Talazoparib + NHT vs. NHT Monotherapy in DDR+ mCRPC

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Primary Purpose: Treatment

• Drug: Talazoparib with NHT
  
  Talazoparib 1 mg/day plus either [enzalutamide 160 mg/day] or [abiraterone acetate 1000 mg/day with prednisone 5 mg twice a day]
• Drug: Placebo with NHT
  
  Placebo plus either [enzalutamide 160 mg/day] or [abiraterone acetate 1000 mg/day with prednisone 5 mg twice a day]

• Experimental: Combination arm
  
  Talazoparib plus physician's choice of NHT
  Intervention: Drug: Talazoparib with NHT
• Active Comparator: Monotherapy arm
  
  Physician's choice of NHT.
  Intervention: Drug: Placebo with NHT

Inclusion Criteria:

Histologically or cytologically confirmed adenocarcinoma of the prostate.

Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (CRPC) (score on BPI-SF Question #3 must be < 4).

For enrollment into Part 2 only (optional in Part 1): Consent to a fresh tumor biopsy before enrollment unless sufficient archival tissue (preferably of metastatic disease) is available for molecular analyses

For patients enrolling in Part 2, DNA damage repair deficiency as assessed centrally by an NGS biomarker mutation panel that contains DDR genes likely to sensitize to PARP inhibition.

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.

Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral orchiectomy

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 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.

Eastern Cooperative Oncology Group (ECOG) performance status ? 1.

Life expectancy ? 12 months as assessed by the investigator.

Exclusion Criteria:

Progression of metastatic CRPC while on prior treatment with taxane-based chemotherapy, or NHT initiated after onset of castration resistance. Men previously treated with NHT or taxane-based chemotherapy in the hormone sensitive prostate cancer setting or for nonmetastatic CRPC may be considered.

Treatment with cytotoxic chemotherapy, other hormonal therapy (e.g., bicalutamide, nilutamide, flutamide, estrogens, 5-alpha reductase inhibitors), biologic therapy including sipuleucel-T (other than approved bone-targeting agents and GnRH agonist/antagonist therapy), or radionuclide therapy in the 28 days prior to screening.

Treatment with any investigational agent within 4 weeks or 5 half-lives of the drug (whichever is longer) before Day 1.

Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.

Prior progression on platinum-based therapy or prior treatment with platinum-based therapy within the past 6 months

Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days before screening unless no pain related to prostate cancer is reported within 28 days prior to screening.

For patients the investigator chooses to receive enzalutamide, unwilling to agree to avoid the use of strong cytochrome P450 2C8 (CYP2C8) inhibitors, strong CYP3A4 inducers, or substrates of CYP3A4, CYP2C9, or CYP2C19 with a narrow therapeutic index.

For patients the investigator chooses to receive abiraterone acetate/prednisone, unwilling to agree to avoid the use of strong CYP3A4 inducers and CYP2D6 substrates with a narrow therapeutic index.

Use of a strong P-gp inhibitor (eg, dronedarone, quinidine, ranolazine, itraconazole, ketoconazole), strong P-gp inducer (eg, rifampin, tipranavir, ritonavir), or strong inhibitor of BCRP (eg, elacridar [GF120918]).

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 involvement).
• Albumin < 3.0 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).