• Histologically confirmed adenocarcinoma of the prostate.
• Metastatic prostate cancer documented by positive bone scan and/or measurable soft tissue metastatic lesions by CT or magnetic resonance imaging (MRI).
• Progressive disease at study entry demonstrated during continuous androgen-deprivation therapy (ADT)/post orchiectomy defined as one or more of the following:
• PSA progression
• Radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST)1.1 for soft tissue and/or per Prostate Cancer Working Group 3 (PCWG3) for bone, with or without PSA progression
• Be able and willing to undergo mandatory tumor biopsy of at least one metastatic site.
• Have adequate organ function.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Prior therapy with cytochrome P450 (CYP)17 inhibitors.
• Prior treatment with abemaciclib or any cyclin-dependent kinase (CDK) 4 & 6 inhibitors.
• Prior cytotoxic chemotherapy for metastatic castration resistant prostate cancer (participants treated with docetaxel in the metastatic hormone-sensitive prostate cancer [mHSPC] are eligible), prior radiopharmaceuticals for prostate cancer, or prior enzalutamide, apalutamide, darolutamide or sipuleucel-T. Participants who had prior radiation or surgery to all target lesions.
• Currently enrolled in a clinical study involving an investigational product.
• Gastrointestinal disorder affecting the absorption or ability to swallow large pills.
• Clinically significant heart disease, active or chronic liver disease, moderate/severe hepatic impairment (Child-Pugh Class B and C).

• histologically proven adenocarcinoma of the prostate within 6 months of screening
• Eastern Cooperative Oncology Group(ECOG) score 0-2
• adequate organ and and blood marrow function
• must be a candidate for long-term androgen deprivation in combination with external beam radiation for the treatment of high risk prostate cancer
• patient must permit a targeted prostate biopsy at the time of study initiation or at the beginning of radiation treatment
• men who are sexually active with female partners of child-bearing potential mush agree to use adequate contraception
• prior treatment with agents known to have endocrine effects on prostate cancer
• treatment with corticosteroids within 4 weeks of enrollment
• treatment with androgens within 6 months of enrollment
• may not be receiving any other investigational agents
• Prostate specific antigen greater than 160ng/dL
• history of malignancy( other than non-melanoma skin cancer) within 5 years
• uncontrolled intercurrent illness
• cardiovascular event within 6 months of enrollment
• seizure or seizure disorder history
• contraindications to MRI- pacemakers, clips, etc

• Patients with suspected prostate cancer (e.g., abnormal digital rectal exam, elevated and/or rising PSA) as determined by referring physician
• Patients must have had a diagnostic, standard of care mpMRI of the prostate with at least one lesion with a PI-RADS v2.1 score ≥ 4
• In men with PI-RADS v2.1 score 4, PSA should be ≥ 10 ng/mL. In men with at least one PI-RADS v2.1 score 5 lesion, there is no restriction on PSA level.
• Patients must be scheduled for biopsy or radical prostatectomy
• Patients should not have had any type of curative or palliative therapy for prostate cancer before enrolling in the study
• Patients must be medically stable as judged by the patient's physician
• Patients must be able to lie still for a total of 60 minutes for the PET/CT scans
• Ability to understand and the willingness to sign a written informed consent
• Patients who have had a prior prostatectomy or radiotherapy for prostate cancer cannot participate in the study
• Patients who have had a prior biopsy for prostate cancer cannot participate in the study
• Patients who have been treated for cancers other than skin cancers
• Subjects may not be receiving any other investigational agents for the treatment of the cancer under study
• Patients may not weigh more than the maximum weight limit for the PET/CT scanner table (>200 kilograms or 440 pounds)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to 68Ga PSMA-11 or other agents used in the study such as gadolinium-based intravenous contrast agent used during the mpMRI
• Prior TURP/BPH procedures, including steam/laser therapies

• Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding and must be willing to use contraception
• Willing to provide written informed consent and to comply with study requirements
• Histologically confirmed locally advanced or metastatic clear cell renal cell carcinoma that has progressed during or after two prior therapeutic regimens which must include vascular endothelial growth factor (VEGF)-targeted therapy and checkpoint inhibitor therapy or that has otherwise failed such therapies, is measurable disease per RECIST 1.1 criteria, is biopsy accessible
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
• Estimated life expectancy of longer than 3 months
• Adequate organ function at screening
• History of untreated brain metastasis or leptomeningeal disease or spinal cord compression
• Failure to recover from reversible effects of prior anticancer therapy
• Has received systemic therapy or radiation therapy within 2 weeks prior to screen
• History of solid organ or stem cell transplantation
• Current use of anti-VEGF or mammalian target of rapamycin (mTOR) agents, or chronic immunosuppressive therapy
• Any prior use of hypoxia inducible factor 2 (HIF2) inhibitors
• Current use of immune checkpoint inhibitors
• Use of an investigational agent or device within 2 weeks prior to dosing, or current participation in an investigational study
• Known HIV, hepatitis B or hepatitis C
• History of other clinically meaningful disease
• Major surgery within 4 weeks of Screening
• Active malignancy requiring therapy other than ccRCC within 3 years of study entry

1. Male, age 45 to 80 years 2. Biopsy-confirmed adenocarcinoma of the prostate. Biopsy (minimum 10 cores) obtained ≥ 6 weeks and ≤ 6 months before treatment, or at the discretion of PI. 3. Clinical stage ≤ T2b 4. Gleason score ≤ 3 + 4 5. PSA ≤ 15 ng/ml 6. Eligible for MRI 7. Eligible for general anesthesia (ASA category ≤ 3) 8. Prostate volume ≤ 90 cc, on Baseline MRI 9. Prostate size ≤ 5.0 cm in sagittal length, and ≤ 6.0 cm in axial diameter, on Baseline MRI 10. Life expectancy ≥ 10 years 1. Evidence (including Baseline MRI and bone scan) of extracapsular extension, sphincter involvement, seminal vesicle invasion, lymph node invasion or metastases 2. Suspected tumour on Baseline MRI within 3 mm of the prostatic urethra, or in the prostate apex within 3 mm from the sphincter plane 3. Prior definitive treatment of prostate cancer 4. Prior transurethral resection of the prostate (TURP) 5. Use of 5-alpha reductase inhibitors (5-ARIs) or hormone therapy within 3 months prior to the baseline visit. Baseline PSA must be established after a minimum of 3 months following 5-ARIs discontinuation. Additionally, use of 5-ARIs is not permitted following treatment during the study follow-up period. 6. Prostate calcifications > 1 cm in largest diameter, on Baseline Ultrasound 7. Cysts > 1 cm in largest diameter, on Baseline MRI 8. Bleeding disorder (INR > ULN and PTT > ULN) 9. Abnormal coagulation and current anticoagulant therapy. Patients whose anticoagulation therapy can be temporarily reversed within 7 days prior to treatment are eligible. Platelet inhibitors (ie: ASA) and heparin are not exclusion criteria. 10. Acute unresolved Urinary Tract Infection (UTI) 11. Interest in future fertility 12. History of any other malignancy other than skin cancer, or low grade bladder cancer which has been completely resected, within the previous 2 years. Patients that have had curative treatment of a previous malignancy and no recurrence of that malignancy within the past 2 years will be allowed. 13. Patients with peripheral arterial disease with intermittent claudication or Leriches Syndrome 14. Patients with diabetes who have evidence of complications from their diabetes, such as end organ sequelae of diabetes or Hemoglobin A1c > 7%. 15. History of any major rectal or pelvic surgery or radiotherapy 16. History of ulcerative colitis or other chronic inflammatory conditions affecting rectum (includes rectal fistula, anal stenosis) 17. Documented clinical prostatitis requiring therapy within 6 months prior to Treatment 18. History of urethral and bladder outlet disorders, including urethral stricture disease, urethral diverticulae, bladder neck contracture, urethral fistulae, urethral stenting, urethral sling, urethroplasty or chronic indwelling urethral catheter 19. Patients with artificial urinary sphincter or any penile implant 20. Severe neurogenic bladder 21. Untreated bladder stones 22. History of acute urinary retention within the last 12 months 23. Active untreated gross hematuria for any cause 24. Post Void Residual (PVR) bladder volume > 250 mL 25. Obstructing median lobe enlarged out of proportion to the rest of the prostate and protruding significantly into the bladder, sometimes referred to as "ball valve" median lobe, determined on Baseline MRI 26. Any prostate related investigational therapy within 6 months of Visit 1 27. History of Parkinson's disease or multiple sclerosis 28. History of drug abuse 29. Known infectious disease including HIV positivity or AIDS-related illness, HBV and HCV 30. Current unilateral or bilateral hydronephrosis 31. Allergy or contraindications to administration of the GI anti-spasmodic drug: 1. Patients in the USA: Glucagon 2. Patients in Canada and Europe: Buscopan (Hyoscine) 32. Contraindications to administration of gadolinium-based MRI contrast agent (e.g. Magnevist), such as chronic, severe kidney disease, acute kidney injury, history of Sickle Cell Disease, history of anemia, or intolerance/allergy to the contrast agent 33. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results

