Phase 3 Randomized Double-Blind Study of Talazoparib and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2023-509087-20-00
- Protocol
- C3441021
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of **talazoparib** in combination with **enzalutamide** compared to placebo with enzalutamide in prolonging blinded independent central review (BICR) assessed radiographic progression-free survival (rPFS) in participants with metastatic castration-resistant prostate cancer (mCRPC). This is assessed in two distinct participant groups: those unselected for DNA damage repair (DDR) status and those harboring DDR deficiencies. The clinical relevance of this objective lies in its potential to improve treatment outcomes for mCRPC, a condition with limited therapeutic options and significant morbidity.
Secondary objectives include:
- Characterizing the steady-state pharmacokinetics (PK) of talazoparib and enzalutamide, along with its N-desmethyl metabolite, when administered in combination.
- Demonstrating that talazoparib combined with enzalutamide is superior to placebo with enzalutamide in prolonging overall survival (OS) in participants with mCRPC unselected for DDR status.
- Demonstrating that talazoparib combined with enzalutamide is superior to placebo with enzalutamide in prolonging OS in participants with mCRPC harboring DDR deficiencies.
Participants
The clinical trial involves a total of **716 participants** diagnosed with **Metastatic Castration-resistant Prostate Cancer**. The study population is exclusively male, with an age range starting from 18 years, and for participants in Japan, from 20 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have a life expectancy of at least 12 months and be able to comply with the study's requirements, including scheduled visits and treatment plans. Lifestyle considerations include the ability to swallow the study treatment and adherence to specific contraceptive measures if sexually active. The trial population was selected based on histologically or cytologically confirmed adenocarcinoma of the prostate, with evidence of metastatic disease in bone or soft tissue. Participants must be surgically or medically castrated, with ongoing androgen deprivation therapy if they have not undergone bilateral orchiectomy. The trial excludes individuals with small cell or signet cell features in their cancer diagnosis. The sponsor has not provided information on specific dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **talazoparib** in combination with **enzalutamide** in patients with **metastatic castration-resistant prostate cancer** (mCRPC). The trial is structured in two parts: Part 1 aims to determine the starting dose of talazoparib when combined with enzalutamide, while Part 2 seeks to demonstrate the superiority of this combination over placebo in prolonging radiographic progression-free survival (rPFS) as assessed by blinded independent central review (BICR). The study is expected to conclude by December 31, 2025, with participant recruitment having commenced on December 18, 2017.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and disease characteristics. Following successful screening, participants will be randomized to receive either the investigational combination or placebo. The trial includes regular follow-up visits to monitor safety, efficacy, and compliance with the treatment regimen. These visits will involve clinical assessments, laboratory tests, and imaging studies as per protocol requirements. 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 24 months, corresponding to the maximum treatment period. Participants may be withdrawn from the study early due to reasons such as adverse events, disease progression, or withdrawal of consent. The trial's primary endpoints include the occurrence of target safety events in Part 1 and BICR-assessed rPFS in Part 2. Secondary endpoints involve pharmacokinetic parameters and overall survival (OS) in participants with mCRPC, both unselected and selected for DNA damage repair (DDR) deficiencies.
Treatment
The clinical trial involves the administration of **enzalutamide**, marketed under the name Xtandi, which is provided in the form of 40 mg **soft capsules**. The pharmaceutical form is designed for **oral use**. The maximum daily dose of enzalutamide is 160 mg, and the treatment period extends up to 24 months. The medication is of chemical origin and is manufactured by Astellas Pharma Europe B.V. The administration schedule requires participants to take the medication daily, and compliance is monitored through regular assessments.
In addition to enzalutamide, the trial includes the administration of **talazoparib**, which is provided in the form of **hard capsules**. Talazoparib is also administered orally, with a maximum daily dose of 0.5 mg. The treatment period for talazoparib is similarly set at 24 months. This medication is of chemical origin, and its administration is monitored to ensure adherence to the dosing schedule. Talazoparib is used in combination with enzalutamide to evaluate its efficacy in the treatment of metastatic castration-resistant prostate cancer (mCRPC).
