Phase II Randomized Trial Evaluating Enzalutamide and Talazoparib in Metastatic Hormone-Naïve Prostate Cancer Patients
- Trial ID
- 2023-509387-24-00
- Protocol
- MEDOPP234
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized phase II trial is to evaluate the **antitumor activity** of talazoparib in combination with enzalutamide and androgen deprivation therapy (ADT) in patients with metastatic hormone-naïve prostate cancer (mHNPC). This is determined by the confirmed prostate-specific antigen-complete response (PSA-CR). The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with mHNPC by assessing the efficacy of this combination therapy in achieving a complete response, which could lead to better disease management and patient prognosis.
Secondary objectives include:
- Analyzing the **PSA response** and time to development of castration resistance (TTCR) when ADT and enzalutamide are administered with talazoparib in this population.
- Assessing the correlation between molecular and transcriptomic signatures of DNA damage repair (DDR) function and antitumor activity in this population.
- Evaluating the impact of ADT and enzalutamide treatment on DNA repair function in this population.
- Evaluating the safety and tolerability of talazoparib in combination with enzalutamide and ADT in this population.
Participants
The clinical trial involves **adult male patients** diagnosed with **metastatic hormone-naïve prostate cancer (mHNPC)**. The study population comprises individuals aged 18 years and older, with a focus on those who have a life expectancy of at least 12 months and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Participants are required to have high-volume metastatic disease, as evidenced by imaging scans, and must have histologically confirmed adenocarcinoma of the prostate. The trial does not include female subjects or vulnerable populations. Participants are expected to maintain stable dosages of bisphosphonates or denosumab if applicable, and must demonstrate adequate hematologic and organ function. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, phase II study to evaluate the antitumor activity of **talazoparib** in combination with **enzalutamide** and androgen deprivation therapy (ADT) in patients with metastatic hormone-naïve prostate cancer (mHNPC). The trial aims to determine the confirmed prostate-specific antigen-complete response (PSA-CR) in this patient population. The study is structured as a two-arm, open-label trial, with participants randomly assigned to receive either the investigational treatment or a control. The trial is expected to conclude by May 2025, with recruitment having commenced in September 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, performance status, and disease characteristics. Following successful screening, participants will enter the treatment phase, which involves regular follow-up visits to monitor treatment response, safety, and adherence to the protocol. These visits will include assessments of PSA levels, imaging studies, and laboratory tests. The primary endpoint is the percentage of patients achieving a PSA level of less than 0.2 ng/mL at month 12 of therapy. Secondary endpoints include PSA response rates at various time points, progression-free survival, and overall survival.
The expected duration of participant involvement is approximately 230 to 238 days, depending on the specific treatment arm. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants are required to comply with scheduled visits, treatment plans, and study procedures, including the provision of tumor biopsies for exploratory analyses. The trial's design ensures rigorous monitoring of safety and efficacy, with adverse events assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Treatment
The clinical trial involves the administration of **Talazoparib**, marketed under the name Talzenna, in two different dosages: 0.25 mg and 0.1 mg. Talzenna is provided in the form of hard capsules and is administered orally. The active substance, talazoparib, is a chemical compound classified under the ATC code L01XK04. The maximum daily dose for each formulation is 1 mg, with a total maximum dose of 1610 mg over a treatment period of up to 230 days. The pharmaceutical product is manufactured by Pfizer Europe MA EEIG and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial.
In addition to Talzenna, the trial includes the administration of **Enzalutamide**, marketed as Xtandi, in the form of 40 mg film-coated tablets. Enzalutamide is also a chemical compound, classified under the ATC code L02BB04, and is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 266.56 g over a treatment period of up to 238 days. Xtandi is produced by Astellas Pharma Europe B.V. and is not intended for pediatric use. The trial aims to evaluate the antitumor activity of talazoparib in combination with enzalutamide and androgen deprivation therapy (ADT) in patients with metastatic hormone-naïve prostate cancer (mHNPC).
Efficacy
The efficacy of the treatment in this clinical trial will be assessed primarily through the measurement of **prostate-specific antigen-complete response (PSA-CR)**. The primary endpoint is defined as the percentage of patients achieving a PSA level of less than 0.2 ng/mL at month 12 of therapy. Secondary endpoints include the rate of PSA complete response at any time point and specifically at month 7, PSA response at 7 and 12 months, and PSA progression-free survival (PSA-PFS) based on the Prostate Cancer Working Group 3 (PCWG3) criteria. Additionally, radiologic progression-free survival (rPFS) will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, along with time to castration resistance (TTCR) and overall survival (OS).
The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, with PSA levels being a critical biomarker for assessing treatment response. The trial will also monitor the incidence of adverse events and changes from baseline in targeted vital signs and clinical laboratory test results, as per the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. These assessments will provide comprehensive data on the antitumor activity of the combination therapy involving **talazoparib** and **enzalutamide** in patients with metastatic hormone-naïve prostate cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult patients (>18 y.o.) who signed informed consent form (ICF) prior to participation in any study-related activities.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- High-volume metastatic disease documented on bone scan or computed tomography (CT)/magnetic resonance imaging (MRI) scan, defined as the presence of either visceral disease and/or at least four bone metastases on bone scan, with at least one of them beyond spine/pelvis.
- Life expectancy of ≥ 12 months.
- Histologically confirmed adenocarcinoma of the prostate without predominance of small-cell or neuroendocrine features according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines based on local testing on the most recent analyzed biopsy. Note: Central confirmation of adenocarcinoma is not required for study entry. However, tissue blocks, or slides, must be submitted to confirm the diagnoses by a Sponsor-designated central laboratory retrospectively and/or exploratory biomarker analyses.