1. Biopsy proven prostate cancer 2. Patient must currently be on androgen deprivation or anti-androgen therapy with castrate levels of testosterone (< 50ng/dl). Medical castration should continue until disease progression 3. Radiographic evidence of metastatic disease documented with bone scan or CT scan. Patients with any number of metastatic site are allowed to enroll. However, only up to six sites will be selected for SBRT treatment, at the discretion of the treating radiation oncologist. 4. PSA ≥ 5 ng/ml 5. Asymptomatic or minimally symptomatic patients1. Visual Analog Scale (VAS) ≤ 4;vNo narcotic use in the last 21 days 6. Adequate hematologic, renal, and liver function 7. Previous treatment with surgery, radiation or hormonal therapy is allowed. 8. Performance status ECOG 0 or 1. 9. Life expectancy of at least 6 months 10. Negative serology tests for human immunodeficiency virus (HIV) 1 and 2, human T cell lymphotropic virus (HTLV)-1, Hepatitis B and C. 11. Age ≥ 18 years. 12. Ability to understand and the willingness to sign a written informed consent 1. Subjects must not have had more than two different regiments of chemotherapy previously or any chemotherapy within the past three months. 2. Subjects may not be receiving any other investigational agents for the treatment of prostate cancer. 3. Subjects with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 4. Subjects with malignant pleural effusions and malignant ascites 5. Systemic corticosteroid use within past 28 days. Use of inhaled, intranasal, and topical steroids is acceptable. 6. Systemic immunosuppressive therapy in the past 28 days. 7. Use of any of the following within the past 28 days: Megestrol acetate (Megace®), diethyl stilbestrol (DES), or cyproterone acetate, Ketoconazole, high dose calcitriol [1,25(OH)2VitD] (i.e., > 7.0 μg/week). 8. Inability to tolerate contrast dye for baseline CT imaging. 9. Initiation or discontinuation of biphosphonate use within past 28 days. 10. Subjects with pathologic long-bone fractures 11. Subjects with spinal cord compression 12. Paget's disease of bone. 13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Patient must have histologically confirmed diagnosis of prostate cancer
• Patient must have had previous treatment with definitive surgery or radiation therapy or cryoablation
• Patient may have prior salvage therapy (surgery, radiation or other local ablative procedures) within 4 weeks prior to randomization if the intent was for cure; prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to randomization is allowed
• Patient must have no evidence of metastatic disease on physical exam, computed tomography (CT) abdomen/pelvis (or magnetic resonance imaging [MRI]), chest x-ray (or CT chest) and bone scan within 8 weeks prior to randomization
• Patient may have had prior neoadjuvant and/or adjuvant therapy (chemotherapy, vaccines or experimental agents) within 4 weeks prior to randomization, if the PSA rise and PSA doubling time (PSADT) were documented after the testosterone level was > 150 ng/dL
• Patient may not have had therapy modulating testosterone levels (such as luteinizing-hormone, releasing-hormone agonists/antagonists and antiandrogens) within 1 year prior to randomization, unless it was in the neoadjuvant and/or adjuvant setting; agents such as 5 alpha reductase inhibitors, ketoconazole, abiraterone, systemic steroids, or herbal supplements known to decrease PSA levels including any dose of megestrol acetate, finasteride (e.g., Saw Palmetto and PC-SPES, African pygeum extract, lycopene, alanine, glutamic acid and glycine, beta-sitosterol, lycopene, nettle root extract, quercitin, Belizian Man Vine extract, mulra puama extract and epimedium extract campesterol, beta-sitosterol, stigmasterol, sitostanol and brassicasterol) are not permitted at any time during the period that the PSA values are being collected
• Patient must have hormone-sensitive prostate cancer as evident by a serum total testosterone level > 150 ng/dL within 12 weeks prior to randomization
• Patient must have evidence of biochemical failure after primary therapy and subsequent progression
• Biochemical failure is declared when the PSA reaches a threshold value after primary treatment and it differs for radical prostatectomy or radiation therapy
• For radical prostatectomy the threshold for this study is PSA >= 0.4 ng/mL
• For radiation therapy the threshold is a PSA rise of 2 ng/mL above the nadir PSA achieved post radiation with or without hormone therapy (2006 Radiation Therapy Oncology Group [RTOG]-American Society for Radiation Oncology [ASTRO] Consensus definition)
• PSA progression requires a PSA rise above the threshold (PSA1) measured at any time point since the threshold was reached
• The PSADT must be < 12 months; requires two consecutive PSA rises (PSA2 and PSA3) above the PSA1; PSA2 and PSA3 must be obtained within 6 months of study entry; all baseline PSAs should be obtained, preferably, at the same reference lab
• PSADT calculation needs 3 PSA values:
• PSA1 is any PSA value that is equal or greater than the threshold PSA (0.4 ng/mL for radical prostatectomy or 2 ng/mL above the nadir for primary radiation therapy) indicating biochemical relapse
• PSA2 must be higher than PSA1, obtained at least 2 weeks after PSA1 and within 6 months or less from randomization
• PSA3 must be higher than PSA2 and obtained at least 2 weeks after PSA2
• Baseline PSA must have reached a minimum of 2 ng/mL but be no greater than 50 ng/mL and equal or higher than PSA3; PSA3 may be used as baseline PSA if obtained within 1 week of randomization
• Patient's PSA doubling time (PSADT) must be less than 12 months
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Granulocytes >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Serum creatinine within normal institutional limits or creatinine clearance >= 50 ml/min for patients with creatinine levels above institutional normal
• Serum total bilirubin =< 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase (ALP) =< 2.5 x ULN
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x institutional upper limit of normal
• Human immunodeficiency virus (HIV)-positive patients are excluded from this study
• Patient cannot receive concurrent therapeutic administration of anticoagulant therapy; low dosage aspirin =< 325 mg per day is allowed
• Patients with impaired cardiac function including any one of the following will be excluded from entry on study:
• Baseline corrected QT interval (QTc) > 450 msec (male) (patients with QTc 450-480 msec will be allowed to participate in this trial if they do not have any of the other cardiac conditions mentioned in this section)
• Patients with congenital long QT syndrome
• History of sustained ventricular tachycardia
• Any history of ventricular fibrillation or torsades de pointes
• Concomitant use of drugs with a risk of causing torsades de pointes
• Bradycardia defined as heart rate < 50 beats per minute; patients with a pacemaker and heart rate >= 50 beats per minute are eligible
• Myocardial infarction or unstable angina within 6 months of study entry
• Congestive heart failure (New York Heart Association class III or IV)
• Right bundle branch block and left anterior hemi-block (bifascicular block)
• Patient must not have gastrointestinal (GI) tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis)
• Patient may not be receiving any other investigational agents or receiving concurrent anticancer therapy (chemotherapy, immunotherapy, radiation therapy, surgery for cancer, or experimental medications) at time of randomization
• Patient may not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206 or bicalutamide
• Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with diabetes or at risk for hyperglycemia MUST not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled before the patient enters the trial
• Patients receiving any medications or substances that are inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible
• Patient must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:
• Basal cell or squamous cell carcinoma of the skin OR
• Prior malignancy has been adequately treated and patient has been continuously disease free for >= 2 years
• Patient must agree to use barrier contraception during and for 3 months after discontinuation of study treatment; if patient impregnates a woman while on treatment or within 3 months of discontinuing treatment, he should inform his treating physician immediately
• Patients must discontinue use of enzyme-inducing anti-epileptic drugs (EIAEDs) >= 14 days prior to study enrollment; the investigator may prescribe non-EIAEDs; patients who must begin EIAED therapy while on study will be allowed to remain
• Patients must not be taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), St John's Wort, ketoconazole, dexamethasone, the dysrhythmic drugs (terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, indapamide or flecainide), haloperidol, risperidone, rifampin, grapefruit, or grapefruit juice within two weeks of randomization and during the course of therapy
• Patients may have received targeted agents (angiogenesis inhibitors, epidermal growth factor receptor [EGFR] inhibitors, mammalian target of rapamycin [mTOR] inhibitors, phosphatidylinositol 3 kinase [PI3K] inhibitors, etc.), however patients must have discontinued treatment with the targeted agent(s) at least 4 weeks prior to enrollment; if the patient stopped targeted agent(s) due to unresolved or persistent grade 3 or 4 toxicity, patient cannot be enrolled onto the study regardless of the length of time since discontinuation of treatment with targeted agent(s)

• Age between 40-89 years
• Biopsy proven, low-risk, localized prostate cancer (minimum of 8 cores)
• May have had biopsy within last 12 months ≤4 cores involved with cancer
• Gleason score ≤6 with no Gleason pattern 4
• Clinical stage T1c-T2a/b
• Serum PSA ≤15 ng/ml
• Life expectancy > 5 years
• Any previous prostate cancer treatment (radiotherapy, chemotherapy, hormonal therapy, oral glucocorticoids, GnRH analogues, prostatectomy)
• Concurrent or previous use within 6 months of screening of any 5α-reductase inhibitor
• Use of anabolic steroids or drugs with antiandrogenic properties
• Prostate volume >150 grams
• Patients who are taking antiplatelet, anticoagulant agents or have a history of a bleeding disorder. Patients taking 81 mg of Aspirin will be allowed to enroll with close observation
• History of gastric or duodenal ulcers or untreated hyperacidity syndromes. Patients on stable doses of GERD medication allowed.
• Patients who are currently taking or plan to take Curcumin during the study
• Patients with a history of gallbladder surgery or gallstones or biliary obstruction will be excluded, unless patient had cholecystectomy

• STEP I REGISTRATION CRITERIA
• Histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid features.
• Any metastatic disease, including visceral, lymph node, other soft tissue and bone, measurable per RECIST 1.1.
• Measurable disease as defined in the protocol.
• Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria (1 or more of the following: Karnofsky performance status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN], corrected calcium concentration greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN, platelet count > ULN).
• Central nervous system (CNS) disease permitted, if stable and not otherwise causing symptoms or needing active treatment.
• Karnofsky performance status >= 70%.
• No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting T-cell co-stimulation or checkpoint pathways. The only exception is for prior treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or post-operative trials, as long as > 1 year since completion of systemic therapy.
• No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above are allowed).
• No cancer therapy less than 28 days prior to registration; this includes radiation therapy, except for bone lesions less than 14 days prior to registration. There must be a complete recovery and no ongoing complications from radiotherapy.
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
• Age >= 18 years
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Hemoglobin >= 8 g/dL.
• Calculated (Calc.) creatinine clearance >= 30 mL/min.
• Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
• Total bilirubin =< 1.5 x upper limit of normal (ULN).
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present.
• STEP 2 REGISTRATION ELIGIBILITY CRITERIA
• Successful completion of at least 1 cycle of ipilimumab/nivolumab.
• Resolution of any treatment-related adverse events to grade 1 or less per dose modification section (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment-related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed.
• No more than 70 days from last dose of ipilimumab/nivolumab.
• Active autoimmune disease requiring ongoing therapy.
• Ongoing acute toxicity > grade 2 from previous treatment.
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies.
• History of human immunodeficiency virus (HIV) or active hepatitis B/C, or active tuberculosis (purified protein derivative [PPD] response without active TB is allowed).
• Concurrent use of immunosuppressive medication including prednisone above 10 mg daily.
• Uncontrolled adrenal insufficiency.
• Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP > 90 mmHg).
• Major surgery less than 28 days prior to registration.
• Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to registration.
• Any arterial thrombotic events within 180 days prior to registration.
• Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks prior to registration.
• Cavitating pulmonary lesions or known endotracheal or endobronchial disease manifestations.
• Lesions encasing or invading any major blood vessels (this does not include tumor thrombus extending into/through renal vein/inferior vena cava [IVC]). Patients with tumor thrombus extending into/through renal vein are considered eligible.
• Moderate of severe hepatic impairment (Child-Pugh B or C).
• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in the 180 days prior to registration. (Any asymptomatic, treated pulmonary embolism or asymptomatic, treated deep venous thrombosis > 30 days prior to registration allowed).
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
• Unstable cardiac arrhythmia within 6 months prior to registration.
• Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs of pulmonary hemorrhage =< 90 days prior to registration.
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration.
• Active peptic ulcer disease, inflammatory bowel disease, or malabsorption syndrome within 28 days prior to registration.
• Untreated hypothyroidism, evidence of pancreatitis, history of organ transplant, or history of congenital QT syndrome.
• Active treatment with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g., clopidogrel) within 5 days of registration. Allowed anticoagulants include: prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, apixaban. Allowed also in patients with known brain metastases who are on a stable dose of the anticoagulant for at least 1 week prior to registration without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] or non-ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart Association class 3-4 heart failure symptoms

