Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC
Condition: mCRPC
Intervention: Talazoparib with enzalutamide; Placebo with enzalutamide
Intervention description: Talazoparib 0.5 mg/day plus enzalutamide 160mg/day; Placebo plus enzalutamide 160 mg/day
Intervention MeSH terms: Talazoparib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: To assess radiographic PFS in men with mCRPC (with no systemic treatments initiated after documentation of mCRCP) treated with talazoparib and enzalutamide vs. placebo plus enzalutamide
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blind
Enrollment: 1125.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: mCRPC (metastatic castration-resistant prostate cancer)

Summary:

      This study compares rPFS in men with mCRPC treated with talazoparib plus enzalutamide vs.
      enzalutamide after confirmation of the starting dose of talazoparib in combination with
      enzalutamide.
    

Eligibility criteria:

        Inclusion Criteria:

        Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell
        or signet cell features

        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

        Consent to a saliva sample collection for a germline comparator unless prohibited by local
        regulations or ethics committee decision (optional for patients in Part 1).

        Surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at
        screening.

        Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI
        scan.

        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 a minimum of 2 rising PSA
             values from 3 consecutive assessments with an interval of at least 7 days between
             assessments..

          -  Soft tissue disease progression as defined by RECIST 1.1.

          -  Bone disease progression defined by Prostate Cancer Working Group 3 (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 drug and have no known intolerance to study drugs or excipients.

        Must agree to use a condom when having sex with a partner from the time of the first dose
        of study drug 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.

        Must agree not to donate sperm from the first dose of study drug to 4 months after the last
        dose of study drug.

        Evidence of a personally signed and dated informed consent document (and molecular
        prescreening consent if appropriate) indicating that the patient [or a legally acceptable
        representative/legal guardian] 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 in the non metastatic CRPC and mCRPC
        disease state.

        Patients 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).

        Treatment with cytotoxic chemotherapy, 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).

        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).

        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

        Significant renal dysfunction as defined by any of the following laboratory abnormalities:

        • Renal: eGFR < 30 mL/min/1.73 m2 by the MDRD equation (available via www.mdrd.com).

        Patients enrolled in Part 1 only: Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) at
        screening.

        Significant hepatic dysfunction as defined by any of the following laboratory abnormalities
        on screening labs:

          -  Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 × ULN for
             patients with documented Gilbert syndrome or for whom indirect bilirubin
             concentrations suggest an extrahepatic source of elevation).

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times ULN (>5
             × ULN if liver function abnormalities are due to hepatic metastasis).

          -  Albumin <2.8 g/dL

        Absolute neutrophil count < 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 values at screening).

        Known or suspected brain metastasis or active leptomeningeal disease.

        Symptomatic or impending spinal cord compression or cauda equina syndrome.

        Any history of myelodysplastic syndrome, acute myeloid leukemia, or prior malignancy except
        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

        Gastrointestinal disorder affecting absorption.

        Fertile male subjects who are unwilling or unable to use highly effective methods of
        contraception for the duration of the study and for 4 months after the last dose of
        investigational product.

        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 Pfizer employees, including their family members, directly involved in the conduct
        of the study.

        Other acute or chronic medical (concurrent disease, infection, or comorbidity) or
        psychiatric condition including recent (within the past year) or active suicidal ideation
        or behavior or laboratory abnormality that interferes with ability to participate in the
        study, may increase the risk associated with study participation or investigational product
        administration, or may interfere with the interpretation of study results and, in the
        judgment of the investigator, would make the patient inappropriate for entry into this
        study.

        History of seizure or any condition that may predispose to seizure (eg, prior cortical
        stroke, significant brain trauma). Also, history of loss of consciousness or transient
        ischemic attack within 12 months of randomization (Part 2).