The study also incorporates a **placebo** control group to assess the efficacy of the combination treatment. The placebo is administered in a manner identical to the active treatments, ensuring blinding and maintaining the integrity of the trial. Compliance with the placebo regimen is monitored in the same manner as the active treatments, with regular assessments to ensure adherence to the study protocol.
Efficacy
Efficacy in the clinical trial titled "C3441021 - TALAPRO 2: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Talazoparib with Enzalutamide in Metastatic Castration-Resistant Prostate Cancer" will be assessed using specific primary and secondary endpoints. The primary efficacy endpoint for Part 2 of the trial is the **BICR assessed rPFS** (radiographic progression-free survival) per RECIST 1.1 for soft tissue disease and PCWG3 for bone disease in participants with metastatic castration-resistant prostate cancer (mCRPC), both unselected for DDR status and those harboring DDR deficiencies. Secondary endpoints include overall survival (OS) in participants with mCRPC, both unselected for DDR status and those with DDR deficiencies, with alpha protection applied.
The trial will utilize a double-blind, placebo-controlled design to ensure objective assessment of efficacy. The efficacy parameters will be measured and collected at predefined intervals throughout the study, with specific timepoints not detailed in the provided data. The analysis will be conducted using validated criteria such as RECIST 1.1 and PCWG3 to evaluate disease progression in both soft tissue and bone. The study aims to demonstrate the superiority of talazoparib in combination with enzalutamide over placebo in combination with enzalutamide in prolonging rPFS in the specified patient populations.
Inclusion and Exclusion Criteria
Inclusion Criteria
- At least 18 years of age. For Japan, at least 20 years of age.
- Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features. If the participant does not have a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis and to support biomarker analysis.
- Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI SF Question #3 must be <4).
- For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status by prospective analysis of blood (liquid biopsy), or tissue (de novo or archival tissue), or historical analysis (with Sponsor pre approval), of most recent tumor tissue per FoundationOne® testing. (Note: for participants enrolling in Part 1, DDR deficiency testing is optional). • Biopsies of the brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel may not be performed for the sole purpose of determining study eligibility.
- For enrollment into Part 2 only (optional for Part 1): Unless prohibited by local regulations or ethics committee decision, consent to a saliva sample collection for retrospective sequencing of the same DDR genes tested on tumor tissue and blood (liquid biopsy), or a subset thereof, and to serve as a germline control in identifying tumor mutations.
- Surgically or medically castrated, with serum testosterone ≤50 ng/dL (≤1.73 nmol/L) at screening. Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist for participants who have not undergone bilateral orchiectomy must be initiated at least 4 weeks before Day 1 (Part 1) or randomization (Part 2) and must continue throughout the study.
- Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan. Scans obtained as part of standard of care in the 6 weeks (42 days) prior to Day 1 (Part 1) or randomization (Part 2) can be used if they meet study requirements. Measurable soft tissue disease is not required. (Adenopathy below the aortic bifurcation alone does not qualify).
- Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria: • 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 third (or the fourth) confirmatory PSA should be taken within 4 weeks prior to randomization. The third (or the fourth) PSA value, obtained before randomization must be ≥1 µg/L if qualifying only by PSA progression. • Soft tissue disease progression as defined by RECIST 1.1. • Bone disease progression defined by Prostate Cancer Working Group (PCWG3) with 2 or more new metastatic bone lesions on a whole-body radionuclide bone scan.
- Ongoing bisphosphonate or denosumab use prior to Day 1 (Part 1) or randomization (Part 2) is allowed but not mandatory.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
- Life expectancy ≥12 months as assessed by the investigator.
- Able to swallow the study treatment and have no known intolerance to study treatments or excipients.
