Apalutamide, Abiraterone Acetate, Prednisone, and Radiation Therapy in Treating Patients with Prostate Cancer

Inclusion Criteria

• Willing and able to provide written informed consent and authorization for use and release of health and research study information (Health Insurance Portability and Accountability Act [HIPAA] authorization) * NOTE: HIPAA authorization may be either included in the informed consent or obtained separately
• Male aged 18 years and above
• Serum testosterone of >= 150 ng/dL (For cohorts A and B1, testosterone level requirement is exempted if they are already on ADT prior to treatment start. For cohort B2, subjects will be considered eligible if their testosterone is currently >= 150 ng/dL). Clinical phenotypes as described in either one of the following cohorts:
• Cohort A * Clinically localized disease with histologically confirmed adenocarcinoma of the prostate with either >= 3 positive cores or 2 positive cores if > 1cm in length with at least 50% tumor content WITH ** Gleason score 8-10 or ** Gleason 4 + 3 or 3 + 4 with one of the following features: *** PSA >= 20 ng/mL within 2 months prior to diagnostic biopsy *** MRI suspicious for radiographic >= T3 disease (if urologist deems tumor is resectable at baseline); defined as > 75% probability of extracapsular extension or seminal vesicle invasion in the opinion of the reading radiologist or ** Gleason 3 + 4 or 4 + 3 and Oncotype Dx Genomic Prostate score of > 40 WITH/WITHOUT ** Clinical N1 (size > 1.5 cm in the short axis) (Gleason score requirement can be omitted if node positive) OR
• Cohort B1 * Newly diagnosed low-volume metastatic disease with either: ** Bone metastases as documented by CT, MRI, or radionuclide bone scan amenable to treatment with a maximum of 3 radiation isocenters; these lesions must have a structural correlate on CT or MRI to allow for adequate radiation targeting (Note: subjects with PET scans that show osseous metastases that would not be amenable to 3-isocenter radiation treatment are still eligible if conventional imaging shows osseous disease that can be treated with 3 radiation isocenters) AND/OR ** Retroperitoneal nodes up to the level of the renal hilum with/without pelvic nodal metastasis > 1.5 cm in the short axis ** NOTE: For Cohort B1, biopsy confirmation of metastases is strongly encouraged if safe and feasible, but not required
• Cohort B2 (Cohort B2 expansion) * Biochemically persistent/recurrent disease (defined as PSA > 0.2) after RP +/- extended pelvic nodal dissection with metastatic lesions identified on PSMA PET scans. ** PSMA PET evidence of M1a/M1b disease that could be covered in up to 3 radiation plans (note that the isocenter for planned prostate bed/pelvic nodal irradiation does not count towards the 3 isocenter limit). * No radiographic evidence of local or regional recurrence on imaging in subjects with prior salvage radiation to these areas. ** Prior salvage radiotherapy is permitted. Prior metastasis-directed radiation is not permitted. *Castration sensitive disease * Multiple lesions within one isocenter may be permitted upon review by the sponsor’s radiation oncologist * NOTE: For Cohort B2, biopsy confirmation of metastases is strongly encouraged if safe and feasible, but not required
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
• Absolute neutrophil count (ANC) >= 1500/ul (within 28 days prior to treatment start)
• Hemoglobin >= 9 g/dL (within 28 days prior to treatment start)
• Platelet count >= 100,000/ul (within 28 days prior to treatment start)
• Serum creatinine glomerular filtration rate (GFR) >= 30 mL/min (within 28 days prior to treatment start)
• Potassium within institutional normal range (within 28 days prior to treatment start)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to treatment start) (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)
• Albumin >= 3.0 g/dL (within 28 days prior to treatment start)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 28 days prior to treatment start)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN (within 28 days prior to treatment start)
• Subjects must have a clinical T stage documented by the treating urologist/medical oncologist within 90 days prior to treatment start using the seventh (7th) edition American Joint Committee on Cancer (AJCC) staging system, recorded as the urologist’s/medical oncologist’s best clinical assessment of extent of local disease by digital rectal examination and/or available imaging studies such as transrectal ultrasound, CT scan, and/or MRI. (Applicable to Cohort A and B1 only)
• The primary tumor must be considered resectable by RP based on initial imaging with gross negative margins as determined by a urologist and documented as such (Applicable to cohorts A and B1 only)
• Recovery of reversible effects of prior surgery (i.e., incisional pain, wound drainage) to grade =< 1, and at least 4 weeks from prior surgery to treatment start (biopsy excluded)
• Able to swallow the study drug(s) whole as a tablet
• Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least one hour before and for at least two hours after the dose of abiraterone acetate is taken. (Not applicable to Cohort B2 expansion) (Note: apalutamide does not have to be taken on an empty stomach)
• Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug. Must also agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug

Exclusion Criteria

• Prior treatment for prostate cancer including prior surgery (excluding transurethral resection of the prostate [TURP] and subjects with rising PSA after RP), pelvic lymph node dissection,and/or radiation therapy (Applicable to Cohorts A and B1 only)
• Prior cytotoxic chemotherapy or biologic therapy for prostate cancer
• Up to 12 months of prior ADT with gonadotrophin releasing hormone (GnRH) antagonist/agonist at time of treatment start. Bicalutamide given for =< 12 months at the time of registration as flare prevention is allowed; For Cohort B2, prior ADT and/or first generation anti-androgen treatment in the (neo)adjuvant and/or salvage setting in conjunction with radiation or surgery is allowed provided last effective dose of ADT and/or first generation anti-androgen is > 12 months prior to the on treatment date and total duration of prior therapy is 12 months or lesser, and their testosterone is currently > 150 ng/dL
• Prior exposure to ketoconazole (systemic), abiraterone acetate, enzalutamide or other agents targeting the androgen receptor (AR) signaling pathway
• Concomitant therapy with any other experimental drug
• Known brain, liver, lung, or other visceral metastasis (except for retroperitoneal and/or pelvic nodal metastases as per inclusion criteria
• Prior prostate cancer metastasis-directed therapies
• Currently active second malignancy or past history of malignancies diagnosed within the last 2 years that require active therapy and/or in remission with life expectancy of < 5 years, with the exception of resected non-melanoma skin cancers, non-muscle invasive bladder cancer, stage I head and neck cancer, or stage I colorectal cancer
• Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to: * Any medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily * Active infection requiring systemic therapy * History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents * Uncontrolled hypertension (systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg); subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment (systolic BP <160 mmHg or diastolic BP <95 mmHg) * Active or symptomatic viral hepatitis or chronic liver disease * Acute or chronic hepatitis B or hepatitis C infection. (Hepatitis B and C testing are not mandatory) ** Presence of hepatitis B surface antibody is acceptable * Human immunodeficiency virus (HIV),-positive subjects with 1 or more of the following: ** Not receiving highly active anti-retroviral therapy ** A change in anti-retroviral therapy within 6 months of the start of screening (except if, after consultation with the principal investigator (PI) / sponsor, a change is made to avoid a potential drug-drug interaction with the study drug) ** Receiving anti-retroviral therapy that may interfere with the study drug(s) (consult the PI / sponsor for review of medication prior to enrollment) ** CD4 count < 350 cell/mm^3 at screening ** An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening ** (HIV testing is not mandatory) * History of pituitary or adrenal dysfunction * History of hypogonadism * Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < 50% at baseline, or clinically significant ventricular arrhythmias within 6 months prior to treatment start. * History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness =< 1 year prior to treatment start; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect) * Uncontrolled diabetes mellitus * History of an inflammatory bowel disease. (Crohn's or ulcerative colitis) that would interfere with absorption of tablets * History or current diagnosis of myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) * Baseline moderate and severe hepatic impairment (Child Pugh class B & C)
• Use of any prohibited concomitant medications within 14 days prior to treatment start, or use of prohibited concomitant medications within the outlined windows * Note: Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to treatment start
• Pre-existing condition that warrants long-term corticosteroid use in excess of 10 mg prednisone/prednisolone daily. (Note: If a subject has been receiving glucocorticoids other than prednisone or prednisolone, it will be necessary to switch the glucocorticoids to prednisone or prednisolone 5 mg twice daily prior to day 1)
• Known allergies, hypersensitivity, or intolerance to apalutamide, abiraterone acetate, prednisone, or GnRH agonist or GnRH antagonist. (Allergies or hypersensitivity to abiraterone and/or prednisone would not be applicable to subjects enrolling to B2 expansion)
• Administration of an investigational therapeutic agent within 30 days of treatment start
• Subjects that cannot tolerate MRI
• Any condition which, in the opinion of the investigator, would preclude participation in this trial
• Radiographic evidence of loco-regional recurrence in a previously irradiated field that is not amenable to re-irradiation (Cohort B2)