Clinical Trials

Inclusion Criteria:

• Signed informed consent form (ICF).
• ≥ 18 years of age (or the local legal age of consent).
• Histologically confirmed prostate cancer.
• Can provide a blood sample for determination of HRR gene alterations.
• Willing to provide a tumor tissue sample (archival or recently collected) for determination of HRR gene alterations.
• Metastatic prostate cancer in the setting of castrate levels of testosterone (i.e., taking a gonadotropin releasing hormone analog [GnRHa], or history of bilateral orchiectomy at study entry).
• HRR gene alteration status (as identified by the sponsor’s required assays or local testing for HRR gene alteration) as follows:
  • Cohort 1: positive for HRR gene alteration;
  • Cohort 2: not positive for HRR gene alteration (i.e., no HRR gene alteration);
  • Cohort 3: positive for HRR gene alteration
• Metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI).
• Metastatic prostate cancer in the setting of castrate levels of testosterone ≤ 50 ng/dL on a GnRHa or bilateral orchiectomy as evidenced by prostate-specific antigen (PSA) progression or radiographic progression.
• Able to continue GnRHa during the study if not surgically castrate.
• Eastern Cooperative Oncology Group Performance Score (ECOG PS) Grade of 0 or 1.
• Score of ≤ 3 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain in last 24 hours).
• Clinical laboratory values at Screening:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L;
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusions for at least 30 days;
  • Platelet count ≥ 100 x 10^9/L;
  • Serum albumin ≥ 3.0 g/dL;
  • Creatinine clearance ≥ 30 mL/min either calculated or directly measured via 24-hour urine collection;
  • Serum potassium ≥ 3.5 mmol/L; 
  • Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) or direct bilirubin ≤ 1 x ULN;
  • Note: in subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible as determined by the medical monitor);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN.
• Able to swallow the study drug tablets and capsules whole.
• While on study drug and for 3 months following the last dose of study drug, a male subject must agree to use an adequate contraception method as deemed appropriate by the investigator and agree not to donate sperm.
• Willing and able to adhere to the prohibitions and restrictions specified in this protocol.

Exclusion Criteria:

• Prior treatment with a PARP inhibitor.
• Systemic therapy (i.e., novel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or more than 4 months of AA-P prior to randomization) in the mCRPC setting; or AA-P outside of the mCRPC setting.
• For subjects who received 2 to 4 months of AA-P prior to randomization for the treatment of mCRPC, evidence of progression by PSA (per PCWG3) during screening. These potential subjects are required to have 2 PSA values during the Prescreening and Screening Phases. The second PSA value should be within 2 weeks of randomization. If PSA rise is thought to be due to flare, the investigator should confirm that there is no radiographic progression.
• Symptomatic brain metastases.
• History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).
• Other prior malignancy (exceptions: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) ≤ 2 years prior to randomization, or malignancy that currently requires active systemic therapy. 
• Severe or unstable angina, myocardial infarction or ischemia requiring coronary artery bypass graft or stent within the previous 6 months, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization or New York Heart Association (NYHA) Class II to IV heart disease.
• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg). Subjects with a history of hypertension are allowed, if BP is controlled to within these limits by anti-hypertensive treatment.
• Current evidence of any of the following:
  • Any medical condition that would make prednisone use contraindicated;
  • Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone (or equivalent) once daily.
• Active or symptomatic viral hepatitis or chronic liver disease (as evidenced by ascites, encephalopathy, or bleeding disorders secondary to hepatic dysfunction).
• History of adrenal dysfunction 
• Known allergies, hypersensitivity, or intolerance to AA or niraparib or the corresponding excipients (refer to Investigator's Brochures).
• Subjects who are receiving opioid analgesics at the time of screening.
• Human immunodeficiency virus (HIV) positive subjects with 1 or more of the following:
  • Not receiving highly active antiretroviral therapy;
  • Receiving antiretroviral therapy that may interfere with the study drug (consult the sponsor for review of medication prior to enrollment);
  • A change in antiretroviral therapy within 6 months of the start of screening (except if, after consultation with the sponsor on exclusion criterion 14.b, a change is made to avoid a potential drug-drug interaction with the study drug);
  • CD4 count < 350 at screening;
  • An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening.
• Subjects who have had the following ≤ 28 days prior to randomization:
  • A transfusion (platelets or red blood cells);
  • Hematopoietic growth factors;
  • An investigational agent for prostate cancer;
  • Major surgery (sponsor should be consulted regarding what constitutes major surgery);
  • Radiation therapy.