Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC

Study Overview
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Brief Summary
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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.

Detailed Description
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Part 1 is an open-label, non-randomized, safety and PK run-in study designed to confirm the starting dose of talazoparib in combination with enzalutamide through assessment of target safety events and PK at select sites. Part 2 is a randomized, double-blind, placebo-controlled, multinational study comparing talazoparib plus enzalutamide vs. placebo plus enzalutamide in patients with mCRPC.

Official Title
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A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF TALAZOPARIB WITH ENZALUTAMIDE IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Conditions
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mCRPC

Intervention / Treatment
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* Drug: Talazoparib with enzalutamide
* Drug: Placebo with enzalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate withoutsmall 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination arm<br>Talazoparib plus enzalutamide | Drug: Talazoparib with enzalutamide<br>* Talazoparib 0.5 mg/day plus enzalutamide 160mg/day<br>|
| Active Comparator: Monotherapy arm<br>Ezalutamide plus placebo | Drug: Placebo with enzalutamide<br>* Placebo plus enzalutamide 160 mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirm the dose of Talazoparib (part 1) | determined based on the safety profile | Day 1 up to 28 days | 
| Radiographic PFS (part 2) in unselected patients and in patients harboring DDR deficiencies | time from the date of randomization to first objective evidence of radiographic progression by blinded independent review, or death (occurring within 168 days of treatment discontinuation), whichever occurs first | randomization up to 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (part 2) in unselected patients and in patients harboring DDR deficiencies | time from randomization to death from any cause | randomization up to 47 months | 
| Objective response in measurable soft tissue disease (part 2) in unselected patients and in patients harboring DDR deficiencies | proportion of patients with measurable soft tissue disease at baseline with objective response per RECIST 1.1 | baseline up to 6 months | 
| Duration of soft tissue response (part 2) in unselected patients and in patients harboring DDR deficiencies | duration of responses in patients with measurable soft tissue disease at baseline per RECIST 1.1 | baseline up to 25 months | 
| PSA response (part 2) in unselected patients and in patients harboring DDR deficiencies | proportion of patients with PSA response grater than or equal to 50% | baseline up to 25 months | 
| Time to PSA progression (part 2) in unselected patients and in patients harboring DDR deficiencies | time from baseline to PSA progression | baseline up to 25 months | 
| Time to initiation of cytotoxic chemotherapy (part 2) in unselected patients and in patients harboring DDR deficiencies | time from randomization to initiation of cytotoxic chemotherapy | randomization up to 47 months | 
| Time to initiation of antineoplastic therapy (part 2) in unselected patients and in patients harboring DDR deficiencies | time from randomization to initiation of antineoplastic treatment | randomization up to 47 months | 
| Time to first symptomatic skeletal event (part 2) in unselected patients and in patients harboring DDR deficiencies | time from randomization to first symptomatic skeletal event (symptomatic fractures, spinal cord compression, surgery or radiation to the bone whichever is first) | randomization up to 47 months | 
| PFS on next line of therapy (PFS2) in unselected patients and in patients harboring DDR deficiencies | PFS2 based on investigator assessment | randomization up to 47 months | 
| Opiate use for cancer pain (part 2) in unselected patients and in patients harboring DDR deficiencies | time from randomization to opiate use for prostate cancer pain | randomization up to 47 months | 
| Incidence of adverse events (part 1 and 2) | AEs and SAEs incidence by type and severity (graded by NCI CTCAE version 4.03) | Day 1 up to 26 months | 
| Pharmacokinetic assessment of talazoparib (part 1) | plasma concentration of talazoparib | Week 1, 5, 9, and 13 | 
| Pharmacokinetic assessment of talazoparib (part 2) | plasma concentration of talazoparib | week 3, 5, 9 13, and 17 | 
| Pharmacokinetic assessment of enzalutamide (part 1) | plasma concentration of enzalutamide | week 1, 5, 9, and 13 | 
| Pharmacokinetic assessment of enzalutamide (part 2) | plasma concentration of enzalutamide | week 3, 5, 9 13, and 17 | 
| Patient-reported outcome:pain symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies | change from baseline in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF) | baseline up to 47 months | 
| Patient-reported outcome: pain symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies | time to deterioration in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF) | baseline up to 47 months | 
| Patient-reported outcome: cancer specific global health status/QoL, functioning, and symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies | change from baseline in patient-reported Global health status/QoL per EORTC QLQ-C30 | baseline up to 47 months | 
| Patient-reported outcome: cancer specific global health status/QoL, functioning, and symptoms (part 2) in unselected patients and in patients harboring DDR deficiencies | time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30 | baseline up to 47 months | 
| Patient-reported outcome: general health status (part2) in unselected patients and patients harboring DDR deficiencies | change from baseline in patient-reported general health status per EQ-5D-5L | baseline up to 47 months | 
| Patient-reported outcome: general health status (part 2) in unselected patients and patients harboring DDR deficiencies | time to definitive deterioration in patient-reported disease-specific urinary symptoms per EORTC QLQ-PR25 | baseline up to 47 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mCRPC (metastatic castration-resistant prostate cancer)