• ELIGIBILITY CRITERIA FOR SCREENING BIOPSY (STEP 0)
• Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration; patients that are pregnant or breast feeding are excluded; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of study; should a woman become pregnant or suspect while she or her partner is participating in this study, she should inform her treating physician immediately
• Patients must have histologically documented solid tumors or histologically confirmed diagnosis of lymphoma or multiple myeloma requiring therapy and meet one of the following criteria:
• Patients must have progressed following at least one line of standard systemic therapy and there must not be other approval/standard therapy available that has been shown to prolong overall survival (i.e. in a randomized trial against another standard treatment or by comparison to historical controls); patients who cannot receive other standard therapy that has been shown to prolong overall survival due to medical issues will be eligible, if other eligibility criteria are met; if the patient is currently receiving therapy, the clinician must have assessed that the current therapy is no longer benefitting the patient prior to enrolling on MATCH, regardless of whether it is considered standard OR
• Patients for whose disease no standard treatment exists that has been shown to prolong overall survival
• NOTE: No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer; in situ cervical cancer; adequately treated stage I or II cancer from which the patient is currently in complete remission; any other cancer from which the patient has been disease-free for 5 years
• Patients must have measurable disease
• Patients must meet the criteria below and have received results from one of the designated outside laboratories indicating a "rare variant" that is an actionable Mutation of Interest (aMOI) for specific select subprotocols.
• The following requirements apply:
• The outside laboratory specifically notified the site that patient may be a potential candidate for MATCH due to a detected "rare variant"; the outside lab reports are NOT sufficient for this purpose
• NOTE: The content and format of these specific notifications for the Outside Assay process will vary depending on the designated outside lab in question, as they are each responsible for their own outreach efforts; it is strongly recommended that the designated outside laboratory be contacted to confirm the format and receipt of this notification prior to registering any patients to Step 0
• Patients with an applicable "rare variant" must be able to meet the eligibility criteria for the appropriate subprotocols within 4 weeks following notification of treatment assignment
• NOTE: The receipt of this notification (and the start of the associated deadline for Step 1 registration) may occur shortly after Step 0 registration, since these patients will not be submitting tissue for screening purposes; however, for certain "rare variant" arms, submission of archival tissue for central immunohistochemistry (IHC) testing may be required
• Registration to Step 0 must occur after stopping prior systemic anti-cancer therapy; there is no specific duration for which patients must be off treatment prior to registration to Step 0, as long as all eligibility criteria are met
• There is no particular window of time after notification of potential eligibility from an outside lab in which the patient must be registered to Step 0, but treatment slots will be assigned on a first come, first serve basis to those who do register to Step 0, and are not held for those notified of potential eligibility who do not register to Step 0
• Patients may have received other non-targeted, immunotherapy or targeted treatment between the prior genetic testing at the outside lab and registration to Step 0; the decision to stop such treatment in favor of participation in MATCH, if no further clinical benefit is expected, is per the treating physician's discretion; documentation of a lack of response to the prior treatment is not required in these cases
• NOTE: Other potential aMOIs that would be eligibility criteria for "NON RARE" arms, as determined by the designated laboratories, are not applicable for this process in MATCH
• NOTE: Tumor tissue for the confirmation of "rare variant" by the MATCH assay is to be submitted, preferably from the same time of collection as that evaluated by the designated outside laboratory
• Patient must not require the use of full dose coumarin-derivative anticoagulants such as warfarin; low molecular weight heparin is permitted for prophylactic or therapeutic use; factor X inhibitors are permitted
• NOTE: Warfarin may not be started while enrolled in the EAY131 study
• Stopping the anticoagulation for biopsy should be per site standard operating procedure (SOP)
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 and a life expectancy of at least 3 months
• Patients must not currently be receiving any other investigational agents
• Patients must not have any uncontrolled intercurrent illness including, but not limited to:
• Symptomatic congestive heart failure (New York Heart Association [NYHA] classification of III/IV)
• Unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration to Step 0, 2, 4, 6
• Cardiac arrhythmia (ongoing cardiac dysrhythmias of National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4 grade >= 2)
• Psychiatric illness/social situations that would limit compliance with study requirements
• Intra-cardiac defibrillators
• Known cardiac metastases
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (ECHO) (as clinically indicated); (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
• NOTE: To receive an agent, patient must not have any uncontrolled intercurrent illness such as ongoing or active infection; patients with infections unlikely to be resolved within 2 weeks following screening should not be considered for the trial
• Patients must be able to swallow tablets or capsules; a patient with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
• Patients who are human immunodeficiency virus (HIV)-positive are eligible if:
• CD4+ cell count greater or equal to 250 cells/mm^3
