Phase 3 Randomized Study of PF-06821497 with Enzalutamide vs. Enzalutamide or Docetaxel in Metastatic Castration-Resistant Prostate Cancer Post-Abiraterone
- Trial ID
- 2024-511650-50-00
- Protocol
- C2321014
- 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 physician's choice therapy (PCT) of enzalutamide or docetaxel in prolonging radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with abiraterone acetate. This is clinically relevant as extending rPFS can potentially improve the quality of life and delay the need for subsequent therapies in this patient population.
Secondary objectives include:
- To demonstrate that PF-06821497 in combination with enzalutamide is superior to PCT (enzalutamide or docetaxel) in prolonging overall survival (OS).
- To evaluate anti-tumor activity.
- To compare safety and tolerability between the treatment arm and the control arm.
- To compare patient-reported outcomes between the treatment arm and the control arm.
- To evaluate the pharmacokinetics (PK) of PF-06821497 when dosed with enzalutamide.
- To assess the relationship between circulating tumor DNA (ctDNA) burden and outcome.
Participants
The clinical trial involves a total of **395 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 evidence of progressive disease under castration conditions and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, with a life expectancy of at least six months. Participants are required to have resolved acute effects of any prior therapy to baseline severity or to CTCAE Grade 1, except for certain adverse events deemed not to constitute a safety risk. The trial does not include female subjects or vulnerable populations, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, open-label study designed to evaluate the efficacy of **PF-06821497** in combination with **enzalutamide** compared to enzalutamide or **docetaxel** in participants with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with abiraterone acetate. The primary objective is to demonstrate the superiority of the combination therapy in prolonging radiographic progression-free survival (rPFS). The trial is expected to commence recruitment on December 15, 2024, and conclude by October 29, 2028.
Participants will be randomly assigned to one of the treatment arms. The study will involve several key visits, starting with a screening visit to confirm eligibility based on inclusion criteria such as age, histological confirmation of prostate adenocarcinoma, and evidence of metastatic disease. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 29 days for those receiving PF-06821497 and enzalutamide, with a maximum treatment period of 7 days for those receiving docetaxel or prednisolone. Participants may be withdrawn from the study early due to adverse events, disease progression, or at the discretion of the investigator if deemed in the participant's best interest. The study will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of **PF-06821497**, a small molecule drug provided in tablet form. The active substance is 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 maximum daily dose is 1750 mg, with a total maximum dose of 177625 mg over a treatment period of 29 days. The route of administration is oral, and the drug is manufactured by Pfizer Inc.
**Docetaxel** is used as a comparator treatment in this study. It is provided as a solution for infusion, with a maximum daily dose of 75 mg/m². The administration route is intravenous, and the treatment period is limited to 7 days. Docetaxel is a chemical medicinal product, and the supply is managed by Pfizer, utilizing commercially manufactured bulk enzalutamide capsules packaged as clinical supply.
**Prednisolone** is included as an auxiliary treatment, provided in tablet form. The active substance is prednisolone, with a maximum daily dose of 5 mg and a total maximum dose of 1050 mg over a 7-day treatment period. The administration route is oral, and it is classified as a chemical medicinal product.
**Dexamethasone** is also used as an auxiliary treatment, available in tablet form. The active substance is dexamethasone, with a maximum daily dose of 8 mg and a total maximum dose of 80 mg over a 7-day treatment period. The administration route is oral, and it is categorized as a chemical medicinal product.
**Xtandi - 40 mg soft capsules**, containing the active substance **enzalutamide**, are used as a comparator treatment. The maximum daily dose is 160 mg, with a total maximum dose of 3280 mg over a 29-day treatment period. The administration route is oral, and the product is manufactured by Astellas Pharma Europe B.V. Enzalutamide is provided by Pfizer, utilizing commercially manufactured bulk capsules packaged as clinical supply.
Efficacy
The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **radiographic progression-free survival (rPFS)**, which will be evaluated by blinded independent central review (BICR) according to RECIST v1.1 for soft tissue disease and PCWG3 criteria for bone disease. Secondary endpoints include overall survival (OS), the proportion of participants with measurable soft tissue disease at baseline achieving an objective response per RECIST v1.1, and the duration of response in soft tissue disease. Additionally, the trial will assess the proportion of participants with a prostate-specific antigen (PSA) response of at least 50% in those with detectable PSA values at baseline, time to PSA progression, and time to initiation of new antineoplastic therapy.
Further secondary endpoints involve the time to the first symptomatic skeletal event, progression-free survival 2 (PFS2) based on investigator assessment, and the type, incidence, severity, seriousness, and relationship to study medications of adverse events (AEs) as graded by NCI CTCAE v5.0. Patient-reported outcomes will be measured using changes from baseline in pain symptoms per the Brief Pain Inventory-Short Form (BPI-SF), health-related quality of life (HRQoL), functioning and symptoms per the Functional Assessment of Cancer Therapy-Prostate (FACT-P), and health status per the EQ-5D-5L. Symptomatic toxicity and overall side effect burden will be assessed using items from the Patient-Reported Outcome CTCAE (PRO-CTCAE) and FACT-GP5. The trial will also evaluate the time to confirmatory deterioration in patient-reported pain symptoms and time to definitive deterioration in HRQoL and physical well-being.
