• 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

• 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 (2 months of therapy) of GERD medication allowed.
• Patients who are currently taking Curcumin and are unwilling to stop or plan to take Curcumin during the study
• Patients with a history of gallbladder problems or gallstones or biliary obstruction,unless patient had cholecystectomy

• STEP I REGISTRATION CRITERIA
• Histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid or rhabdoid 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 systemic cancer therapy less than 28 days prior to registration; no radiation therapy 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) (except for patients with known or likely Gilbert's syndrome, for whom total bilirubin up to 3 mg/dL is allowed with direct bilirubin =< 20% total bilirubin)
• 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), with prednisone-equivalent dosing at 10 mg daily or less. 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 80 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.
• Active hepatitis B/C, or active tuberculosis (PPD response without active TB is allowed)
• Human immunodeficiency virus (HIV) -infected patients with detectable viral load within 6 months prior to registration. Patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible.
• 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 (treated hypothyroidism on thyroid replacement therapy is allowed. Abnormal thyroid-stimulating hormone (TSH) is acceptable with normal T3/free T4 if treated on thyroid replacement therapy)
• 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

1. Is greater than 50 years of age 2. Has at least a 10-year life expectancy 3. Has histologically confirmed organ-confined prostate cancer, clinical stage ≤ T2c 4. Has a PSA ≤ 15 ng/mL or PSA density < 0.2 ng/mL2 if PSA is > 15 ng/mL 5. Has Gleason score 3+4 or 4+3 6. Has no evidence of extraprostatic extension by mpMRI 7. Has no evidence of seminal vesicle invasion by mpMRI, and if suspected, confirmed by biopsy 8. Physician is able to visualize prostate gland adequately on transrectal ultrasound imaging during enrollment evaluation 9. Transperineal or transrectal targeted prostate biopsies of lesion, plus 10 core systematic biopsies to include adequate sampling of the peripheral zone correlating with an intermediate risk lesion in the area of the MR-visible lesion 10. A visible lesion on mpMRI that is accessible to Irreversible Electroporation (IRE) treatment (Note: A non-MRI visible lesion detected via systematic standard biopsy will not be considered an exclusion criterion provided the non-MRI visible lesion is singularly located in the contralateral hemisphere of the prostate; is Gleason 6; and comprises no more than 6 mm linear extent of prostate-bearing tissue in a single core on standard biopsy) 11. Has signed a written informed consent and in the judgment of the physician, the study is in the best interest of the subject 12. Understands and accepts the obligation and is logistically able to present for all scheduled follow-up visits 1. Has known hypersensitivity to pancuronium bromide, atricurium or cisatricurium 2. Is unfit for anesthesia or has a contraindication for agents listed for paralysis 3. Has an active urinary tract infection (UTI) 4. Has a history of bladder neck contracture 5. Is interested in future fertility 6. Has a history (within 3 years) of inflammatory bowel disease 7. Has a concurrent major debilitating illness 8. Had active treatment for a malignancy within 3 years, including malignant melanoma, except for prostate cancer or other types of skin cancer 9. Has any active implanted electronic device (e.g., pacemaker) 10. Is unable to catheterize due to a urethral stricture disease 11. Has had prior or current prostate cancer therapies: 1. Biologic therapy for prostate cancer 2. Chemotherapy for prostate cancer 3. Hormonal therapy for prostate cancer within three months of procedure 4. Radiotherapy for prostate cancer 5. Surgery for prostate cancer 12. Has had prior transurethral prostatectomy (TURP), stricture surgery, urethral stent or prostatic implants 13. Has had prior major rectal surgery (except hemorrhoids) 14. Is unfit for pelvic MRI scanning (e.g., severe claustrophobia, permanent cardiac pacemaker, metallic implants that are likely to contribute significant image artifacts, allergy or contraindication to gadolinium (to enhance MRI)) 15. Is actively bleeding, is anticoagulated or on blood thinning medications, or has a bleeding disorder 16. Is a member of a vulnerable population such as prisoners, handicapped or mentally disabled persons, or economically or educationally disadvantaged persons 17. In the opinion of the treating physician, has a contraindication listed in the current NanoKnife System User Manual (section 2.3)

• Status post radical prostatectomy for histologically confirmed adenocarcinoma of the 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 curcumin and are unwilling to stop or plan to take curcumin during the study

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 (which is not a required exam on the protocol). 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) within 1 year of enrollment 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 active with partners of reproductive potential who do not agree that they will use an effective contraceptive method during treatment and 6 months after treatment. 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 on this basis.