• If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; for experimental cancer therapeutics with CYP3A/4 interactions, protease inhibitor therapy is disallowed; suggested regimens to replace protease inhibitor therapy include dolutegravir given with tenofovir/emtricitabine; raltegravir given with tenofovir and emtricitabine; once daily combinations that use pharmacologic boosters may not be used
• No history of non-malignancy acquired immune deficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
• Probable long-term survival with HIV if cancer were not present
• Any prior therapy, radiotherapy (except palliative radiation therapy of 30 gray [Gy] or less), or major surgery must have been completed >= 4 weeks prior to start of treatment; all adverse events due to prior therapy have resolved to a grade 1 or better (except alopecia and lymphopenia) by start of treatment; palliative radiation therapy must have been completed at least 2 weeks prior to start of treatment; the radiotherapy must not be to a lesion that is included as measurable disease
• NOTE: Prostate cancer patients may continue their luteinizing hormone-releasing hormone (LHRH) agonist
• NOTE: For patients entering the study via the original screening process, patients may receive non-protocol treatment after biopsy (if clinically indicated) until they receive notification of results; however, lack of response must be documented prior to registration to Step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; the only intervening treatment permitted is prior therapy that the patient already received prior to Step 0 registration; the decision to stop the intervening non-protocol treatment will be left up to the treating physician if patient has an aMOI; however, patients will need to be off such therapy for at least 4 weeks before receiving any MATCH protocol treatment
• NOTE: For patients entering the study via a designated outside laboratory, no intervening systemic non-protocol treatment is permitted after Step 0 registration; all other eligibility requirements still apply to these patients, including the washouts for prior therapy noted above in this section, the time restrictions outlined, and the eligibility criteria for the intended subprotocol
• Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 4 weeks prior to start of treatment
• Patients must have discontinued steroids >= 1 week prior to registration to Step 0 and remain off steroids thereafter, except as permitted (see below); patients with glioblastoma (GBM) must have been on stable dose of steroids, or be off steroids, for one week prior to registration to treatment (Step 1, 3, 5, 7)
• NOTE: The following steroids are permitted (low dose steroid use is defined as prednisone 10 mg daily or less, or bioequivalent dose of other corticosteroid):
• Temporary steroid use: e.g. for computed tomography (CT) imaging in setting of contrast allergy
• Low dose steroid use for appetite
• Chronic inhaled steroid use
• Steroid injections for joint disease
• Stable dose of replacement steroid for adrenal insufficiency or low doses for non-malignant disease
• Topical steroid
• Steroids required to manage toxicity related to study treatment, as described in the subprotocols
• Steroids required as pre- or post-chemotherapy medication for acceptable intervening chemotherapy
• NOTE: Steroids must be completed alongside last dose of chemotherapy
• Leukocytes >= 3,000/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Absolute neutrophil count >= 1,500/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Platelets >= 100,000/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• NOTE: Patients with documented bone marrow involvement by lymphoma are not required to meet the above hematologic parameters, but must have a platelet count of at least 75,000/mcL and neutrophil count of at least 1,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin =< 3 x institutional ULN is permitted) (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (up to 5 times ULN in presence of liver metastases) (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• As defined by the Cockcroft-Gault equation (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Patients must have an electrocardiogram (ECG) within 8 weeks prior to registration to screening step and must meet the following cardiac criteria:
• Resting corrected QT interval (QTc) =< 480 msec
• NOTE: If the first recorded QTc exceeds 480 msec, two additional, consecutive ECGs are required and must result in a mean resting QTc =< 480 msec; it is recommended that there are 10-minute (+/- 5 minutes) breaks between the ECGs
• The following only need to be assessed if the mean QTc > 480 msec
• Check potassium and magnesium serum levels
• Correct any identified hypokalemia and/or hypomagnesemia and may repeat ECG to confirm exclusion of patient due to QTc
• For patients with heart rate (HR) 60-100 beats per minute (bpm), no manual read of QTc is required
• For patients with baseline HR < 60 or > 100 bpm, manual read of QT by trained personnel is required, with Fridericia correction applied to determine QTc
• Patient must not have hypokalemia (value < institutional lower limit of normal)
• No factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
• NOTE: Patient must be taken off prohibited medication prior to registration to the screening step (Step 0, 2, 4, 6) and remain off these medications thereafter, unless permitted on a subprotocol for the management of treatment related toxicity; patient must be off the drug for at least 5 half-lives prior to registration to the treatment step (Step 1, 3, 5, 7); the medication half-life can be found in the package insert for Food and Drug Administration (FDA) approved drugs
• ELIGIBILITY CRITERIA FOR FIRST TREATMENT (STEP 1)
• If patients have been biopsied or submitted archived tumor tissue obtained within the last 6 months for assessment with the MATCH assays, patients may receive non-protocol treatment after biopsy/tissue submission (if clinically indicated) until they receive notification of results however, lack of response must be documented prior to registration to step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; for pat