Inclusion Criteria 1. Pathologic biopsy proven adenocarcinoma of the prostate 2. At least one of the following criteria:
• cN1 on conventional or PET imaging
• Grade group 5
• Grade group 4 and PSA ≥10 ng/mL
• Grade group 3 and PSA ≥20 ng/mL
• High probability of Radiographic T3 on MRI AND Grade group ≥2
• Grade Group 3 AND PSA ≥10 ng/mL AND ≥50% positive biopsy cores 3. Age ≥ 18 4. ECOG < 1 5. Adequate organ and marrow function as defined per protocol. 6. Use of highly effective contraception (e.g. condoms) for the duration of treatment and a minimum of 90 days thereafter. Men must also agree not to donate sperm for the duration of the study participation, and for at least 90 days thereafter. 7. International Prostate Symptoms Score (IPSS) ≤ 20 8. Medically fit for treatment and agreeable to follow-up 9. Ability to understand and the willingness to sign a written informed consent 10. Tissue available for MiOncoSeq testing to assign DNA repair deficiency status Exclusion Criteria 1. Clinical or radiographic evidence of distant metastatic disease by CT/bone scan 2. Clinical or radiographic evidence of high probability of clinical T4 disease 3. Prostate gland size >80 cc measured by ultrasound or MRI 4. Prominent median lobe assessed by treating physician 5. Lack of tissue from biopsy to be sent for correlative studies 6. Any prior treatment for prostate cancer (incudes TURP, chemotherapy, radiation therapy, or anti-androgen therapy) 7. Prohibited within 30 days prior to administration to study treatment: spironolactone and other investigational drug therapies. 8. Prohibited 3 months before participant registration and during administration of study treatment: non-steroidal anti-androgens (e.g., bicalutamide, flutamide, nilutamide), steroidal antiandrogens (megestrol acetate, cyproterone acetate), oral ketoconazole, chemotherapy, immunotherapy, estrogens, radiopharmaceuticals. 9. History of prior pelvic radiation therapy 10. Concurrent treatment with strong CYP3A4 inducers such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital 11. Enrollment concurrently in another investigational drug study within 1 month of registration 12. History of another active malignancy within the previous 3 years except for adequately treated skin cancer or superficial bladder cancer 13. History of or active Crohn's disease or ulcerative colitis 14. Contraindication to or inability to tolerate MRIs 15. Patients with severe depression 16. Uncontrolled diabetes or known HbA1c>10 17. Any gastrointestinal disorder affecting absorption 18. Active pituitary or adrenal dysfunction 19. Patients with significant cardiovascular disease potentially including severe / unstable angina, recent history of myocardial infarction, clinically significant heart failure, cerebrovascular disease, venous thromboembolic events, clinically significant arrhythmias) 20. Uncontrolled hypertension with persistently elevated systolic blood pressure >160 mmgHg or diastolic blood pressure >100 mmHg despite anti-hypertensive agents. 21. Prolonged QTc >450 ms or any ECG changes that interfere with QT interval interpretation 22. Major surgery within 1 month of registration 23. History of myelodysplastic syndrome or leukemia 24. A known hypersensitivity to niraparib, abiraterone acetate, leuprolide, and/or prednisone 25. Active infection or other medical condition that would be a contraindication to prednisone use 26. Patients with known active hepatitis or chronic liver disease including cirrhosis 27. Any condition that in the opinion of the investigator would preclude participation in this study

• radical prostatectomy for adenocarcinoma of prostate
• pathologically confirmed T1-T3 disease
• no sign of lymph node or metastatic disease
• pT1-pT3pNxMx patients in whom standard NCCN or AUA guidelines would suggest are at low risk for pelvic lymph node or metastatic disease and who would not require confirmatory imaging for metastatic disease. This includes patients with Gleason 6 or 7(T2 disease) and PSA less than 20.
• Eastern Cooperative Oncology Group(ECOG) status 0-2
• adequate renal and liver function as well as bone marrow reserve (measured serum creatinine <2mg/dl, bilirubin ≤ 1.5 mg/dl, ANC ≥ 1.5 x 10 (3) uL, platelets ≥ 50 x K/uLL, and hemoglobin ≥ 10 g/dL)
• 30-80 y/o at time of diagnosis with a life expectancy of >= 3 yrs
• focally positive surgical margins are permitted
• no plan to receive adjuvant hormone or radiation therapy
• PSA at the time of enrollment must be undetectable
• life expectancy of 3 years
• must not have exceeded 3 months from time of surgery to enrollment into study
• T3b or T4 or node positive disease
• macroscopic residual disease after surgery
• hormone therapy before surgery
• history of gallbladder problems or gallstones, or biliary obstruction, unless patient had cholecystectomy
• radiation therapy as primary treatment after surgery
• INR value greater than 1.5
• AST/ALT are equal or greater than 2 times the upper limit of normal
• antiplatelet or anticoagulant agents- patients taking 81mg of Aspirin will be allowed with close observation
• history of gastric or duodenal ulcers or untreated hyperacidity syndromes
• patients who are currently taking or plan to take Curcumin during the study

DISEASE CHARACTERISTICS:
• Pathologically (histologically or cytologically) proven diagnosis of prostatic adenocarcinoma within 180 days of registration at moderate- to high-risk for recurrence as determined by one of the following combinations:
• Gleason score 7-10 + T1c-T2b (palpation) + prostate-specific antigen (PSA) < 50 ng/mL (includes intermediate- and high-risk patients)
• Gleason score 6 + T2c-T4 (palpation) + PSA < 50 ng/mL OR
• Gleason score 6 + >= 50% (positive) biopsies + PSA < 50 ng/ml
• Gleason score 6 + T1c-T2b (palpation) + PSA > 20 ng/mL Patients previously diagnosed with low risk prostate cancer undergoing active surveillance who are re-biopsied and found to have unfavorable intermediate risk disease or favorable high risk disease according to the protocol criteria are eligible for enrollment within 180 days of the repeat biopsy procedure.
• History and/or physical examination (to include at a minimum digital rectal examination of the prostate and examination of the skeletal system and abdomen) within 90 days prior to registration
• Clinically negative lymph nodes as established by imaging (pelvic and/or abdominal CT or MR), (but not by nodal sampling, or dissection) within 90 days prior to registration
• Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.5 cm
• Patients status post a negative lymph node dissection are not eligible
• No evidence of bone metastases (M0) on bone scan within 120 days prior to registration (Na F PET/CT is an acceptable substitute)
• Equivocal bone scan findings are allowed if plain films (or CT or MRI) are negative for metastasis
• Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech) within 120 days prior to registration
• Study entry PSA should not be obtained during the following time frames:
• Ten-day period following prostate biopsy
• Following initiation of hormonal therapy
• Within 30 days after discontinuation of finasteride
• Within 90 days after discontinuation of dutasteride PATIENT CHARACTERISTICS:
• Zubrod performance status 0-1
• Absolute neutrophil count (ANC) ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin (Hgb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable)
• No prior invasive (except non-melanoma skin cancer) malignancy unless disease-free for a minimum of 3 years (1,095 days) and not in the pelvis
• E.g., carcinoma in situ of the oral cavity is permissible; however, patients with prior history of bladder cancer are not allowed
• No prior hematological (e.g., leukemia, lymphoma, or myeloma) malignancy
• No previous radical surgery (prostatectomy) or cryosurgery for prostate cancer
• No previous pelvic irradiation, prostate brachytherapy or bilateral orchiectomy
• No previous hormonal therapy, such as LHRH agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g. degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone acetate), estrogens (e.g., DES), or surgical castration (orchiectomy)
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both LHRH agonist and oral anti-androgen) is ≤ 45 days prior to the date of registration.
• No severe, active co-morbidity, defined as any of the following:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects or severe liver dysfunction
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition
• Protocol-specific requirements may also exclude immuno-compromised patients
• HIV testing is not required for entry into this protocol
• No patients who are sexually active and not willing/able to use medically acceptable forms of contraception
• No prior allergic reaction to the hormones involved in this protocol PRIOR CONCURRENT THERAPY:
• See Disease Characteristics
• No prior radical surgery (prostatectomy) or cryosurgery for prostate cancer
• No prior pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy
• No prior hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g., degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone acetate), estrogens (e.g., diethylstilbestrol (DES) ), or surgical castration (orchiectomy)
• No prior pharmacologic androgen ablation for prostate cancer unless the onset of androgen ablation is ≤ 45 days prior to the date of registration
• No finasteride within 30 days prior to registration
• No dutasteride or dutasteride/tamsulosin (Jalyn) within 90 days prior to registration
• No prior or concurrent cytotoxic chemotherapy for prostate cancer
• Prior chemotherapy for a different cancer is allowable
• No prior radiotherapy, including brachytherapy, to the region of the study cancer that would result in overlap of radiation therapy fields