- Sexually active participants that in the opinion of the investigator are capable of ejaculating, must agree to use a condom when having sex with a partner (female or male) from the time of the first dose of study treatment through 4 months after last dose of study treatment. Must also agree for female partner of childbearing potential to use an additional highly effective form of contraception (Section 4.4.1) from the time of the first dose of study treatment through 4 months after last dose of study treatment when having sex with a non pregnant female partner of childbearing potential.
- Must agree not to donate sperm from the first dose of study treatment to 4 months after the last dose of study treatment.
- Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the participant [or a legally acceptable representative] has been informed of all pertinent aspects of the study.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion Criteria
- Any prior systemic cancer treatment initiated in the non metastatic CRPC or mCRPC disease state. (ADT and first generation anti-androgens received in the CRPC disease state are NOT exclusionary).
- Participants whose only evidence of metastasis is adenopathy below the aortic bifurcation.
- Prior treatment with second generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.
- Prior treatment with platinum based chemotherapy within 6 months (from the last dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum based therapy within 6 months (from the last dose).Prior treatment with platinum based chemotherapy within 6 months (from the last dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum based therapy within 6 months (from the last dose).
- Treatment with cytotoxic chemotherapy which includes but is not limited to docetaxel, biologic therapy including sipuleucel T, or radionuclide therapy received in the castration sensitive prostate cancer is NOT exclusionary if discontinued in the 28 days prior to Day 1 (Part 1) or randomization (Part 2). Prior treatment with abiraterone in the castration-sensitive settings is not exclusionary if discontinued prior to randomization. Hormonal therapy (eg, bicalutamide, nilutamide, flutamide, estrogens) are not exclusionary if discontinued prior to randomization. Prednisone >10 mg/day (or equivalents) is exclusionary.
- Treatment with any investigational agent within 4 weeks before Day 1 (Part 1) or randomization (Part 2).
- Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2).
- Current use of potent P-gp inhibitors within 7 days prior to Day 1 (Part 1) or randomization (Part 2). For a list of potent P gp inhibitors, and other medications which are exclusionary because of interaction with either talazoparib or enzalutamide, refer to Section 5.9.
- Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or palliative localized radiation therapy within 3 weeks before randomization (Part 2).
- Clinically significant cardiovascular disease, including any of the following: • Myocardial infarction or symptomatic cardiac ischemia within 6 months before Day 1 (Part 1) or randomization (Part 2). • Congestive heart failure New York Heart Association class III or IV. • History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before screening. • History of Mobitz II second degree or third-degree heart block unless a permanent pacemaker is in place. • Hypotension as indicated by systolic blood pressure <86 mm Hg at screening. • Bradycardia as indicated by a heart rate of <45 beats per minute on the screening electrocardiogram. • Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at screening. However, participants can be rescreened after adequate control of blood pressure is achieved.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Dec 2017 | 25 |
 Czechia | Not Recruiting | 18 Dec 2017 | 15 |
 Finland | Not Recruiting | 18 Dec 2017 | 43 |
 France | Not Recruiting | 18 Dec 2017 | 52 |
 Germany | Not Recruiting | 18 Dec 2017 | 21 |
 Hungary | Not Recruiting | 18 Dec 2017 | 20 |
 Italy | Not Recruiting | 18 Dec 2017 | 55 |
 Norway | Not Recruiting | 18 Dec 2017 | 32 |
 Poland | Not Recruiting | 18 Dec 2017 | 47 |
 Portugal | Not Recruiting | 18 Dec 2017 | 18 |
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 |
|---|---|---|---|---|---|---|
TALAZOPARIB | Placebo | — | ORAL USE | 0.5 | 24 | SUB180394 |
TALAZOPARIB | Test | — | ORAL USE | 0.5 | 24 | SUB180394 |
TALAZOPARIB | Test | — | ORAL USE | 0.5 | 24 | SUB180394 |
Xtandi - 40 mg soft capsules | Test | SOFT CAPSULES | ORAL USE | 160 | 24 | PRD1863628 |
TALAZOPARIB | Placebo | — | ORAL USE | 0.5 | 24 | SUB180394 |