• Age between 45-99 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 will be excluded

• radical prostatectomy for adenocarcinoma of prostate
• pathologically confirmed T1-T3 disease
• no sign of lymph node or metastatic disease
• Eastern Cooperative Oncology Group(ECOG) status 0-2
• adequate renal and liver function
• no plan to receive adjuvant hormone or radiation therapy
• 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
• hormone therapy before surgery
• history of gallbladder problems or gallstones, or biliary obstruction
• radiation therapy as primary treatment after surgery
• antiplatelet or anticoagulant agents
• history of gastric or duodenal ulcers or hyperacidity syndromes

• Appropriate staging studies identifying patient as American Joint Committee on Cancer (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.
• The patient's Zubrod performance status must be 0-2 (see Appendix II for definition).
• 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 Prostate imaging
•reporting and data system (PIRADS) v2 4-5).
• Baseline AUA symptom score ≤19 (see Appendix IV for questionnaire) without need for maximum medical therapy (specifically, not on tamsulosin 0.8mg daily)
• EPIC sexual domain composite score 60-100 (see Appendix V)
• Multi-parametric MRI evaluation of the prostate is required for this study within 90 days 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.
• 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.
• 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.
• All patients must be willing and capable to provide informed consent to participate in the protocol within the 30 days prior to registration
• 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.
• 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.
• 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.
• Inability to undergo multi-parametric MRI.
• Evidence of metastatic disease. Note bone scan is not required for this study given the low-intermediate NCCN risk cohort to be enrolled.
• Evidence of clinical nodal involvement of the pelvis. Biopsy is required for lymph nodes over ≥1.5cm in short-axis measured size.
• No current 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 full testosterone recovery (>280ng/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).
• Testosterone ≤ 280 ng/dL (any one measurement >280 ng/dL suffices for inclusion)
• 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 ablative procedures to the prostate for benign prostatic hyperplasia or other conditions (i.e. cryotherapy, HIFU).
• 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).
• Subjects who have a history of significant psychiatric illness that would confound informed consent.
• Severe, active co-morbidity, defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at time of registration
• Patients with active inflammatory colitis (including Crohn's Disease and ulcerative colitis) currently requiring systemic steroids and/or systemic immunosuppression are not eligible.
• Subjects with a known allergy to polyethylene glycol hydrogel (rectal spacer material) or contraindication to spacer products (Duraseal or SpaceOAR)
• Subjects with uncontrolled coagulation disorder which cannot be controlled with anticoagulants
• Men of reproductive potential who do not agree that they or their partner will use an effective contraceptive method such as condom/diaphragm and spermicidal foam, intrauterine device (IUD), or prescription birth control pills.
• 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.
• Men who have clinically significant penile malformation (i.e. Peyronie's disease) or history of penile implantation are excluded.
• 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 on this basis.