1. Age ≥ 18 years. 2. Appropriate staging studies identifying patient as AJCC 7th edition clinical stage T1 (a, b, or c) or T2 (a, b, or c) adenocarcinoma of the prostate gland. The patient should not have direct evidence of regional or distant metastases after appropriate staging studies. See Appendix I for details on AJCC 7th Edition staging criteria. Histologic confirmation of cancer will be required by biopsy performed within 12 months of registration. T-staging may be assessed by multi-parametric imaging alone if digital rectal examination was deferred. 3. The patient's Zubrod performance status must be 0-2 (see Appendix II for definition). 4. The Gleason summary score should be less than or equal to 7 [Grade group 1 (Gleason 3+3=6), group 2 (Gleason 3+4=7), and group 3 (Gleason 4+3=7) are allowed]. See Appendix III for details on definitions. While a template biopsy is recommended, it is not required in the case of MRI fusion biopsy performed on all dominant MR lesions (defined as PIRADS v2 4-5). 5. Baseline AUA symptom score ≤19 (see Appendix IV for questionnaire) without need for maximum medical therapy (specifically, not on tamsulosin 0.8mg daily) 6. EPIC sexual domain composite score 60-100 (see Appendix V) 7. Multi-parametric MRI evaluation of the prostate is required for this study within 12 months of registration. Gross radiographic disease on MRI (defined as PIRADS v2 score 3-5) must be > 5mm at minimum distance from at least one side's neurovascular bundle, which is typically the closest of the neurovascular elements to the prostate. 8. The serum PSA should be less than or equal to 20 ng/ml within 90 days of registration. Study entry PSA must not be obtained during the following time frames: (1) 10-day period following prostate biopsy; (2) following initiation of ADT or anti-androgen therapy; (3) within 30 days after discontinuation of finasteride; (4) within 90 days after discontinuation of dutasteride; (5) within 5 days of a digital rectal examination. 9. Ultrasound or MRI based volume estimation of prostate gland ≤ 80 grams. Cytoreduction therapy (finasteride or dutasteride only) may be considered for those with >60 gram size. 10. All patients must be willing and capable to provide informed consent to participate in the protocol within the 30 days prior to registration 1. Subjects with clinical (digital rectal examination) evidence of extraprostatic extension (T3a) or seminal vesicle involvement (T3b). MRI evidence of equivocal/potential but not definite extraprostatic extension is allowed, as long as it is unilateral and not on the side of the gland proposed for neurovascular element sparing. In equivocal cases of potential extracapsular extension on MRI only, discretion is left to the treating physician. 2. MRI evidence of gross disease (defined as PIRADS v2 score 3-5 lesions) ≤5mm of BOTH neurovascular bundles, which are the most proximate of the neurovascular elements planned for sparing on this protocol. 3. Patients with all three intermediate risk factors (PSA >10 and ≤ 20, Gleason 7, clinical stage T2b-T2c) who ALSO have ≥50% of the number of their template biopsy cores positive for cancer are ineligible. 4. Inability to undergo multi-parametric MRI. 5. Evidence of metastatic disease. Note bone scan is not required for this study given the low-intermediate NCCN risk cohort to be enrolled. 6. Evidence of clinical nodal involvement of the pelvis. Biopsy is required for lymph nodes over ≥1.5cm in short-axis measured size. 7. No currently active ADT or anti-androgen therapy at time of registration is allowed. Further, no more than 3 cumulative months of prior ADT or anti-androgen therapy is allowed. If either has been used by the patient, there must be a demonstration of testosterone recovery (>50ng/dL serum blood level), EPIC sexual domain score ≥60, and at least 1 month between demonstration of testosterone recovery and study registration (any one measurement of testosterone recovery suffices). 8. Testosterone ≤ 50 ng/dL (any one measurement >50 ng/dL suffices for inclusion) within 90 days of study entry. 9. Subjects who have had previous pelvic radiotherapy or have had chemotherapy or surgery for prostate cancer. 10. Subjects who have plans to receive other concomitant or post treatment adjuvant antineoplastic therapy while on this protocol including surgery, cryotherapy, conventionally fractionated radiotherapy, hormonal therapy, or chemotherapy given as part of the treatment of prostate cancer. 11. Subjects who have undergone previous transurethral resection of the prostate (TURP) or ablative procedures to the prostate for benign prostatic hyperplasia or other conditions (i.e. cryotherapy, HIFU). 12. Subjects who have baseline severe urinary symptoms, as defined by AUA symptom score >19 (alpha-blocker medication allowed except if taking tamsulosin 0.8mg daily at baseline which indicates compensated severe symptoms and also can affect sexual function). 13. Subjects who have a history of significant psychiatric illness that would confound informed consent. 14. Severe, active co-morbidity, defined as follows: 1. Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months 2. Myocardial infarction within the last 6 months 3. Acute bacterial or fungal infection requiring intravenous antibiotics at time of registration 4. Patients with active inflammatory colitis (including Crohn's Disease and ulcerative colitis) currently requiring systemic steroids and/or systemic immunosuppression are not eligible. 15. Subjects with a known allergy to polyethylene glycol hydrogel (rectal spacer material) or contraindication to spacer products (SpaceOAR) 16. Subjects with uncontrolled coagulation disorder which cannot be controlled with anticoagulants 17. Men of reproductive potential who do not agree that they will use an effective contraceptive method. 18. Men who require erectile function medication or aid to achieve an erection sufficient for intercourse. Ability to achieve erection sufficient for intercourse without medication or aid at least once time in the month prior to registration is sufficient for inclusion. 19. Men who have clinically significant penile malformation (i.e. Peyronie's disease) or history of penile implantation are excluded 20. If DRE is performed, patient may not have palpable disease on side of gland to be planned for neurovascular sparing. Given the poor accuracy of DRE, such a finding should be confirmed by MRI and/or biopsy to harbor actual disease before excluding a patient

DISEASE CHARACTERISTICS:
• Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration at high risk for recurrence as determined by one of the following combinations (risk group):
• Gleason Score (GS) ≥ 9, PSA ≤ 150 ng/mL, any T stage
• GS ≥ 8, PSA < 20 ng/mL, T stage ≥ T2
• GS ≥ 8, PSA ≥ 20-150 ng/mL, any T stage
• GS ≥ 7, PSA ≥ 20-150 ng/mL, any T stage
• Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech), obtained prior to any luteinizing hormone-releasing hormone (LHRH) agonist or antiandrogen therapy, within 180 days of randomization
• Androgen deprivation therapy (ADT), such as LHRH agonists (e.g., goserelin, leuprolide), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., diethyl- stilbestrol [DES]), or surgical castration (orchiectomy), may have been started prior to registration, provided that registration is within 50 days of beginning ADT; please note: if the patient has started ADT he will not be eligible to participate in the quality of life component of this study
• Clinically negative lymph nodes as established by imaging (abdominal and/or pelvic CT or abdominal and/or pelvic MRI), nodal sampling, or dissection within 90 days prior to registration
• Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are < 2.0 cm
• No distant metastases (M0) on bone scan within 90 days prior to registration
• Equivocal bone scan findings are allowed if plain films are negative for metastasis
• No definite evidence of metastatic disease
• Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostate volume < 60 cc, American Urological Association (AUA) score ≤ 15 within 60 days of registration, and no history of prior transurethral resection of the prostate (TURP)
• Prior TURP is permitted for patients who receive external-beam radiotherapy (EBRT) only PATIENT CHARACTERISTICS:
• Height, weight, Zubrod performance status 0-1
• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 8.0 g/dL (The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable)
• Serum creatinine < 2.0 mg/dL
• Creatinine clearance > 40 mL/minute
• Bilirubin < 1.5 x upper limit of normal (ULN)
• Alanine aminotranserase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN
• No PSA > 150 ng/mL
• Screening calculated ejection fraction ≥ ULN by multiple-gated acquisition (MUGA) scan or by echocardiogram
• Androgen deprivation therapy (ADT), such as LHRH agonists (e.g., goserelin, leuprolide), anti-androgens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration (orchiectomy) may have been started prior to registration, provided that registration is within 50 days of beginning ADT.
• Patients, even if surgically sterilized (i.e., status post vasectomy), must agree to practice effective barrier contraception during the entire study treatment period and for 4 months (120 days) after the last dose of study drug
• No prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or not requiring systemic therapy for a minimum of 3 years
• No known hypersensitivity to TAK-700 or related compounds
• No history of adrenal insufficiency
• No history of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of grade > 2 (NCI CTCAE, version 4.02) thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g., pericardial effusion restrictive cardiomyopathy) within 6 months prior to registration
• Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed
• No New York Heart Association Class III or IV heart failure
• No ECG abnormalities of Q-wave infarction, unless identified 6 or more months prior to screening, or corrected QT (QTc) interval > 460 msec
• No prior allergic reaction to the drugs involved in this protocol
• No Cushing syndrome
• No severe chronic renal disease or chronic liver disease
• No uncontrolled hypertension despite appropriate medical therapy within 21 days prior to registration (blood pressure of greater than 150 mm Hg systolic and 90 mm Hg diastolic at 2 separate measurements no more than 60 minutes apart during screening visit)
• No serious infection within 14 days prior to registration
• No uncontrolled nausea, vomiting, or diarrhea (CTCAE grade ≥ 3) despite appropriate medical therapy at the time of registration
• No known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-700, including difficulty swallowing tablets PRIOR CONCURRENT THERAPY:
• See Disease Characteristics
• Prior testosterone administration is allowed if last administered at least 90 days prior to registration
• No prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason
• No prior systemic chemotherapy for prostate cancer
• Prior chemotherapy for a different cancer is allowed
• No prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields
• No previous hormonal therapy for > 50 days
• No chronic treatment with glucocorticoids within one year
• No major surgery within 14 days prior to registration
• No other investigational agent
• No other anticancer therapy
• No concurrent hormonal therapies including estrogens or herbal products
• No concurrent ketoconazole or aminoglutethimide
• No chronic use of systemic corticosteroids, such as oral prednisone

