Olaparib with LHRH Agonist Followed by Radical Prostatectomy in the Treatment of Unfavorable Intermediate or High Risk Prostate Cancer with BRCA1/2 Gene Alterations

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Age ≥ 18 years at the time of consent
• T stage 1-3 prostatic adenocarcinoma per American Joint Committee on Cancer (AJCC) staging manual edition (Ed)8
• Histologically confirmed adenocarcinoma of the prostate without histological variants comprising > 50% of the sample with the exception of intraductal carcinoma
• Must have 3 core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within 7 months from registration. Less than 3 core biopsies are allowed if the patient has > 1 cm or T3 disease on magnetic resonance imaging (MRI)
• Localized unfavorable intermediate or high-risk prostate cancer patients. Patients must have at least one of the following features: * Gleason ≥ 4+3 (grade group 3, 4, 5) OR * PSA > 20 ng/dL OR * T3 disease NOTE: Patients with intraductal carcinoma are eligible independent of Gleason score, PSA and T stage.
• Must have evidence of germline or somatic BRCA1/2 gene alteration via standard of care Clinical Laboratory Improvement Act (CLIA) based assay detection. Testing will be confirmed centrally but results of central testing not required for enrollment
• No evidence of metastatic disease as determined by radionuclide bone scan and CT/MRI. Lymph nodes must be less than 20 mm in the short (transverse) axis
• Participants must be candidates for RP and considered surgically resectable by urologic evaluation
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 28 days prior to registration
• White blood cell count ≥ 3,000/mcL (obtained within 28 days prior to registration)
• Absolute neutrophil count ≥ 1,500/mcL (obtained within 28 days prior to registration)
• Hemoglobin ≥ 10 g/dL with no transfusion support in the past 28 days (obtained within 28 days prior to registration)
• Platelets ≥ 100,000/mcL (obtained within 28 days prior to registration)
• Aspartate aminotransferase, alanine aminotransferase, and total bilirubin ≤ 1.5 x institutional upper limit of normal (obtained within 28 days prior to registration)
• Calculated creatinine clearance ≥ 51 mL/min based on Cockcroft-Gault formula or 24 hour urine (obtained within 28 days prior to registration)
• Life expectancy ≥ 16 weeks
• Subjects must use a condom plus spermicide beginning prior to treatment cycle 1 day 1, during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria

• Active infection requiring systemic therapy
• Prior treatments not allowed: hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, apalutamide and others), CYP17 inhibitors (including abiraterone, TAK-700, galeterone, ketoconazole, and others), estrogens and radiation therapy. Prior bicalutamide is allowed if taken for < 4 weeks prior to registration and there is a washout period of 2 weeks prior to the initiation of study treatment. LHRH therapy allowed if begun within 4 weeks of registration. LHRH agonist/antagonist therapy is allowed if begun within 4 weeks of registration. Prior 5-alpha reductase inhibitors are allowed but require a washout period of 2 weeks to initiation of study treatment
• Prior treatment with a PARP inhibitor
• Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200 ng/dL
• Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including: * Tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis [TB] testing in line with local practice)
• Known active hepatitis infection, positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody at screening. Testing is not required unless there was a prior known positive hepatitis B or C test or hepatitis is suspected at screening. Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Known to have tested positive for human immunodeficiency virus (HIV) unless currently on effective anti-retroviral therapy with an undetectable viral load within 6 months
• Severe hepatic impairment (Child-Pugh class C)
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Pre-existing condition that warrants long-term corticosteroid use greater than the equivalent of 10 mg prednisone daily. Physiologic replacement is permitted. Topical, intra-articular steroids or inhaled corticosteroids are permitted
• Active cardiac disease, defined as: * Myocardial infarction within 6 months of study treatment * Uncontrolled angina within 3 months of study treatment * Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless an echocardiogram performed within 3 months of the screening visit results in a left ventricular ejection fraction that is ≥ 45%. * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes) * Other clinically significant cardiovascular disease within 6 months of registration
• Uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, Fridericia's correction formula (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
• Individuals with a history of another malignancy are not eligible if the cancer is under active treatment or the cancer can be seen on radiology scans or if they are off cancer treatment but in the opinion of their oncologist have a high risk of relapse within 5 years
• Major surgery within 4 weeks from start of treatment. Subjects must have recovered from any effects as the surgery as assessed by investigator discretion
• Treatment with any investigational drug within 28 days prior to registration
• Persistent toxicities grade > 2 caused by previous cancer therapy, excluding alopecia (per Common Terminology Criteria for Adverse Event [CTCAE])
• Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
• Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
• Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria)
• Patients with a known hypersensitivity to olaparib or any of the excipients of the product