• 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 (≥ 0.7 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 ≥ 0.7 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 109/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.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 4 months prior to registration
• Seizure disorder or condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma)
• 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.
• 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.

• 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

• Signed study specific informed consent form.
• PSA ≥20
• OR Gleason score ≥ 8
• OR Appropriate staging studies identifying as AJCC stage cT3+
• (MR stage T3a without other high risk factors permitted at investigator discretion).
• No direct evidence of regional or distant metastases after appropriate staging studies as indicated clinically.
• Clinically negative lymph nodes as established by imaging (abdominal and pelvic CT or abdominal and 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 in the short axis.
• No distant metastases (M0) on bone scan within 90 days prior to registration.
• Histologic confirmation of cancer by biopsy
• Adenocarcinoma of the prostate
• Age ≥18
• Zubrod Performance Status 0-2
• AUA score must be ≤20 (alpha blockers allowed)
• CT or Ultrasound-based volume estimation of prostate gland ≤80 grams (repeat ultrasound measurement after hormone downsizing allowed)
• Agreement to use effective contraceptive methods such as condom/diaphragm and spermicidal foam, intrauterine device, or prescription birth control pills.
• Equivocal bone scan findings are allowed if plain films are negative for metastasis.
• Deemed eligible for Complete Androgen Blockade (CAB) hormone therapy by treating physician, including baseline liver function evaluation. For patients not eligible for anti-testosterone therapy, hormone therapy with LHRH agonist alone will be permitted on case by case basis by study P.I.
• Use of previous hormonal therapy for up to 9 months is allowed for the treatment of prostate cancer as well as for prostate volume reduction.
• MRI Pelvis/Prostate feasible for staging and planning
• Clinically eligible for rectal spacer insertion (e.g. Duraseal, SpaceOAR, or equivalent product) per physician evaluation
• Positive lymph nodes or metastatic disease from prostate cancer by imaging studies (CT or MRI), unless biopsy proven to be negative.
• Evidence of metastatic disease by imaging study
• Prior invasive malignancy unless disease free for a minimum of 3 years (oral cavity, or non-melanomatous skin cancer are all permissible)
• Previous pelvic radiotherapy
• Previous surgery or chemotherapy for prostate cancer
• Previous transuretheral resection of the prostate (TURP) or cryotherapy to the prostate
• Previous androgen depravation therapy given for more than 9 months prior to therapy
• Concomitant antineoplastic therapy (including surgery, cryotherapy, conventionally fractionated radiotherapy, and chemotherapy) while on this protocol.
• History of Crohn's Disease or Ulcerative Colitis.
• Not actively on immunosuppressive medications.
• Previous significant obstructive symptoms; AUA score must be ≤20 (alpha blockers allowed)
• Significant psychiatric illness
• Men of reproductive potential may not participate unless they agree to use an effective contraceptive method.
• Ultrasound or CT estimate of prostate volume > 80 grams (after hormone downsizing allowed).
• Severe, active co-morbidity
• No nodal disease
• No known allergies to spacer material: Polyethylene glycol (PEG) hydrogel

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.

• 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, bladder cancer, and ovarian cancer
• Histologically diagnosed by an open biopsy procedure
• Tumors at sites of which the surgeon would assess that in vivo intraoperative imaging would not be feasible
• Life expectancy <12 weeks
• Significant liver disease including active hepatitis, cirrhosis, or alanine aminotransferase or bilirubin above upper limit of normal

Males one month to 21 years of age with: Painful acute scrotum or testis OR Abdominal pain (+/- nausea, vomiting) and waddling gait ("cowboy shuffle") from painful scrotum. Males with: Synchronous bilateral testicular torsion History of known testicular or scrotal surgery Current hernia or painless hydrocele Current obvious scrotal bug bites History of chronic respiratory, hematological or vascular problems that will affect total body tissue oxygenation levels (Home oxygen).