• Pathologically (histologically) proven adenocarcinoma confirmed by prostatectomy performed within 10 years prior to registration and any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted.
• PSA level (≥ 0.2 ng/mL) within 90 days prior to registration. GnRH analog may be started no more than 42 days prior study entry, but patients must have a PSA ≥ 0.2 ng/mL prior to starting ADT.
• Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 90 days prior to registration.
• Platelet count ≥ 75,000 x 10^9/µL independent of transfusion and/or growth factors within 90 days prior to registration.
• At least 1 of the following aggressive features:
• Gleason score of 8-10 (note any Gleason score is eligible)
• Seminal vesicle invasion (SVI) (note any pT stage [AJCC v8.0] is eligible but a pT stage ≥ pT3b is considered aggressive)
• Locoregional node involvement at radical prostatectomy (pN1)
• Persistently elevated PSA post-RP nadir (PEPP) defined as PSA > 0.1 ng/mL after radical prostatectomy
• Serum albumin ≥ 3.0 g/dL within 90 days prior to registration
• GFR ≥35 mL/min estimated by Cockcroft-Gault or measured directly by 24 hour urine creatinine within 90 days prior to registration.
• Serum total bilirubin ≤1.5 × ULN (Note: In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject is eligible) within 90 days prior to registration.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN within 90 days prior to registration.
• Testosterone >50 ng/dL within 90 days prior to registration. Prior androgen deprivation (GnRH analog and/or non-steroidal antiandrogen) therapy is allowed provided that serum testosterone concentration must be ≥ 50 ng/dL prior to registration or starting ADT, whichever occurs first; 5-alpha reductase inhibitors will not impact eligibility, but must be discontinued prior to starting protocol treatment.
• History and physical with ECOG Performance Status 0-1 or within 90 days prior to registration.
• Definitive clinical or radiologic evidence of metastatic disease with the exception of locoregional lymph nodes.
• Prior invasive malignancy (except non-melanomatous skin cancer carcinoma in situ of the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely resected melanoma) unless disease free for a minimum of 2 years).
• Prior systemic chemotherapy for the study cancer. Note: prior chemotherapy for a different cancer is allowable.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• History of any of the following:
• Documented inflammatory bowel disease
• Transmural myocardial infarction within the last 4 months prior to registration.
• New York Heart Association Functional Classification III/IV within 4 months prior to registration.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 4 months prior to registration
• History of loss of consciousness or transient ischemic attack within 12 months prior to randomization
• History of seizure disorder or condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma)
• History of uncontrolled hypertension defined as a sustained systolic blood pressure in excess of 150 mmHg or a sustained diastolic blood pressure in excess of 90 mmHg despite optimized antihypertensive therapy.
• History of repeated falls and fractures over the past 12 months that in the opinion of the treating investigator would put the patient at risk for poor bone outcomes from androgen receptor targeted therapy
• Known gastrointestinal disorder affecting absorption of oral medications.
• Active uncontrolled infection defined as an identified infectious condition that requires active therapy that has not yet been completed.
• HIV positive patients with CD4 count < 200 cells/microliter within 30 days prior to registration OR HIV patients under treatment with highly active antiretroviral therapy (HAART) within 30 days prior to registration regardless of CD4 count. Note: HIV testing is not required for eligibility for this protocol as it is self-reported. This exclusion criterion is necessary because the treatments involved in this protocol may be immunosuppressive and/or interact with HAART.

1. Adenocarcinoma of the prostate treated primarily with radical prostatectomy, pathologically proven to be lymph node negative by pelvic lymphadenectomy (N0) or lymph node status pathologically unknown (undissected pelvic lymph nodes [Nx]), i.e. lymph node dissection is not required; • Any type of radical prostatectomy will be permitted, including retropubic, perineal, laparoscopic or robotically assisted. There is no time limit for the date of radical prostatectomy. 2. A post-radical prostatectomy entry prostate-specific antigen (PSA) of ≥ 0.1 and < 2.0 ng/mL at least 6 weeks (45 days) after prostatectomy and within 30 days of registration; 3. One of the following pathologic classifications:
• T3N0/Nx disease with or without a positive prostatectomy surgical margin; or
• T2N0/Nx disease with or without a positive prostatectomy surgical margin; 4. Prostatectomy Gleason score of 9 or less; 5. Zubrod Performance Status of 0-1; 6. Age ≥ 18; 7. No distant metastases, based upon the following minimum diagnostic workup:
• History/physical examination (including digital rectal exam) within 8 weeks (60 days) prior to registration;
• A computerized tomography (CT) scan of the pelvis (with contrast if renal function is acceptable; a noncontrast CT is permitted if the patient is not a candidate for contrast) or magnetic resonance imaging (MRI) of the pelvis within 120 days prior to registration;
• Bone scan within 120 days prior to registration; if the bone scan is suspicious, a plain x-ray and/or MRI must be obtained to rule out metastasis. 8. Adequate bone marrow function, within 90 days prior to registration, defined as follows:
• Platelets ≥ 100,000 cells/mm^3 based upon compete blood count (CBC);
• Hemoglobin ≥ 10.0 g/dl based upon CBC (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is recommended). 9. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 x the upper limit of normal within 90 days prior to registration; 10. Serum total testosterone must be ≥ 40% of the lower limit of normal (LLN) of the assay used (testosterone ÷ LLN must be ≥ 0.40) within 90 days prior to registration (Note: Patients who have had a unilateral orchiectomy are eligible as long as this requirement is met); 11. Patients must sign a study-specific informed consent prior to study entry. 1. A palpable prostatic fossa abnormality/mass suggestive of recurrence, unless shown by biopsy under ultrasound guidance not to contain cancer; 2. N1 patients are ineligible, as are those with pelvic lymph node enlargement ≥ 1.5 cm in greatest dimension by CT scan or MRI of the pelvis, unless the enlarged lymph node is sampled and is negative; 3. Androgen deprivation therapy started prior to prostatectomy for > 6 months (180 days) duration. Note: The use of finasteride or dutasteride (±tamsulosin) for longer periods prior to prostatectomy is acceptable; 4. Androgen deprivation therapy started after prostatectomy and prior to registration (Note: The use of finasteride or dutasteride (±tamsulosin) after prostatectomy is not acceptable
•must be stopped within 3 months after prostatectomy. Androgen deprivation therapy must be stopped within 3 months after prostatectomy); 5. Neoadjuvant chemotherapy before or after prostatectomy; 6. Prior chemotherapy for any other disease site if given within 5 years prior to registration; 7. Prior cryosurgery or brachytherapy of the prostate; prostatectomy should be the primary treatment and not a salvage procedure; 8. Prior pelvic radiotherapy; 9. Prior invasive malignancy (except non-melanomatous skin cancer) or superficial bladder cancer unless disease free for a minimum of 5 years [for example, carcinoma in situ of the oral cavity is permissible]; 10. Severe, active co-morbidity, defined as follows:
• History of inflammatory bowel disease;
• History of hepatitis B or C; Blood tests are not required to determine if the patient has had hepatitis B or C, unless the patient reports a history of hepatitis.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
• Transmural myocardial infarction within the last 6 months;
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration;
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; AST or ALT are required; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol.
• Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; Note, however, that human immunodeficiency viruses (HIV) testing is not required for entry into this protocol. The need to exclude patients with acquired immunodeficiency syndrome (AIDS) from this protocol is necessary because the treatments involved in this protocol may result in increased toxicity and immunosuppression. 11. Prior allergic reaction to the study drug(s) involved in this protocol.

DISEASE CHARACTERISTICS:
• Histologically confirmed adenocarcinoma of the prostate diagnosed within the past 180 days and at intermediate-risk for recurrence by meeting 1 or more of the following criteria:
• Gleason score = 7
• Prostate Specific Antigen (PSA) > 10 and ≤ 20 ng/mL
• Baseline serum PSA value performed within 60 days with an FDA-approved assay (e.g., Abbott, Hybritech)
• Baseline PSA must not be obtained during any of the following time frames:10-day period after prostate biopsy, after initiation of androgen-deprivation therapy, or within the past 30 days after discontinuation of finasteride (90 days for dutasteride)
• Clinical stage T2b or T2c disease
• Patients previously diagnosed with low-risk (Gleason score < 6, clinical stage < T2a, and PSA < 10 ng/mL) prostate cancer undergoing active surveillance who are re-biopsied and found to have intermediate-risk disease according to the protocol criteria are eligible for enrollment within 6 months of the repeat biopsy procedure
• Patients with Gleason Score ≥ 8, PSA > 20 ng/mL, OR clinical stage ≥ T3 are ineligible for this trial
• If findings of extracapsular extension or seminal vesicle invasion are noted on prostate MRI, this study, if used, will not render patients ineligible for accrual to this protocol
• Primary tumor staging for eligibility purposes is to be based on palpable or core biopsy evidence only with respect to extracapsular extension or seminal vesicle involvement
• No patients with all 3 intermediate-risk factors who also have ≥ 50% of the number of their biopsy cores positive for cancer
• The percentage of biopsy cores involved will only be considered with respect to eligibility for those patients with all 3 of the above risk factors (i.e., patients with one or two of the above risk factors are eligible irrespective of the percentage of biopsy cores involved)
• Clinically negative lymph nodes as established by imaging (pelvic and/or abdominal CT scan or MRI), nodal sampling, or dissection within the past 60 days (required for patients with 2-3 risk factors)
• Abdominal imaging not required for a single intermediate-risk factor (these studies may be obtained at the discretion of the treating physician)
• Lymph nodes that are equivocal or questionable by imaging allowed without biopsy if nodes ≤ 1.5 cm
• Any node > 1.5 cm on imaging requires a negative biopsy
• No evidence of bone metastases on bone scan within the past 60 days
• Bone scan not required for patients with a single intermediate-risk factor (scan may be obtained at the discretion of the treating physician)
• Equivocal bone scan findings allowed if plain film x-rays negative for metastasis PATIENT CHARACTERISTICS:
• Zubrod performance status 0-1
• Absolute neutrophil count (ANC) ≥ 1,800/mm^3*
• Platelet count ≥ 100,000/mm^3*
• Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve level allowed)*
• NOTE: *For patients undergoing brachytherapy only.
• Fertile patients must use effective contraception during and for the 3 months after cessation of protocol treatment
• No invasive malignancy or hematological malignancy (e.g., leukemia, lymphoma, myeloma) within the past 5 years except adequately treated non-melanomatous skin cancer
• Prior diagnoses of carcinoma in situ allowed
• No severe or active co-morbidity with any of the following:
• Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
• Transmural myocardial infarction within the past 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy, within the past 30 days
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Laboratory tests for liver function and coagulation parameters not required for entry into this protocol
• AIDS based upon current Centers for Disease Control (CDC) definition
• HIV testing not required for entry into this protocol
• HIV-seropositive patients who do not meet criteria for diagnosis of AIDS allowed PRIOR CONCURRENT THERAPY:
• See Disease Characteristics
• No prior radical surgery (prostatectomy), high-intensity focused ultrasound, or cryosurgery for prostate cancer
• No prior hormonal therapy, such as LHRH agonists (e.g., goserelin, leuprolide), antiandrogens (e.g., flutamide, bicalutamide), estrogens (e.g., DES), or bilateral orchiectomy
• No finasteride within past 30 days (90 days for dutasteride)
• No prior or concurrent cytotoxic chemotherapy for prostate cancer
• Prior chemotherapy for a different cancer allowed
• No prior radiotherapy (RT), including brachytherapy, to the region of the study cancer that would result in overlap of RT fields
• Patients undergoing brachytherapy must have transrectal ultrasound confirmation of prostate volume < 60 cc, American Urological Association (AUA) score ≤ 15 within the past 60 days of registration, and no history of prior transurethral resection of the prostate (TURP)
• TURP allowed for patients who receive external-beam radiation therapy only

• Subject is considered an adult according to local regulation at the time of signing informed consent.
• Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell histology.
• Subject has metastatic prostate cancer documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan. Subjects whose disease spread is limited to regional pelvic lymph nodes are not eligible.
• Once randomized at day 1, subject must maintain ADT with an LHRH agonist or antagonist during study treatment or have a history of bilateral orchiectomy (i.e., medical or surgical castration).
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Subject has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer (the following exceptions are permitted):
• Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
• Subject may have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to day 1;
• Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of day 1 and no evidence of disease progression during or after the completion of docetaxel therapy;
• Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1 if subject was treated with docetaxel, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
• Prior ADT given for < 39 months in duration and > 9 months before randomization as neoadjuvant/adjuvant therapy.
• Subject had a major surgery within 4 weeks prior to day 1.
• Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks prior to day 1.
• Subject received treatment with estrogens, cyprotoerone acetate or androgens within 4 weeks prior to day 1.
• Subject received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to day 1.
• Subject received treatment with herbal medications that have known hormonal antiprostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior to day 1.
• Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or enzalutamide for the treatment of prostate cancer or participation in a clinical study of an investigational agent that inhibits the AR or androgen synthesis (e.g., TAK-700, ARN-509, ODM-201).
• Subject has known or suspected brain metastasis or active leptomeningeal disease.
• Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or hemoglobin < 10 g/dL (6.2 mmol/L).
• Subject has total bilirubin (TBL) ≥ 1.5 x the upper limit of normal (ULN) (except subjects with documented Gilbert's disease), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 x the ULN .
• Subject has creatinine > 2 mg/dL (177 μmol/L).
• Subject has albumin < 3.0 g/dL (30 g/L).
• Subject has a history of seizure or any condition that may predispose to seizure.
• Subject has history of loss of consciousness or transient ischemic attack within 12 months prior to day 1.
• Subject has clinically significant cardiovascular disease.
• Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless administered at stable dose or to treat diagnosed osteoporosis

• Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPPA) authorization for the release of personal health information.
• Males aged 18 years of age and above
• Patients must have adenocarcinoma of the prostate gland
• Patients must have received primary treatment with radical prostatectomy.
• Patients must have evidence of biochemical (PSA) relapse after prostatectomy
• Patients must have PSA within study range
• Patients must have non-metastatic (M0) disease, as defined by a lack of metastases seen on CT scan of the chest/abdomen/pelvis and whole-body radionuclide 99Technetium (Tc) bone scan, (or sodium fluoride PET scan) taken within 3 months of study entry.
• Patients must have had node negative (pN0) disease found at the time of surgery.
• Patients must have non-castrate levels of serum testosterone levels within study range.
• Patients must not have previously received hormonal therapy (LHRH agonist, antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones given in conjunction with prostatectomy.
• Patients must have Eastern Cooperative Oncology Group (ECOG)performance status of 0-1, and life expectancy greater 3 years.
• Patients must have laboratory test results within the certain ranges
• Patients must be disease-free from prior malignancies for greater than 3 years, with the exception of non-melanoma skin cancers and superficial urothelial cancers.
• Patients must have the ability to swallow the study drug whole as a tablet or capsule.
• Throughout study, male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration or per local guidelines where these require additional description of contraceptive methods.
• Throughout the study, patients must use a condom if having sex with a pregnant woman.
• Currently active second malignancy
• Primary treatment with radiation therapy.
• Radiographic or clinical evidence of local-regional tumor recurrence,
• Concurrent use of other antiandrogens, estrogen-like agents, or 5a-reductase inhibitors.
• Use of systemic corticosteroids equivalent to prednisone (inhaled corticosteroids are permitted).
• Concurrent use of other anti-cancer agents or treatments.
• Serious concurrent medical illnesses (including uncontrolled major cardiac, pulmonary, Child-Pugh C liver or psychiatric diseases) or active major infections (including HIV, Hepatitis A-C).
• Clinically significant cardiovascular disease including:
• Myocardial infarction within 6 months of Screening visit.
• Uncontrolled angina within 3 months of Screening visit.
• Congestive heart failure (within certain ranges)
• History of clinically significant ventricular arrhythmias
• Prolonged corrected QT interval
• History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
• Hypotension within certain ranges
• Uncontrolled hypertension within certain ranges
• Medications which lowers seizure threshold.
• History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12months of enrollment (Day 1 visit).
• Patients taking medications that may have adverse interactions with enzalutamide

• Pathologically (histologically) proven diagnosis of prostate adenocarcinoma; prostatectomy must have been performed within 10 years prior to Step 1 registration and any type of radical prostatectomy is permitted, including retropubic, perineal, laparoscopic or robotically assisted
• Post-prostatectomy patients with a detectable serum PSA (≥ 0.1, but ≤ 1.0 ng/mL) at study entry (within 90 days of Step 1 registration) and at least one of the following:
• Gleason score 7-10 (International Society of Urological Pathology [ISUP] grade group 2 to 5)
• ISUP grade group:
• Grade Group 1: Gleason score ≤ 6,
• Grade Group 2: Gleason score 3 + 4 = 7,
• Grade Group 3: Gleason score 4 + 3 = 7,
• Grade Group 4: Gleason score 8,
• Grade Group 5: Gleason scores 9 and 10
• >= T3a disease
• Persistent elevation of PSA after prostatectomy measured within 90 days after surgery (PSA never became undetectable) of > 0.04 but < 0.2 ng/mL (PSA nadir)
• pN0 or pNx
• History/physical examination within 90 days prior to Step 1 registration
• Karnofsky performance status of 70-100 within 90 days prior to Step 1 registration
• Surgical formalin-fixed paraffin-embedded (FFPE) specimen must be available for submission to GenomeDx for genomic analysis on Decipher GRID platform; Note: if Decipher results have already been obtained, in lieu of tissue, results must be submitted to GenomeDx for validation
• Prior androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH] agonist and/or non-steroidal anti-androgen) is allowed if discontinued at least 90 days prior to Step 1 registration and given for ≤ 90 days duration
• For example: patients on prior LHRH analogs (post-prostatectomy), the discontinuation date should be calculated based on the expected duration of the sustained release injection, not simply the injection date of the drug; for instance, if a 22.5 mg sustained release dose of leuprolide acetate is given (3 month duration), then the expected duration of such a dose would be 90 days after the injection date; for a 7.5 mg leuprolide (1 month duration), the discontinuation date would be 30 days after the injection date
• Please note: finasteride or dutasteride must be stopped before treatment starts but prior usage will not affect eligibility
• Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 90 days prior to Step 1 registration
• Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors within 90 days prior to step 1 registration
• Serum albumin ≥ 3.0 g/dL within 90 days prior to Step 1 registration
• Glomerular filtration rate (GFR) ≥ 35 mL/min estimated by Cockcroft-Gault or measured directly by 24 hour urine creatinine within 90 days prior to Step 1 registration
• Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (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 is eligible) within 90 days prior to Step 1 registration
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x ULN within 90 days prior to Step 1 registration
• Testosterone > 50 ng/dL within 90 days prior to Step 1 registration
• Concomitant medications known to lower the seizure threshold discontinued or substituted at least 4 weeks (30 days) prior to Step 1 registration.
• The patient must agree 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 agree 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
• The patient must agree not to donate sperm during the study treatment and for 3 months after receiving the last dose of study drug
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Definitive clinical, radiologic, or pathologic evidence of metastatic disease (M1) or lymph node involvement (N1)
• Prior invasive malignancy (except non-melanomatous skin cancer, carcinoma in situ of the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely resected melanoma) unless disease free for a minimum of 2 years
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• History of any of the following:
• Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year prior to Step 1 registration)
• History of documented inflammatory bowel disease
• Transmural myocardial infarction within the last 4 months prior to Step 1 registration.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to Step 1 registration
• History of any condition that in the opinion of the investigator, would preclude participation in this study
• Current evidence of any of the following:
• Known gastrointestinal disorder affecting absorption of oral medications
• Active uncontrolled infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)
• Uncontrolled hypertension
• Any current condition that in the opinion of the investigator, would preclude participation in this study
• Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused ultrasound [HIFU]) for prostate cancer is not allowed
• HIV positive with CD4 count < 200 cells/microliter within 30 days prior to registration
• HIV patients under treatment with highly active antiretroviral therapy (HAART) within 30 days prior to registration regardless of CD4 count. (Note: HIV testing is not required for eligibility for this protocol as it is self-reported.)
• For patients who have not undergone prior Decipher analysis, submission of the specimen to GenomeDx should be as soon as possible after study registration (Step 1) as these results can take up 21 days after the specimen is received at GenomeDx; Step 2 registration must occur within 6 weeks (42 days) of Step 1 registration; if Decipher results have already been obtained, in lieu of tissue, results must be submitted to GenomeDx for validation

• All patients must be willing and capable to provide informed consent to participate in the protocol.
• Eligible patients must have appropriate staging studies identifying them as AJCC stage T1 (a, b, or c) or T2a or T2b adenocarcinoma of the prostate gland. The patient should not have direct evidence of regional or distant metastases after appropriate staging studies. Histologic confirmation of cancer will be required by biopsy performed within 180 days of registration.
• The patient's Zubrod performance status must be 0-2.
• The Gleason score should be less than or equal to 6 or 3+4 if < 50% of a 12 core biopsy was involved.
• The serum PSA should be less than or equal to 10 ng/ml.
• Study entry PSA must not be obtained during the following time frames: 10 day period following prostate biopsy; following initiation of ADT; within 30 days after discontinuation of finasteride; or within 90 days after discontinuation of dutasteride.
• Age ≥ 18 years.
• Patients may have used prior hormonal therapy, but it should be limited to no more than 9 months of therapy prior to enrollment.
• The ultrasound, or CT based volume estimation of the patient's prostate gland should be ≤ 60 grams.
• Subjects who have had previous pelvic radiotherapy or have had chemotherapy or surgery for prostate cancer.
• Subjects who have plans to receive other concomitant or post treatment adjuvant antineoplastic therapy while on this protocol including surgery, cryotherapy, conventionally fractionated radiotherapy, hormonal therapy, or chemotherapy given as part of the treatment of prostate cancer.
• Subjects who have undergone previous transurethral resection of the prostate (TURP) or cryotherapy to the prostate. Subjects who have significant urinary obstructive symptoms; AUA score must be ≤15 (alpha blockers allowed).
• Subjects who have a history of significant psychiatric illness.
• Men of reproductive potential who do not agree that they or their partner will use an effective contraceptive method such as condom/diaphragm and spermacidal foam, intrauterine device (IUD), or prescription birth control pills.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (e.g., carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• Severe, active co-morbidity, defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months.
• Transmural myocardial infarction within the last 6 months.
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration.
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.
• Patients with history of inflammatory colitis (including Crohn's Disease and Ulcerative colitis) are not eligible.
• Subjects with a known allergy to polyethylene glycol hydrogel (spacer material) or contraindication to spacer products (Duraseal or SpaceOAR).
• Subjects with evidence of extraprostatic extension (T3a) or seminal vesicle involvement (T3b) on clinical evaluation.

• Patient must have at least one and up to three asymptomatic metastatic tumor(s) of the bone or soft tissue (with at least one bone metastasis) develop within the past 6-months that are ≤ 5.0 cm or <250 cm3
• Patient must have had their primary tumor treated with surgery and/or radiation.
• Histologic confirmation of malignancy (primary or metastatic tumor).
• PSADT <15 months. PSA doubling time (PSADT) will be calculated using as many PSA values that are available from time of relapse (PSA > 0.2). To calculate PSADT, the Memorial Sloan Kettering Cancer Center Prostate Cancer Prediction Tool will be used. It can be found at the following web site: https://www.mskcc.org/nomograms/prostate/psa-doubling-time.
• Patient may have had prior systemic therapy and/or ADT associated with treatment of their primary prostate cancer. Patient may have had ADT associated with salvage radiation therapy (to the primary prostate cancer or pelvis is allowed).
• PSA > 0.5 but <50.
• Testosterone > 125 ng/dL.
• Patient must be ≥ 18 years of age.
• Patient must have a life expectancy ≥ 12 months.
• Patient must have an ECOG performance status ≤ 2.
• Patient must have normal organ and marrow function as defined as: Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. * Patient must have the ability to understand and the willingness to sign a written informed consent document.
• No more than 3 years of ADT is allowed, with the most recent ADT treatment having occurred greater than 6 months prior to enrollment.
• PSMA-PET/MRI or PSMA-PET/CT scan within the past 6 months with results that demonstrate more disease lesions than baseline CT/Bone Scan
• Castration-resistant prostate cancer (CRPC).
• Spinal cord compression or impending spinal cord compression.
• Suspected pulmonary and/or liver metastases (greater >10 mm in largest axis).
• Patient receiving any other investigational agents.
• Patient receiving abiraterone and prednisone.
• Patient is participating in a concurrent treatment protocol.
• Serum creatinine > 3 times the upper limit of normal.
• Total bilirubin > 3 times the upper limit of normal.
• Liver Transaminases > 5-times the upper limit of normal.
• Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT.
• Prior salvage treatment to the primary prostate cancer or pelvis is allowed.
• Refusal to sign informed consent.

• Signed study specific informed consent form.
• Patients must have at least one of the following criteria:
• The serum PSA should be greater than or equal to 20 ng/ml OR
• Study entry PSA must not be obtained during the following time frames: 1. 10-day period following prostate biopsy; 2. following initiation of ADT.
• The Gleason score should be greater than or equal to 8 OR
• Eligible patients must have appropriate staging studies identifying them as AJCC stage T3+ adenocarcinoma of the prostate gland. (MR stage T3a without other high risk factors permitted at investigator discretion
• Male Patient past their 18th birthday at time of registration.
• The patient's Zubrod performance status must be 0-2
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and during radiation treatment.
• All patients must be willing and capable to provide informed consent to participate in the protocol
• Imaging studies can include, but is not limited to the following: ultrasound, CT of pelvis/prostate (abdomen recommended) and MRI of pelvis/prostate and (abdomen recommended)
• The ultrasound, MRI or CT based volume estimation of the patient's prostate gland should not be greater than 80 grams (Repeat measurement after hormone downsizing allowed)
• Clinically negative lymph nodes, within 90 days of study enrollment, established by imaging (pelvic/prostate (abdominal recommended) CT or MRI) OR by nodal sampling OR by dissection. Nodes > 2.0 cm should be biopsied. Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are < 2.0cm in the short axis.
• MRI Pelvis/Prostate feasible for staging and planning
• Patients with contraindications to MRI are not eligible
• Patient deemed eligible for complete androgen blockade, and androgen deprivation therapy by treating physician (this includes consideration of baseline liver function prior to initiation of therapy, if necessary at physician's discretion). For patients not eligible for anti-testosterone therapy, hormone therapy with LHRH agonist alone will be permitted on case by case by study Principal Investigator. AS can be any LHRH agonists, LHRG antagonists or anti-androgens that are approved for androgen suppression for the treatment of prostate cancer.
• Patient does not have known allergy to polyethylene glycol hydrogel (spacer material).
• Patient deemed eligible for rectal spacer ( Space OAR) placement by treating physician.
• Histologic confirmation of diagnosis of adenocarcinoma of the prostate will be required by biopsy.
• Eligible patients should not have had previous pelvic radiotherapy, chemotherapy or surgery for prostate cancer.
• There must be no plans for the patient to receive other concomitant or post treatment adjuvant antineoplastic therapy while on this protocol including surgery, cryotherapy, conventionally fractionated radiotherapy, 2nd generation anti-androgen therapy (i.e Enzalutamide, Abiraterone, etc.),or chemotherapy given as part of the treatment of prostate cancer.
• The patient should not have direct evidence of regional or distant metastases after appropriate staging studies, including no distant metastases (M0) on bone scan within 90 days of study enrollment. Equivocal bone scan findings are allowed if plain films are negative for metastasis. PET or PSMA scans can be performed instead of a bone scan.
• Patients diagnosed with invasive malignancy are not eligible (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (e.g., oral cavity).
• Patients diagnosed with severe, active co-morbidity, defined as follows are not eligible:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months.
• Transmural myocardial infarction within the last 6 months.
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration.
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.
• Patients with history of inflammatory colitis (including Crohn's Disease and Ulcerative colitis), active lupus, and scleroderma or active collagen vascular disease are not eligible.
• Patients should not have undergone previous transurethral resection of the prostate (TURP) within 1 year.
• Patients with history of inflammatory colitis (including Crohn's Disease and Ulcerative colitis) are not eligible.
• Eligible patients should not have had previous pelvic radiotherapy, chemotherapy or surgery for prostate cancer.
• There must be no plans for the patient to receive other concomitant or post treatment adjuvant antineoplastic therapy while on this protocol including surgery, cryotherapy, conventionally fractionated radiotherapy, 2nd generation anti-androgen therapy (i.e Enzalutamide, Abiraterone, etc.),or chemotherapy given as part of the treatment of prostate cancer.
• The patient should not have direct evidence of regional or distant metastases after appropriate staging studies, including no distant metastases (M0) on bone scan within 90 days of study enrollment. Equivocal bone scan findings are allowed if plain films are negative for metastasis. PET or PSMA scans can be performed instead of a bone scan.
• Patients diagnosed with invasive malignancy are not eligible (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (e.g., oral cavity).
• Patients diagnosed with severe, active co-morbidity, defined as follows are not eligible:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months.
• Transmural myocardial infarction within the last 6 months.
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration.
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients.
• Patients with history of inflammatory colitis (including Crohn's Disease and Ulcerative colitis), active lupus, and scleroderma or active collagen vascular disease are not eligible.
• Patients should not have undergone previous transurethral resection of the prostate (TURP) within 1 year.
• Patients with history of inflammatory colitis (including Crohn's Disease and Ulcerative colitis) are not eligible.
• Patients should not have a history of significant psychiatric illness.
• Patients may have used prior hormonal therapy, but it should be limited to no more than 9 months of therapy prior to enrollment.

1. Patients must have the ability to understand and sign an approved ICF. 2. Patients must have the ability to understand and comply with all protocol requirements. 3. Patients must be ≥18 years of age. 4. Patients must have an ECOG performance status of 0 to 2. 5. Patients must have a life expectancy >6 months. 6. Patients must have histological, pathological, and/or cytological confirmation of prostate cancer. 7. Patients must be 68Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor's central reader. 8. Patients must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L). 9. Patients must have received at least one NAAD (such as enzalutamide and/or abiraterone). 10. Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, the patient is eligible if: a. The patient's physician deems him unsuitable to receive a second taxane regimen (e.g. frailty assessed by geriatric or health status evaluation, intolerance, etc.). 11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria: 1. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL. 2. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. 3. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria, Scher et al 2016). 12. Patients must have ≥1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained ≤28 days prior to beginning study therapy. 13. Patients must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy, etc.). 14. Patients must have adequate organ function: a. Bone marrow reserve:
• White blood cell (WBC) count ≥2.5 x 10^9/L (2.5 x 10^9/L is equivalent to 2.5 x 10^3/μL and 2.5 x K/μL and 2.5 x 10^3/cumm and 2500/μL) OR absolute neutrophil count (ANC) ≥1.5 x 10^9/L (1.5 x 10^9/L is equivalent to 1.5 x 10^3/μL and 1.5 x K/μL and 1.5 x 10^3/cumm and 1500/μL)
• Platelets ≥100 x 10^9/L (100 x 10^9/L is equivalent to 100 x 10^3/μL and 100 x K/μL and 100 x 10^3/cumm and 100,000/μL)
• Hemoglobin ≥9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L) b. Hepatic:
• Total bilirubin ≤1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome ≤3 x ULN is permitted
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases c. Renal:
• Serum/plasma creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min 15. Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L) [Inclusion #16 has been removed] 17. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are included in this trial. 18. For patients who have partners of childbearing potential: Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principle investigator during the study and for 6 months after last study drug administration. 19. The best standard of care/ best supportive care options planned for this patient: 1. Are allowed by the protocol 2. Have been agreed to by the treating investigator and patient 3. Allow for the management of the patient without 177Lu-PSMA-617 1. Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed. 2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 28 days prior to day of randomization. 3. Any investigational agents within 28 days prior to day of randomization. 4. Known hypersensitivity to the components of the study therapy or its analogs. 5. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. 6. Transfusion for the sole purpose of making a subject eligible for study inclusion. 7. Patients with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast). 8. A superscan as seen in the baseline bone scan. 9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression. 10. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. 11. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, superficial bladder cancer.

