Apalutamide, Abiraterone Acetate, Prednisone, Leuprolide Acetate, and Stereotactic, Ultra-hypofractionated Radiation Therapy in Treating Patients with Very High Risk Prostate Cancer

Inclusion Criteria

• Histological or cytologic evidence of adenocarcinoma of the prostate confirmed at local institution
• At least one of the following: * Two or more high risk features OR ** Gleason score 8-10 ** PSA >= 20 ng/mL within two months prior to registration ** Clinical stage >= T3 disease, as determined by standard digital rectal examination (DRE) ** Radiographic stage >= T3 disease as determined by a >= 75% probability of extracapsular extension or seminal vesicle invasion per reading radiologist * Any Gleason 9 or 10 disease OR * > 4 cores of Gleason 8 disease
• Karnofsky performance status (KPS) >= 70%
• IPSS (International Prostate Symptom Score) =< 20
• Patient must be available for follow-up
• Bilirubin =< 1.5 times the upper institutional limits of normal (ULN) (within 28 days of study registration); patients with a history of Gilbert's syndrome may be enrolled if the total bilirubin is < 3 mg/dL with a predominance of indirect bilirubin; if the total bilirubin is > 1.5 x the institutional ULN, direct and indirect bilirubin will be measured and if direct bilirubin is =< 1.5 x the institutional ULN, the patient will be eligible to participate
• Serum glutamate-pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 28 days of study registration)
• Creatinine < 2.0 x the institutional ULN (within 28 days of study registration)
• Absolute neutrophil counts >= 1500 cell/mm^3 (within 28 days of study registration)
• Platelets >= 100,000 cells/mm^3 (independent of blood transfusion and/or growth factors within 3 months prior to registration) (within 28 days of study registration)
• Hemoglobin value >= 9 g/dL at the screening visit (independent of blood transfusion and/or growth factors within 3 months prior to registration) (within 28 days of study registration)
• Albumin >= 3.0 g/dL (within 28 days of study registration)
• Potassium >= 3.5 mmol/L (within 28 days of study registration)
• Patients with pelvic and/or retroperitoneal lymph nodes < 1.5 cm in short axis are eligible
• Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for the release of personal health information * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
• The effects of apalutamide, abiraterone, leuprolide and stereotactic, ultrahypofractionated radiation on the developing human fetus at the recommended therapeutic dose are unknown; men (including men with vasectomies) must agree to use adequate contraception (a condom and another effective method of birth control) prior to registration, for the duration of study participation, and for at least 3 months thereafter; men must also agree not to donate sperm for the duration of study participation, and for at least 3 months thereafter

Exclusion Criteria

• Radiographic evidence of metastatic disease
• Patients with one or more positive lymph nodes as determined by radiographic assessment of MRI or computed tomography (CT) * NOTE: lymph nodes noted on MRI or CT to be > 1.5 cm on the short axis will require review by the local reference radiologist per institutional Response Evaluation Criteria in Solid Tumors (RECIST) review practices; if the lymph nodes are considered suspicious on repeat review, they must be confirmed negative for study participation
• Prior treatment for prostate cancer; this includes any prior surgery (including transurethral resection of the prostate [TURP]), prostate cancer treatment), chemotherapy, radiation, or anti-androgen therapy/androgen deprivation therapy with the following exception: patients who will have been on luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy for =< 1 month prior to registration are permitted to enroll with study principal investigator (PI) approval
• Prior use of steroidal antiandrogens (megestrol acetate, cyproterone acetate), AR partial agonists, ketoconazole, chemotherapy, immunotherapy, estrogens, radiopharmaceuticals within 3 months before registration
• Prior use of non-steroidal anti-androgens (e.g., bicalutamide, flutamide, nilutamide) within 1 month before registration
• Prior treatment with medications known to lower the seizure threshold within 4 weeks of registration
• History of another malignancy within the previous 3 years except for the following: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, adequately treated stage I or stage II cancer currently in complete remission, or any other cancer that has been in complete remission for at least 3 years
• Severe hepatic impairment (Child-Pugh class C)
• Concurrent treatment with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital)
• Major surgery within 4 weeks of registration
• Presence of a pacemaker
• Active infection or other medical condition that would make prednisone use contraindicated
• A known hypersensitivity to abiraterone acetate, apalutamide, and prednisone and/or any of their excipients
• Severe or unstable angina, myocardial infarction, 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 registration
• Seizure or known condition that may pre-dispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to randomization, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
• Any electrocardiograph (ECG) changes that interfere with QT interval interpretation (e.g., left bundle branch block, frequent premature ventricular contractions)
• Prolonged corrected QT interval (QTc) > 450 milliseconds (ms) at the screening visit
• Uncontrolled diabetes, heart disease, hypertension
• Gastrointestinal disorder that may affect absorption of study treatment
• Active symptomatic viral hepatitis or chronic liver disease
• History of pituitary or adrenal dysfunction
• Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or other medical condition that would make prednisone/prednisolone corticosteroid) use contraindicated
• Patients with Crohn's disease or ulcerative colitis
• Patients that cannot tolerate MRI
• Inability to have fiducial markers placed
• Any condition that in the opinion of the investigator, would preclude participation in this study
• Enrollment concurrently in another investigational drug study or within 4 weeks of registration