal event, PFS2 based on investigator assessment, and the evaluation of adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. The study will also measure circulating tumor DNA (ctDNA) burden at baseline and during the study, pharmacokinetics (PK) characterized by pre-dose trough and post-dose plasma concentrations of PF-06821497 at selected visits, and changes from baseline in participant-reported outcomes such as pain symptoms, health-related quality of life (HRQoL), and physical well-being using validated instruments like the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EQ-5D-5L.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male participants aged ≥18 years (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 disease in bone documented on bone scan, or in soft tissue documented on CT/MRI scan.
- Surgically or medically castrated, with serum testosterone ≤50 ng/dL (≤1.73 nmol/L) at screening.
- Progressive disease in the setting of medical or surgical castration as defined by meeting 1 or more of the following 3 criteria: a. Prostate specific antigen (PSA) progression defined by rising PSA of at least 2 consecutive rises in most recent PSA to be documented over a reference value (measure 1) taken at least 7 days apart within the last 12 months. If the third PSA measure is not greater than the second measure, a fourth PSA measure is required to be taken and be greater than the second measure. The last of these PSA values, obtained before randomization must be ≥1 μg/L if qualifying only by PSA progression; b. Soft tissue disease progression as defined by RECIST 1.1.; c. Bone disease progression defined by PCWG3 with 2 or more new metastatic bone lesions on a whole-body radionuclide bone scan.
- Prior to randomization, there must be resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≤1 (except for AEs such as alopecia and peripheral neuropathy not constituting a safety risk in the investigator’s judgment).
- ECOG performance status 0 or 1, with a life expectancy of ≥12 months as assessed by the investigator.
Exclusion Criteria
- Any medical or psychiatric condition including recent (within the past year) or 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.
- Clinically significant cardiovascular disease, defined as: a. 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; b. Cardiac rhythm device/pacemaker.; c. QTcF >480 msec 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 non-melanoma 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.
- Participants must be treatment naïve at the mCRPC stage, eg, participants cannot have received any cytotoxic chemotherapy (includes but not limited to docetaxel), received ARSI/ abiraterone acetate in mCRPC, mCSPC or non-metastatic PC. Prior docetaxel in mCSPC is allowed.
- Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to randomization are not permitted.
- Previous administration with an investigational product (drug or vaccine which does not meet exclusion criterion 5 above) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
- Current use or anticipated need for drugs that are known strong CYP3A4/5 inhibitors and inducers (with exception of enzalutamide as part of this study) outlined in Section 6.9.1 and Section 6.9.2, including their administration within 10 days or 5 half-lives, whichever is longer prior to randomization.
- Major surgery or palliative localized radiation therapy within 14 days before randomization.
- 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 Section 10.7.1 to determine eligibility and to provide a baseline to quantify any subsequent kidney safety events.
- Hepatic dysfunction defined as: a. Total bilirubin ≥1.5 × ULN; b. AST >2.5 × ULN; c. ALT >2.5 × ULN
- Hematologic abnormalities defined as: a. ANC <1500/mm3; b. Platelets <100,000/μL; 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 10 Jan 2025 | 20 |
 Czechia | Recruiting | 10 Jan 2025 | 30 |
 Denmark | Recruiting | 10 Jan 2025 | 12 |
 Finland | Recruiting | 10 Jan 2025 | 20 |
 France | Recruiting | 10 Jan 2025 | 48 |
 Germany | Recruiting | 10 Jan 2025 | 15 |
 Greece | Recruiting | 10 Jan 2025 | 24 |
 Hungary | Recruiting | 10 Jan 2025 | 16 |
 Italy | Recruiting | 10 Jan 2025 | 25 |
 The Netherlands | Recruiting | 10 Jan 2025 | — |
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 |
|---|---|---|---|---|---|---|
Tablet to match Placebo for PF-06821497 125mg | Placebo | N/A | — | — | — | N/A |
PF-06821497 | Test | TABLET | ORAL | 1750 | 28 | PRD10984711 |
PF-06821497 | Test | TABLET | ORAL | 1750 | 28 | PRD10984724 |
Tablet to match Placebo for PF-06821497 250mg | Placebo | N/A | — | — | — | N/A |
ENZALUTAMIDE | Comparator | — | ORAL | 160 | 28 | SUB77412 |