DISEASE CHARACTERISTICS:
• Histologically confirmed adenocarcinoma of the prostate
• Stage T1a, T1b, T1c disease
• Stage T2a or T2b
• No direct evidence of regional or distant metastases
• No T2c, T3, or T4 tumors
• Gleason score ≤ 7
• Must meet the following criteria:
• Prostate-specific antigen (PSA) ≤ 20 ng/mL prior to starting hormonal therapy (if given) for patients with a Gleason score of 2-6
• PSA ≤ 15 ng/mL prior to starting hormonal therapy (if given) for patients with a Gleason score of 7
• Risk of pelvic lymph node involvement < 20% according to Roach formula
• Ultrasound-based volume estimation of the prostate gland ≤ 60 g PATIENT CHARACTERISTICS:
• Zubrod performance status 0-2
• Fertile patients must use effective contraception
• No prior invasive malignancy, except for nonmelanoma skin cancer, unless disease-free for a minimum of 3 years (e.g., carcinoma in situ of the breast, oral cavity, or cervix are allowed)
• No significant urinary obstructive symptoms
• American Urological Association (AUA) score of ≤ 15 (alpha blockers allowed)
• No history of inflammatory colitis (including Crohn disease and ulcerative colitis)
• No history of significant psychiatric illness
• No severe, active comorbidity including any of the following:
• Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
• Transmural myocardial infarction within the past 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
• AIDS (based on current CDC definition) or other immunocompromising condition
• HIV testing is not required for entry into this protocol PRIOR CONCURRENT THERAPY:
• See Disease Characteristics
• More than 9 months since prior hormonal therapy as neoadjuvant therapy or to downsize the prostate gland
• No prior pelvic radiotherapy
• No prior chemotherapy or surgery for prostate cancer
• No prior transurethral resection of the prostate (TURP) or cryotherapy to the prostate
• No plans for other concurrent post-treatment, adjuvant, antineoplastic therapy including surgery, cryotherapy, conventionally fractionated radiotherapy, hormonal therapy, or chemotherapy as part of the treatment for prostate cancer

• Biopsy-confirmed diagnosis of primary or recurrent respective tumor type and scheduled to undergo surgical resection
• Part 1: Biopsy-confirmed diagnosis of head and neck squamous cell carcinoma (HNSCC) or breast cancer
• Part 2: Biopsy-confirmed diagnosis of HNSCC, breast cancer, colorectal cancer, prostate cancer, ovarian cancer, urothelial carcinoma and non-small cell lung cancer.
• Part 3: Stage 2 to 4 HNSCC Including T0 or Tx unknown Primary cancers
• Histologically diagnosed by an excisional biopsy procedure
• Tumors at sites of which the surgeon would assess that in vivo intraoperative imaging would not be feasible
• Life expectancy <12 weeks
• Hepatic impairment (Child-Pugh score >5) or significant liver disease including active hepatitis or cirrhosis

• Documented histologic or cytologic diagnosis of renal cell cancer (RCC). All subtypes of RCC are eligible including but not limited to clear cell, papillary, chromophobe, translocation, collecting duct carcinoma, medullary carcinoma, and unclassified categories. Enrollment of non-clear cell patients will be limited to 20% of the total sample size (~ 42 patients). Once this goal is met, accrual of non-clear cell patients will be discontinued (a notice will be sent out 2 weeks in advance). Sarcomatoid and rhabdoid differentiation are allowed
• Presence of at least 2 metastatic bone lesions not treated with prior radiation is required
• The presence of bone metastases can be detected by computed tomography (CT), magnetic resonance imaging (MRI), Tc-99m bone scan or positron emission tomography (PET) (fludeoxyglucose F-18 [FDG] or sodium fluoride [NaF]) imaging. Patients with non-measurable bone-only disease are allowed. Patients may have received prior radiation therapy for bone metastases or other external radiation >= 14 days prior to registration, as long as they still have at least 2 metastatic bone lesions that were not treated with radiation. Patients with visceral metastases are allowed, as long as they have at least two untreated bone metastases
• No more than 2 prior lines of systemic therapy including but not limited to anti-angiogenic therapy, checkpoint inhibitors, mammalian target of rapamycin (mTOR) inhibitors, clinical trial compounds or cytokine-based therapy. Prior radiation therapy does not count as a prior systemic therapy
• No prior treatment with cabozantinb
• No treatment with any type of small molecular kinase inhibitor (including investigational kinase inhibitors) within 2 weeks or 5 half-lives (whichever is shorter) of registration or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of registration
• No prior hemibody external radiotherapy
• No prior therapy with radium-223 dichloride or systemic radiotherapy (such as samarium, strontium)
• No major surgery within 6 weeks of randomization. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Moh's or other topical skin surgery, Lasik eye surgery are not considered major surgery. Patients who have had a nephrectomy may be registered >= 3 weeks after surgery, providing there are no wound-healing complications. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
• Recovery to baseline or =< grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy
• The use of osteoclast targeted therapy including either bisphosphonates or denosumab is mandated on this study except in patients with contraindications as determined by the treating investigator, including:
• Hypocalcemia
• Hypophosphatemia
• Renal impairment including those with a glomerular filtration rate (GFR) < 35 mL/min using the Cockcroft-Gault equation or acute renal impairment
• Hypersensitivity to drug formulation
• Dental condition or need for dental intervention that per the investigator would increase the risk of osteonecrosis of jaw (ONJ).
• Use of osteoclast targeted therapy or reason against use needs to be recorded in the electronic case report form (eCRF). Additionally, reason for discontinuation of osteoclast targeted therapy need to be appropriately documented in the eCRF
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown.
• Therefore, for women of childbearing potential only, a negative urine pregnancy test done =< 28 days prior to registration is required. A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Karnofsky performance status >= 60%
• Symptomatic bone pain defined as either regular use of analgesic medication for cancer related bone pain (>= level 1; World Health Organization [WHO] ladder for cancer pain) or prior SSE defined as bone pain requiring radiation, bone pain secondary to a pathologic fracture related to a bone metastasis, symptomatic spinal cord compression related to a bone metastasis, surgery to bone secondary to symptomatic bone metastasis or radiographic progression of bone metastases as defined by the presence of bone metastases on radiographic imaging
• No brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
• No imminent or established spinal cord compression based on clinical symptoms and/or imaging. In patients with untreated imminent or established spinal cord compression, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration
• No imminent or impending pathologic fracture based on clinical symptoms and/or imaging. In patients with untreated imminent or impending pathologic fracture, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration
• No significant, uncontrolled intercurrent or recent illness, including but not limited to the following conditions:
• Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia; uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment; stroke (including transient ischemic attack), myocardial infarction, or other ischemic event, within 6 months before randomization; thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization; screening Fridericia's correction formula (QTcF) =< 500 msec
• Gastrointestinal disorders: Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 3 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization
• No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization
• No lesions invading major pulmonary blood vessels
• No other clinically significant disorders:
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]) with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]), 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 (with no medications prohibited by this protocol [e.g. drug-drug interactions])
• No serious non-healing wound or ulcer
• No malabsorption syndrome
• No uncompensated/symptomatic hypothyroidism
• No moderate to severe hepatic impairment (Child-Pugh B or C)
• No requirements for hemodialysis or peritoneal dialysis
• No history of solid organ transplantation
• No chronic concomitant treatment with strong CYP3A4 inducers or inhibitors. Because the list of these agents is constantly changing, it is important to regularly consult a frequently updated medical reference. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration
• No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants include:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 10 g/dl (transfusions allowed)
• Calculated (calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation
• Total bilirubin =< 1.5 x upper limit of normal (ULN), for patients with Gilberts disease =< 3.0 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN
• Urine protein to creatinine (UPC) ratio =< 1 mg/mg OR 24-hr urine protein < 1g

All Parts
• Subject has provided informed consent prior to initiation of any study-specific activities/procedures
• Subjects with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed at least 1 (but not more than 2) taxane regimens (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen). Progression on novel antiandrogen therapy may have occurred in the non-metastatic CRPC setting
• Subject should have undergone bilateral orchiectomy or should be on continuous androgen-deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist or antagonist
• Total serum testosterone • Evidence of progressive disease, defined as 1 or more PCWG3 criteria: PSA level >/=1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart, nodal or visceral progression as defined by RECIST 1.1 with PCGW3 modifications, and/or appearance of 2 or more new lesions in bone scan
• Eastern Cooperative Oncology Group (ECOG) performance status of 0
•1
• Life expectancy >/=6 months
• Any anticancer therapy or immunotherapy within 4 weeks of start of first dose, not including luteinizing hormone-releasing hormone agonist (LHRH)/GnRH analogue (agonist/antagonist). Subjects on a stable bisophosphonate or denosumab regimen for >/= 30 days prior to randomization are eligible
• Prior PSMA-targeted therapy (subjects on prior therapy may be eligible if discussed with Amgen medical monitor prior to enrollment)
• Central nervous system (CNS) metastases, leptomeningeal disease, or spinal cord compression
• Active autoimmune disease or any other diseases requiring immunosuppressive therapy while on study
• Needing chronic systemic corticosteroid therapy (prednisone > 10 mg per day or equivalent) or any other immunosuppressive therapies (including anti-tumor necrosis factor alpha [TNF alpha] therapies) unless stopped 7 days prior to start of first dose
• Myocardial infarction, unstable angina, cardiac arrhythmia requiring medication, and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of AMG 160 Part 2 only:
• Subjects on a prior PD-1 or PD-L1 inhibitor who experienced a Grade 3 or higher immune-related adverse event prior to first day of dosing
• History or evidence of interstitial lung disease or active, non-infectious pneumonitis Part 3 only: -Evidence of active tuberculosis on chest radiograph within 3 months prior to the first dose of investigational product Part 6 only: Subjects are excluded from this cohort if any of the following additional criteria apply:
• Subjects taking strong OAT3 inhibitors (eg, probenecid) or adjust the dosing to 1 mg PO QD.
• Subjects with latent or active tuberculosis at screening

• Non-obese (body mass index less than 30 kg/m2) *alternatively, individuals will be permitted to participate if they have a body mass index value below 35 kg/m2 but a waist circumference below 88 cm for females and 102 cm for males
• Systolic blood pressure <140 mmHg
• Diastolic blood pressure <90 mmHg
• Participants who have cardiac, respiratory, neurological, and/or metabolic illnesses
• Current or previous use of anti-hypertensive medications
• Any known history of renal or hepatic insufficiency/disease
• Pregnancy or breast feeding
• Current smokers, as well as individuals who regularly smoked within the past 3 years
• Individuals with a history of drug abuse
• Individuals who have an unexplained positive urine drug screen (e.g., some agents cause false-positive results, but when the agent is abstained for hours/days/weeks, the repeated drug screen is negative. One example could be an over-the-counter supplement)

• Healthy
• Non-obese (body mass index less than 30 kg/m2)
• Body mass greater than or equal to 65 kg
• Subjects who have cardiac, respiratory, neurological and/or metabolic illnesses
• Any known history of renal or hepatic insufficiency/disease
• Pregnancy or breast feeding
• Current smokers, as well as individuals who regularly smoked within the past 3 years
• Positive urine drug screen
• Currently taking pain modifying medication(s)