A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination with Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for the Treatment of Participants with Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

1. 18 years of age or older
2. Pathological diagnosis of prostate adenocarcinoma.
3. Willing to provide an archival tumor tissue sample or a fresh tumor tissue
sample. If germline positive for deleterious germline or somatic HRR gene
mutations, an archived or fresh tumor tissue sample is not required.
4. Metastatic disease documented by conventional imaging with computed
tomography (CT) or magnetic resonance imaging (MRI) (for soft tissue leasions)
or 99mTc bone scan (for bone leasions). Participants with a single bone lesion
on Technetium-99m (99mTc) bone scan with no other non-nodal metastatic disease
must have confirmation of bone metastatis by CT or MRI. Participants with lymph
node-only disease are not elegible.
5 Must have at least one of the deleterious germline or somatic HRR gene
mutations listed in Table 4.
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade <2.
7. Androgen deprivation therapy (either medical or surgical castration) must
have been started >14 days prior to randomization and participants be willing
to continue androgen deprivation therapy (ADT) through the treatment phase.
Participants who start a GnRH agonist <28 days prior to randomization will be
required to take a first-generation anti-androgen for >14 days prior to
randomization. The anti-androgen must be discontinued prior to randomization.
8. Participants who have received prior docetaxel treatment must meet the
following criteria:
a. Received a maximum of 6 cycles of docetaxel therapy for mCSPC
b. Received the last dose of docetaxel <2 months prior to randomization
c. Maintained a response to docetaxel of stable disease or better, by
investigator
assessment of imaging and PSA, prior to randomization.
9. Other allowed prior therapy for mCSPC:
a. Maximum of 1 course of radiation and 1 surgical intervention for symptomatic
control of prostate cancer (example, uncontrolled pain, impending spinal cord
compression or obstructive symptoms). Participants with radiation or surgical
interventions to all known sites of metastatic disease will be excluded from
trial participation). Radiation must be completed prior to randomization.
b. Up to a maximum of <6 months of ADT prior to randomization.
c. Up to a maximum of 45 days of abiraterone acetate + prednisone (AA-P) prior
to randomization.
d. Up to a maximum of 2 weeks of ketoconazole for prostate cancer prior to
randomization.
10. Allowed prior treatments for localized prostate cancer (all treatments must
have been
completed >=1 year prior to randomization):
a. <=3 years total of ADT
b. All other forms of prior therapies including radiation therapy,
prostatectomy, lymph node dissection, and systemic therapies.
11. Clinical laboratory values at Screening:
a. Absolute neutrophil count >=1.5 x 109/L
b. Hemoglobin >=9.0 g/dL, independent of transfusions for at least 28 days
c. Platelet count >=100 x 109/µL
d. Serum albumin >=3.0 g/dL
e. Creatinine <2 x upper limit of normal (ULN)
f. Serum potassium >=3.5 mmol/L
g. Serum total bilirubin <=1.5× ULN or direct bilirubin <=1 x ULN (Note: In
participants with Gilbert*s syndrome, if total bilirubin is >1.5 × ULN, measure
direct and indirect bilirubin, and if direct bilirubin is <=1.5 × ULN,
participant may be eligible as determined by the medical monitor)
h. AST or ALT <=3 × ULN
12. Able to swallow the study medication tablets whole.
13. Must provide informed consent (written or remote/virtual) indicating that
he understands the purpose of, and procedures required for, the study and is
willing to participate in the study including providing a DNA sample.
14. While on study medication and for 3 months following the last dose of study
medication, a male participant must wear a condom when engaging in any activity
that allows for passage of ejaculate to another person. Male participants
should also be advised of the benefit for a female partner to use a highly
effective method of contraception as condom may break or leak. The investigator
should advise of the potential for contraceptive
method failure (eg, noncompliance, recently initiated) in relationship to the
first dose of study medication. Highly effective methods of contraception
include:
a. established use of oral, injected or implanted hormonal methods of
contraception; placement of an intrauterine device or intrauterine system;
b. barrier methods: condom with spermicidal foam/gel/film/cream/suppository or
occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository.
15. A male participant must agree not to donate sperm for the purpose of
reproduction during the study and for a minimum of 3 months after receiving the
last dose of study medication.

1. Pathological finding consistent with small cell ductal or neuroendocrine
carcinoma of the prostate.
2. Prior treatment with a PARP inhibitor.
3.Prior AR-targeted therapy (eg, ketoconazole for prostate cancer, apalutamide,
enzalutamide, darolutamide), immunotherapy, or radiopharmaceutical agents with
the exception of only 30 days of AA-P allowed prior to randomization.
4. Initiation of treatment with a bisphosphonate or denosumab for the
management of bone metastasis <28 days prior to randomization.
5. History of adrenal dysfunction
6. Long-term use of systemically administered corticosteroids >5 mg of
prednisone or the equivalent) during the study is not allowed. Short-term use
(<=4 weeks, including taper) and locally administered steroids (eg, inhaled,
topical, ophthalmic, and intra-articular) are allowed, if clinically indicated.
7. Active malignancies (ie, progressing or requiring treatment change in the
last 24 months) other than the disease being treated under study. The only
allowed exceptions are:
a. non-muscle invasive bladder cancer;
b. skin cancer (non-melanoma or melanoma) treated within the last 24 months
that is considered completely cured;
c. breast cancer - adequately treated lobular carcinoma in situ or ductal
carcinoma in situ;
d. malignancy that is considered cured with minimal risk of recurrence.
8. History or current diagnosis of MDS/AML.
9. Current evidence within 6 months prior to randomization of any of the
following: severe/unstable angina, myocardial infarction, symptomatic
congestive heart failure, clinically significant arterial or venous
thromboembolic events (eg, pulmonary embolism), or clinically significant
ventricular arrhythmias.
10. Presence of sustained uncontrolled hypertension (systolic blood pressure
>160 mm Hg or diastolic blood pressure >100 mm Hg). Participants with a history
of hypertension are allowed, provided that blood pressure is controlled to
within these limits by an antihypertensive
treatment.
11. Known allergies, hypersensitivity, or intolerance to the excipients of
niraparib, AA, or niraparib/AA FDC (refer to the IBs for niraparib and AA).
12. Current evidence of any medical condition that would make prednisone use
contraindicated.
13. Received an investigational intervention (including investigational
vaccines) or used an invasive investigational medical device within 30 days
before the planned first dose of study medication.
14. Participants who have had the following <=28 days prior to randomization:
a. A transfusion (platelets or red blood cells);
b. Hematopoietic growth factors;
c. Major surgery (sponsor should be consulted regarding what constitutes major
surgery).
15. Known active hepatitis B virus (eg, hepatitis B surface antigen reactive)
or active hepatitis C virus (HCV; eg, HCV ribonucleic acid [RNA] [qualitative]
is detected).
16. Human immunodeficiency virus positive participants with 1 or more of the
following:
a. Not receiving highly active antiretroviral therapy or on antiretroviral
therapy for less than 4 weeks.
b. Receiving antiretroviral therapy that may interfere with the study
medication (consult the sponsor for review of medication prior to enrollment).
c. A change in antiretroviral therapy within 6 months of the start of screening
(except if, after consultation with the sponsor on exclusion criterion 16.b, a
change is made to avoid a potential drug-drug interaction with the study
medication).
d. CD4 count<350 at screening.
e. An acquired immunodeficiency syndrome-defining opportunistic infection
within 6 months of the start of screening.
f. Human immunodeficiency virus load >400 copies/mL.