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Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC

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ClinicalTrials.gov Identifier: NCT04821622
Recruitment Status : Recruiting
First Posted : March 29, 2021
Last Update Posted : September 22, 2021
Sponsor:
Collaborator:
Astellas Pharma Inc
Information provided by (Responsible Party):
Pfizer

Brief Summary:
The purpose of the study is to evaluate the safety and efficacy of talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide in participants with DDR-deficient mCSPC.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: talazoparib plus enzalutamide Drug: Placebo plus enzalutamide Phase 3

Detailed Description:

The study will have 5 periods: prescreening, screening, double-blind treatment, safety follow-up, and long-term follow-up.

Approximately 550 men with mCSPC will be randomized. Eligible participants will be randomly assigned to either of 2 treatment groups as follows:

  • Talazoparib in combination with enzalutamide.
  • Placebo capsules identical in appearance to talazoparib capsules in combination with enzalutamide.

Talazoparib or identical placebo treatment will be blinded. Enzalutamide (160 mg/day) will be open label. The dose of talazoparib/placebo to be given in combination with enzalutamide is 0.5 mg once daily. Participants with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2 by the MDRD equation) at screening may be enrolled and the talazoparib/placebo dose will be 0.35 mg once daily.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: TALAPRO-3: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, STUDY OF TALAZOPARIB WITH ENZALUTAMIDE VERSUS PLACEBO WITH ENZALUTAMIDE IN MEN WITH DDR GENE MUTATED METASTATIC CASTRATION-SENSITIVE PROSTATE CANCER
Actual Study Start Date : May 12, 2021
Estimated Primary Completion Date : December 11, 2024
Estimated Study Completion Date : April 10, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1
Talazoparib plus enzalutamide
Drug: talazoparib plus enzalutamide
experimental arm
Other Name: Combination arm

Active Comparator: Arm 2
Placebo plus enzalutamide
Drug: Placebo plus enzalutamide
Active comparator arm
Other Name: Monotherapy arm




Primary Outcome Measures :
  1. radiological Progression-Free Survival [ Time Frame: randomization up to 3 years ]
    time from the date of randomization to first objective evidence of radiographic progression or death, whichever occurs first


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: randomization up to 4 years ]
    time from randomization to death from any cause

  2. Objective response in measurable soft tissue disease [ Time Frame: randomization up to 3 years ]
    proportion of patients with measurable soft tissue disease at baseline with objective response per RECIST 1.1

  3. Duration of response in measurable soft tissue disease [ Time Frame: randomization up to 3 years ]
    duration of responses in patients with measurable soft tissue disease at baseline per RECIST 1.1

  4. Prostate Specific Antigen (PSA) response [ Time Frame: randomization up to 3 years ]
    proportion of patients with PSA response grater than or equal to 50%

  5. Time to PSA progression [ Time Frame: randomization up to 3 years ]
    time from baseline to PSA progression

  6. Time to initiation of antineoplastic therapy [ Time Frame: randomization up to 3 years ]
    Time from randomization to initiation of antineoplastic therapy

  7. Time to first symptomatic skeletal event [ Time Frame: randomization up to 3 years ]
    time from randomization to first symptomatic skeletal event (symptomatic fractures, spinal cord compression, surgery or radiation to the bone whichever is first)

  8. Opiate use for prostate cancer pain [ Time Frame: randomization up to 3 years ]
    time from randomization to opiate use for prostate cancer pain

  9. Incidence of adverse events [ Time Frame: randomization up to 3 years ]
    AEs and SAEs incidence by type and severity (graded by NCI CTCAE version 4.03)

  10. Pharmacokinetic assessment of talazoparib [ Time Frame: Weeks 5, 9, 13, and 17 ]
    plasma concentrations of talazoparib

  11. Pharmacokinetic assessment of enzalutamide and its metabolite [ Time Frame: Weeks 5, 9, 13, and 17 ]
    plasma concentrations of enzalutamide and its metabolite

  12. Relationship between ctDNA burden and outcome [ Time Frame: randomization up to 3 years ]
    ctDNA burden at baseline and on study

  13. Patient-reported outcomes in pain symptoms - change from baseline [ Time Frame: randomization up to 3 years ]
    change from baseline in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)

  14. Patient-reported outcomes in pain symptoms - time to deterioration [ Time Frame: randomization up to 3 years ]
    time to deterioration in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)

  15. Patient-reported outcomes in cancer specific general health status - change from baseline [ Time Frame: randomization up to 3 years ]
    change from baseline in participant-reported general health status per EQ-5D-5L

  16. Patient-reported outcomes in cancer specific global health status/QoL - change from baseline [ Time Frame: randomization up to 3 years ]
    change from baseline in patient-reported Global health status/QoL per EORTC QLQ-C30

  17. Patient-reported outcomes in cancer specific global health status/QoL - time to definitive deterioration [ Time Frame: randomization up to 3 years ]
    time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30

  18. Patient-reported outcomes in cancer specific symptoms - time to definitive deterioration [ Time Frame: randomization up to 3 years ]
    time to definitive deterioration in disease specific urinary symptoms per EORTC QLQ-PR25

  19. Patient-reported outcome: cancer specific functioning, and symptoms - change from baseline [ Time Frame: randomization up to 3 years ]
    change from baseline in PGI-S