Pharmacokinetics will be characterized by pre-dose trough and post-dose plasma concentrations of PF-06821497 at selected visits. Additionally, circulating tumor DNA (ctDNA) burden will be assessed at baseline and during the study. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's protocol, ensuring systematic and consistent data collection throughout the study duration.
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 surgical or medical castration as defined by 1 or more of the following 3 criteria:PSA progression defined as a minimum of two rising PSA levels with an interval of ≥1 week between each determination within the last 12 months. The PSA value at the Screening visit must be ≥1 ng/mL if confirmed rise in PSA is the only indication of progression per PCWG3 criteria;Soft tissue disease progression as defined by RECIST v1.1;Bone disease progression defined by PCWG3 with 2 or more new metastatic bone lesions on a whole-body radionuclide bone scan. d. Evidence of disease progression on treatment with at least 12 weeks of abiraterone acetate in the mCSPC setting or first line mCRPC setting is required. In the non-metastatic setting, evidence of disease progression during treatment (for at least 12 weeks) or within 3 months of treatment completion. In first line mCRPC, prior treatment with abiraterone acetate (for at least 12 weeks) in conjunction with olaparib or niraparib is permissible. e. Prior treatment with PARP monotherapy for BRCAm/HRRm gene mutated mCRPC following cancer progression on abiraterone acetate is not permissible.
- 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 - 2, with life expectancy of at least 6 months as assessed by the investigator.
Exclusion Criteria
- Any medical (including active or clinically significant bacterial, fungal or viral infection) 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.
- Hematologic abnormalities defined as: ANC <1500/mm3; Platelets <100,000/μL; 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.
- 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; Cardiac rhythm device/pacemaker; QTcF >480 msec on screening ECG.
- CNS pathology/neurological findings: Known or suspected brain metastasis or active leptomeningeal disease; Symptomatic or impending spinal cord compression or cauda equina syndrome; 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; 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: Carcinoma in situ or non-melanoma skin cancer; Any prior malignancies ≥3 years before randomization with no subsequent evidence of recurrence or progression regardless of the stage; 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.
- Prior treatment for prostate cancer at any stage with any cytotoxic chemotherapy, radioligand therapy (ie, 177Lu-PSMA-617, radium-223), ARSi (including enzalutamide, apalutamide, darolutamide), PARP monotherapy or other systemic anti-cancer treatment (approved drugs or experimental compounds such as, antibody therapy, immunotherapy, gene therapy, angiogenesis inhibitors, CDK4/6 inhibitors, 5-alpha reductase inhibitors, EZH2 inhibitors) with the following exceptions: a. Treatment with first-generation antiandrogen agents (eg, bicalutamide, nilutamide, and flutamide), but must be discontinued prior to the first dose of study medication.; b. 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; c. Current use of 5-alpha reductase inhibitors is prohibited within 28 days prior to randomization..
- 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 Sections 6.9.1 and 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. For eligibility assessment based upon estimated renal function, the higher of the screening and baseline eGFR values may be used.
- Hepatic dysfunction defined as: Total bilirubin ≥1.5 × ULN; AST >2.5 × ULN; ALT >2.5 × ULN
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 15 Dec 2024 | 12 |
 France | Not Recruiting | 15 Dec 2024 | 57 |
 Germany | Not Recruiting | 15 Dec 2024 | 15 |
 Greece | Not Recruiting | 15 Dec 2024 | 8 |
 Hungary | Not Recruiting | 15 Dec 2024 | 6 |
 Italy | Not Recruiting | 15 Dec 2024 | 9 |
 The Netherlands | Not Recruiting | 15 Dec 2024 | — |
 Poland | Not Recruiting | 15 Dec 2024 | 50 |
 Slovakia | Not Recruiting | 15 Dec 2024 | 12 |
 Spain | Not Recruiting | 15 Dec 2024 | 20 |
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 |
|---|---|---|---|---|---|---|
PF-06821497 | Test | TABLET | ORAL | 1750 | 29 | PRD10984724 |
Xtandi - 40 mg soft capsules | Comparator | SOFT CAPSULES | ORAL | 160 | 29 | PRD894075 |
DEXAMETHASONE | Other | — | ORAL | 8 | 7 | SUB07017MIG |
PF-06821497 | Test | TABLET | ORAL | 1750 | 29 | PRD10984711 |
PREDNISOLONE | Other | — | ORAL | 5 | 7 | SUB10018MIG |
DEXAMETHASONE | Other | — | ORAL | 8 | 7 | SUB07017MIG |
DOCETAXEL | Comparator | — | INTRAVENOUS | 75 | 7 | SUB12492MIG |