- Willingness and ability to provide tumor paired biopsies during the study participation in order to perform exploratory studies. At the study entry, the most recent tumor biopsy since last progression from either metastatic or primary tissues will be provided. If not feasible, patient eligibility should be evaluated by a Sponsor’s qualified designee.
- Adequate hematologic and organ function within 28 days before the first study treatment on Cycle 1 Day 1, defined by the following: a. Hematological: i. White blood cell (WBC) count > 3.0 x 109/L; ii. Absolute neutrophil count (ANC) > 1.5 x 109/L; iii. Platelet count > 100.0 x109/L; iv. Hemoglobin (Hb) > 9.0 g/dL. Note: Patients receiving growth factors or blood transfusions within 14 days before obtaining the hematology values at screening will be excluded. b. Hepatic: i. Total bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (≤ 3 x ULN in the case of Gilbert’s disease); ii. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN); iii. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN in the case of liver and/or bone metastases). c. Renal: i. Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 30 mL/min based on Cockcroft−Gault glomerular filtration rate estimation. d. Coagulation: i. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless on medication known to alter INR and/or aPTT. e. Nutritional status: i. Serum Albumin ≥ 2.8 g/dL.
- Bisphosphonates or denosumab dosage must have been stable for at least 4 weeks before Day 1 for patients receiving these therapies.
- Patients must agree to use a condom when is engaged in sexual activity with a pregnant woman during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after last dose of talazoparib (PF-06944076), whichever occurs later. Patients must also agree to use an additional highly effective form of contraception or two effective contraceptive methods, when is engaged in sexual intercourse with a woman of childbearing potential during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after last dose of talazoparib (PF-06944076), whichever occurs later
- Must agree to refrain to donate sperm during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after last dose of talazoparib (PF-06944076), whichever occurs later.
- PSA ³ 4 ng/mL at diagnosis or before starting ADT therapy.
Exclusion Criteria
- Prior treatment with enzalutamide, apalutamide, darolutamide or abiraterone acetate.
- History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills.
- Known hypersensitivity to recombinant proteins, or any excipient contained in the drug formulation for talazoparib (PF-06944076) and enzalutamide.
- Prior systemic therapy for metastatic prostate cancer (mPCa). Note: Initiation of androgen deprivation therapy (ADT) within 4 weeks prior to study entry would be allowed (with or without first-generation antiandrogens), providing a tumor biopsy sample was taken prior to initiation of ADT is made available for biomarker studies and upon approval by the sponsor. If patient was started on first-generation antiandrogens, these would be discontinued on prior to randomization. Note: Patients relapsing after having received an ADT-based regimen in neoadjuvant or adjuvant setting will be suitable for the study if metastatic progression occured while on non-castrate testosterone levels or at least 12 months after discontinuation of ADT
- Treatment with approved or investigational cancer therapy within 28 days (or 5 half-lives of the drug‒ whichever is longer) prior to initiation of study treatment.
- Known or suspected brain metastases or active leptomeningeal disease
- Symptomatic or impending spinal cord compression or cauda equina syndrome.
- Subject has a history of seizure or any condition that may predispose to seizure (i.e. prior significant brain trauma, brain vascular malformations, …), or subjects that have had unexplained loss of consciousness or transient ischemic attacks within 1 year prior to scheduled Day 1 of treatment.
- Therapeutic radiation therapy within 14 days (seven days for limited-field palliative radiotherapy) prior to study enrolm National Cancer Insitute´s Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v.)5.0.ent, or patients who have not recovered from radiotherapy-related toxicities to grade ≤ 1 according to
- Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 14 days of start of study drugs, or patients who have not recovered from the side effects of any major surgery.
- History of another malignancy within three years of study enrollment with the exception of carcinoma in situ, non-melanoma skin carcinoma, or American Joint Committee on Cancer stage 0 or stage 1 cancer that has a remote probability of recurrence in the opinion of the investigator and the Sponsor’s Medical Monitor is required, or any concurrent malignancy for which the patient is receiving therapy
- Active uncontrolled infection at the time of enrollment.
- Congenital long QT syndrome or Electrocardiogram (ECG) at screening with QT interval corrected using Fridericia's formula (QTcF) > 500 milliseconds.
- Patients with clinically significant cardiovascular disease including but not limited to any of the following: a. Stroke, transient ischemic attack, unstable angina pectoris, or documented myocardial infarction within 12 months prior to study entry. b. Symptomatic pericarditis or clinically significant pericardial effusion or myocarditis. c. Documented congestive heart failure (New York Heart Association functional classification III- IV). d. Uncontrolled, persistent hypertension defined as systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg.
- Patients have any of the following cardiac conduction abnormalities: a. Ventricular arrhythmias except for benign premature ventricular contractions. b. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication. c. Conduction abnormality requiring a pacemaker. d. Other cardiac arrhythmia not controlled with medication.
- Patients have any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment contraindicate patient participation in the clinical study.
- Treatment with estrogens, cyprotoerone acetate or glucocorticoids (at a dose greater than the equivalent to 10 mg/day of prednisone) in the 4 weeks prior to scheduled Day 1 of treatment.
- Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are employees of the trial sponsor, including their family members, directly involved in the conduct of the study.
- Concurrent participation in other clinical trial, except other translational studies or observational studies (defined as those with no therapeutic intervention)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 02 Sept 2020 | 54 |
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 |
|---|---|---|---|---|---|---|
Talzenna 0.25 mg hard capsules | Test | HARD CAPSULES | ORAL | 1 | 230 | PRD7388550 |
Talzenna 0.1 mg hard capsules | Test | HARD CAPSULES | ORAL | 1 | 230 | PRD11072548 |
Xtandi - 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 160 | 238 | PRD5512210 |