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male participants at least 18 years of age at screening (20 years for Japan).
  2. 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 may also be used to support biomarker analysis.
  3. Confirmation of DDR gene mutation status by prospective or historical analysis (with sponsor pre-approval) of blood (liquid biopsy) and/or de novo or archival tumor tissue using FoundationOne Liquid CDx or FoundationOne CDx.
  4. Willing to provide tumor tissue when available (de novo or archived) for retrospective molecular profiling analysis, if not already provided as part of inclusion criterion 3.
  5. 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.
  6. Surgically or medically castrated, with serum testosterone less or equal to 50 ng/dL (less or equal to 1.73 nmol/L) at screening. Ongoing ADT with a GnRH agonist or antagonist for participants who have not undergone bilateral orchiectomy must be initiated at least 4 weeks before randomization and must continue throughout the study.
  7. Metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesions on CT or MRI scan (for soft tissue). Participants whose disease spread is limited to regional pelvic lymph nodes are not eligible. Note: a finding of superscan at baseline is exclusionary.
  8. Prior docetaxel therapy for mCSPC (up to 6 cycles) is allowed (must be completed 2 weeks prior to randomization and all toxicities from treatment have resolved).
  9. Treatment with estrogens, cyproterone acetate, or first-generation anti-androgens is allowed until randomization.
  10. Other prior therapy allowed for mCSPC; ≤6 months of ADT and ≤3 months of approved NHT in mCSPC (ie, abiraterone + prednisone, apalutamide, or enzalutamide), if required prior to randomization.
  11. Participant may have received palliative radiation or surgery for symptomatic control secondary to prostate cancer, which should have been completed at least 2 weeks prior to randomization.
  12. ECOG performance status 0 or 1.
  13. Adequate organ function within 28 days before the first study treatment on Cycle 1 Day 1, defined by the following:

    • ANC ≥1500/µL, platelets ≥100,000/µL, or hemoglobin ≥9 g/dL (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology laboratory tests at screening).
    • Total serum bilirubin <1.5 × ULN (<3 × ULN for participants with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation).
    • AST or ALT <2.5 × ULN (<5 × ULN if liver function abnormalities are due to hepatic metastasis).
    • Albumin >2.8 g/dL.
    • eGFR ≥30 mL/min/1.73 m2 by the MDRD equation.
  14. 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 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.
  15. Must agree not to donate sperm from the first dose of study treatment to 4 months after the last dose of study treatment.
  16. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
  17. Capable of giving signed informed consent.

Exclusion Criteria:

  1. Other acute or chronic medical (concurrent disease, infection or co-morbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that interferes with a participant's ability to participate in the study, may increase the risk of associated with study participation or study treatment administration, or may interfere with the interpretation of study results, and, in the investigator's judgment, make the participant inappropriate for entry into the study.
  2. History of seizure or any condition (as assessed by investigator) that may predispose to seizure (eg, prior cortical stroke, significant brain trauma), including any history of loss of consciousness or transient ischemic attack within 12 months of randomization.
  3. Major surgery (as defined by the investigator) within 2 weeks before randomization.
  4. Known or suspected brain metastasis or active leptomeningeal disease.
  5. Symptomatic or impending spinal cord compression or cauda equina syndrome.
  6. Any history of MDS, AML, or prior malignancy except for the following:

    • Carcinoma in situ or non-melanoma skin cancer.
    • A cancer diagnosed and treated ≥3 years before randomization with no subsequent evidence of recurrence.
    • American Joint Committee on Cancer Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence in the opinion of the investigator and the sponsor.
  7. In the opinion of the investigator, any clinically significant gastrointestinal disorder affecting absorption.
  8. Clinically significant cardiovascular disease, including any of the following:

    • Myocardial infarction or symptomatic cardiac ischemia within 6 months before randomization.
    • 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.
  9. Active COVID-19 infection detected by viral test or based on clinical diagnosis (as assessed by investigator). Asymptomatic participants with no active COVID-19 infection detected but positive antibody tests, indicating past infection are allowed.
  10. Prior ADT in the adjuvant/neoadjuvant setting, where the completion of ADT was less than 12 months prior to randomization and the total duration of ADT exceeded 36 months.
  11. Participant received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to randomization, intended for the treatment of prostate cancer.
  12. Any previous treatment with DNA-damaging cytotoxic chemotherapy (ie, platinum based therapy) within 5 years prior to randomization, except for indications other than prostate cancer.
  13. Prior treatment with a PARPi.
  14. Prior treatment in any setting with NHT, except as described in Inclusion Criterion #10.
  15. Current use of potent P-gp inhibitors within 7 days prior to randomization. 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 6.5.
  16. Treatment with any investigational study intervention within 4 weeks before randomization. Exception: COVID-19 vaccines authorized under an emergency use authorization (or equivalent) can be administered without a washout period.
  17. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >450 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or QRS values should be used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants.
  18. Investigator site staff or Sponsor employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04821622


Contacts
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Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
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Sponsors and Collaborators
Pfizer
Astellas Pharma Inc
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT04821622    
Other Study ID Numbers: C3441052
TALAPRO-3 ( Other Identifier: Alias Study Number )
2021-000248-23 ( EudraCT Number )
First Posted: March 29, 2021    Key Record Dates
Last Update Posted: September 22, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
DDR
prostate cancer
castration-sensitive
PARP-inhibitor
hormone-sensitive
metastatic hormone-sensitive prostate cancer
Advanced prostate cancer
Metastatic castration-sensitive prostate cancer
mCSPC
enzalutamide
metastatic prostate cancer
DNA Damage Response
DNA Damage Repair
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Talazoparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents