Overview

The objective of this study is to see if providing an appropriate therapy based on the genomic testing of prostate tumour tissue will result in an improved clinical response.

Each participant will be treated with 8 weeks of a luteinizing hormone-releasing hormone agonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done. Participants with biopsy specimens deemed unevaluable for genomic testing will remain on LHRHa plus APA for an additional 16 weeks.

Participants with evaluable tissue will be assigned to one of the open-label sub-studies on the basis of genomic profiling results. Within each group, they will be randomized to a specific treatment arm either LHRHa plus APA alone or adding abiraterone acetate and prednisone, docetaxel or niraparib.

The study will evaluate the response rate and outcomes after radical prostatectomy in each arm of the trial.

Eligibility

Inclusion Criteria:

• I. Males ≥ 18 years of age

        II. Histologically confirmed adenocarcinoma of the prostate without pathologic evidence of
        small cell differentiation at the time of initial diagnosis
        III. High-risk localized prostate cancer as defined by:
          -  PSA (prostate specific antigen) >20, any GS or >8 or
          -  Gleason pattern 4 in 6 or more systematic cores (pattern 4 must be dominant, ≥50%
             average across 6 or more systematic cores) or
          -  ≥ 50% Gleason pattern 4 in 3 or more systematic or Magnetic Resonance Imaging
             (MRI)-targeted cores and PSA ≥ 20 (may include G4+3 or G4+4 but pattern 4 must be
             dominant, ≥50% average across 3 or more systematic cores) or
          -  ≥25% Gleason pattern 5 in 3 or more systematic or MRI-targeted cores (may include
             G4+5, or G3+5, but pattern 5 must be ≥25% average across 3 or more systematic cores).
          -  Gleason > 8 or greater on minimum of one core either targeted or systematic biopsy and
             PSA >20
          -  Participants with oligometastatic (< 3) metastases by PSMA (Prostate-Specific Membrane
             Antigen) imaging only who are deemed candidates for radical prostatectomy are eligible
        IV. Participants must consent to genetic testing at registration and prior to assignment by
        a central reference laboratory
        V. No prior systemic or localized treatment for prostate cancer. Up to 30 days of LHRHa is
        allowable prior to treatment.
        VI. ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1 (Appendix II) and a
        life expectancy of ≥ 3 years
        VII. Participants must have adequate end-organ function and all laboratory tests must be
        performed within 4 weeks prior to registration into master protocol.
        VIII. Participant consent must be appropriately obtained in accordance with applicable
        local and regulatory requirements. Each participant must sign a consent form prior to
        enrolment in the trial to document their willingness to participate.
        Exclusion Criteria:
        - I. Received more than 30 days of LHRHa prior to registration and initiation of LHRHa +
        APA
        II. Stage T4 prostate cancer by clinical examination or radiologic evaluation
        III. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone
        more than 50 ng/dL below the normal range for the institution
        IV. Participants with serious illnesses or medical conditions which could cause
        unacceptable safety risks or would not permit the participant to be managed according to
        the protocol. This includes but is not limited to:
          -  Active infection or chronic liver disease requiring systemic therapy;
          -  Active or known human immunodeficiency virus (HIV) with detectable viral load;
          -  Uncontrolled or recent clinically significant cardiac disease, including: angina
             pectoris, symptomatic pericarditis, coronary artery bypass grafting, coronary
             angioplasty, or stenting, or myocardial infarction in the previous 12 months; history
             of documented congestive heart failure (New York Heart Association functional
             classification III-IV) or cardiomyopathy; history of any cardiac arrhythmias, e.g.
             ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the
             previous 12 months;
          -  Participants with uncontrolled hypertension
        V. Participants who are unable to swallow oral medication and/or have impairment of
        gastrointestinal (GI) function or GI disease that may significantly alter the absorption of
        the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
        malabsorption syndrome, or small bowel resection)
        VI. Participants with a history of hypersensitivity to any of the study drugs or any
        excipient
        VII. Participants with a history of non-compliance to medical regimen
        VIII. Severe concurrent disease, infection, or co-morbidity that, in the judgement of the
        Investigator, would make the participant inappropriate for enrollment or prostatectomy
        IX. Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer
        X. Receiving concurrent androgens, estrogens, or pregestational agents, or prior exposure
        to any of these agents within 6 months prior to randomization
        XI. M1 by conventional imaging (CT, bone scan)