• Patients with suspected BCR of prostate cancer following initial treatment with either prostatectomy or definitive EBRT of the prostate or patients with known metastatic prostate cancer who have failed systemic therapy.
• Patients being considered for salvage therapy.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.
• Patients must be medically stable as judged by the patient's physician.
• Patients must be able to lie still for 20-40 minutes for the PET/CT scans.
• Ability to understand and the willingness to sign a written informed consent.
• Patients with BCR and no known lesions should not be on antiandrogen therapy at the time of scans. Patients with known metastases who are currently being treated with anti-androgen therapy may remain on this medication.
• Patients who have or have had a biopsy proven concurrent other malignancy, excluding skin cancers.
• Patients may not weigh more than the maximum weight limit for the PET /CT scanner table (> 200 kg or 440 pounds).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to 68Ga PSMA-11. Furosemide will not be administered to patients with known allergy.
• Patients must not be claustrophobic.

• Male
• Age 40 to 80 years, with >10 years life expectancy
• Biopsy-confirmed, NCCN (favorable and unfavourable) intermediate-risk prostate acquired within last 12 months
• Stage ≤cT2c, N0, M0
• ISUP Grade Group 2 or 3 disease on TRUS-guided biopsy or in-bore biopsy
• PSA ≤20ng/mL within last 3 months
• Treatment-naïve
• Planned ablation volume is < 3 cm axial radius from urethra on mpMRI acquired within last 6 months
• Inability to undergo MRI or general anesthesia
• Suspected tumor is > 30 mm from the prostatic urethra
• Prostate calcifications is > 3 mm in maximum extent obstructing ablation of tumor
• Unresolved urinary tract infection or prostatitis
• History of proctitis, bladder stones, hematuria, history of acute urinary retention, severe neurogenic bladder
• Artificial urinary sphincter, penile implant, or intraprostatic implant
• Patients who are otherwise not deemed candidates for radical prostatectomy
• Inability or unwillingness to provide informed consent
• History of anal or rectal fibrosis or stenosis, or urethral stenosis, or other abnormality challenging insertion of devices

• Adenocarcinoma of the prostate (as the predominant histology)
• High-risk metastatic hormone-sensitive prostate cancer. High risk is defined as:
• Greater than or equal to (≥)4 bone metastases by bone scan and/or
• ≥1 visceral metastases by computed tomography or magnetic resonance imaging
• Must have initiated androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or bilateral orchiectomy prior to randomization. Up to 3 months of ADT prior to randomization is permitted with or without first-generation anti-androgen.
• Adequate organ function
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Prior treatment with abemaciclib or any other cyclin dependent kinase 4 and 6 (CDK4 & 6) inhibitor
• Development of metastatic prostate cancer in the context of castrate levels of testosterone
• Received any prior systemic therapy for metastatic prostate cancer (including investigational agents), except for ADT and first-generation anti-androgen
• Clinically significant cardiovascular disease as evidenced by myocardial infarction, arterial thrombotic events, or severe/unstable angina in the past 6 months, or New York Heart Association Class II to IV heart failure
• History of syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin, or sudden cardiac arrest. Chronic and hemodynamically stable atrial arrhythmia well-controlled on medical therapy is permitted
• Uncontrolled hypertension
• Clinically active or chronic liver disease, moderate/severe hepatic impairment
• Known untreated central nervous system (CNS) metastasis. Participants with a history of treated brain metastases are eligible if stable for at least 8 weeks prior to randomization and off corticosteroid for at least 2 weeks prior to randomization

1. ≥ 18 years of age 2. Histopathological or cytologically documented locally advanced or metastatic solid tumors who have no available standard therapeutic treatment options 3. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Adequate organ function confirmed at screening and within 10 days of initiating treatment, as evidenced by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Hemoglobin (Hgb) ≥ 8 g/dl
• Platelets (plt) ≥ 75 x 10^9/L
• AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present
• Total bilirubin ≤ 1.5 x ULN
• Calculated creatinine clearance ≥ 50 mL/min (Cockcroft Gault formula) 6. Negative pregnancy test within 72 hours before starting study treatment in all premenopausal women and women < 12 months after the onset of menopause 7. Must agree to take sufficient contraceptive methods to avoid pregnancy during the study and until at least 6 months after ceasing study treatment 8. Able to sign informed consent and comply with the protocol 1. Women who are pregnant or lactating 2. Women of child-bearing potential (WOCBP) who do not use adequate birth control 3. Patients with any hematologic malignancy, including leukemia (any form), lymphoma, and multiple myeloma 4. Patients with a history of primary central nervous system tumors or carcinomatous meningitis. 5. Patients with the following mood disorders as judged by the Investigator or a psychiatrist:
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
• ≥ CTCAE grade 3 anxiety 6. Impaired cardiac function or significant diseases, including but not limited to any of the following:
• left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO)
• Congenital long QT syndrome
• QTcF ≥ 480 msec on screening ECG
• Unstable angina pectoris ≤ 3 months prior to starting study drug
• Acute myocardial infarction ≤ 3 months prior to starting study drug 7. Patients with:
• unresolved diarrhea ≥ CTCAE grade 2, or
• impairment of gastrointestinal (GI) function, or
• GI disease that may significantly alter the absorption of TT-00420 8. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., uncontrolled hypertension, uncontrolled hypertriglyceridemia, or active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol 9. Patients who have received chemotherapy, targeted therapy, or immunotherapy ≤ 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy 10. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy 11. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy 12. Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 4 weeks prior to starting study drug. 13. Patients who are currently receiving treatment with therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulants 14. Patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study drug or who have not recovered from the side effects of such treatment. 15. Patients who are currently receiving treatment with strong CYP3A inhibitors or inducers ≤ 2 weeks prior to starting study drug. 16. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory; patients with well controlled HIV might be enrolled) 17. Known history of active infection with Hepatitis B or Hepatitis C 18. Has received a live-virus vaccination within 30 days of planned first dose 19. Inability to swallow or tolerate oral medication 20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that, in the opinion of the investigator, might confound the results of the trial, interfere with the patient's safe participation and compliance in the trial.

The main inclusion and exclusion criteria include but are not limited to the following:
• Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without sarcomatoid features
• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node metastasis and tumor grading: 1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0 2. High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0 3. M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤2 years from nephrectomy (metachronous)
• Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants
• Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to randomization
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days before randomization.
• Male participants must agree to continue contraception at least 7 days after the last dose of belzutifan/placebo
• Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of pembrolizumab or at least 30 days after last dose of belzutifan/placebo, whichever occurs last
• Has adequate organ function
• Has had a major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization
• Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 6 months from first dose of study intervention
• Has other clinically significant disorders such as: serious active nonhealing wound/ulcer/bone fracture; requirement for hemodialysis or peritoneal dialysis
• Has preexisting brain or bone metastatic lesions
• Has received prior systemic therapy for RCC
• Has received prior radiotherapy for RCC
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines are allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has a known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy is allowed
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection, requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection, a known history of Hepatitis B or known active Hepatitis C virus infection
• Has had an allogenic tissue/solid organ transplant

1. Subject is able and willing to comply with all the assessments of the study, 2. Subject or subject's legal representative has been informed of the nature of the study, agrees to participate and has signed the informed consent form, 3. ≥ 45 years of age, 4. Baseline IPSS score ≥ 13; ≥ 1 in the IPSS voiding to storage sub-score ratio (IPSS-V/S), 5. Prostate volume 25
•80 cc by transrectal ultrasound (TRUS), measured within 120 days post study consent, 6. Prostatic urethral length between 25 and 45 mm, as measured by cystoscopic pull-back, 7. Failed, intolerant, or subject choice to not take a medication regimen for the treatment of LUTS. 1. Obstructive intravesical median prostatic lobe as determined by ultrasound (i.e., more than 10 mm intravesical prostatic protrusion on sagittal mid-prostate plane via abdominal ultrasound), 2. High bladder neck with the absence of lateral lobe encroachment indicating a high likelihood of primary bladder neck obstruction as determined by the Investigator, 3. Urethral stricture, meatal stenosis, or bladder neck stricture
•either current or recurrent, 4. Anatomical anomalies that will not accommodate the Implant, as determined by cystoscopy (e.g., prostatic urethral length to height geometry), 5. Requires indwelling catheter or intermittent catheterization to void, 6. Baseline PSA > 10 ng/mL or confirmed or suspected prostate cancer (Subjects with a PSA level above 2.5 ng/mL, or age specific, or local reference ranges should have prostate cancer excluded to the Investigator's satisfaction), 7. One of the following baseline test results, taken from a single uroflowmetry reading: 1. Urinary volume void ≤ 125mL (pre-bladder urinary volume of ≥ 150 mL required), 2. Peak urinary flow rate (Qmax) of ≤ 5 ml/second or > 15 mL/second, 3. Post- void residual volume (PVR) > 250 mL 8. History of other diseases causing voiding dysfunction including urinary retention (e.g., uncontrolled diabetes, diagnosis of neurogenic bladder, Parkinson's disease, multiple sclerosis, etc.), 9. Subjects with overactive bladder in the absence of benign prostatic obstruction, 10. Acute urinary tract infection (UTI) or finding of asymptomatic bacteriuria (Note: subject can be enrolled if the UTI is treated and followed with a negative urine test result), or subjects with history of recurrent UTIs (defined as > 3 UTIs in the past 12 months), 11. Concomitant bladder stones, 12. Previous pelvic irradiation or radical pelvic surgery, 13. Previous prostate surgery, including: enucleation, resection, vaporization, thermotherapy, ablation, stenting or prostatic urethral lift, 14. Chronic prostatitis, recurrent prostatitis, chronic pelvic pain syndrome (CPPS), or painful bladder syndrome within the past 12 months 15. Known allergy to nickel, 16. Life expectancy less than 60 months, 17. Use of concomitant medications (e.g., anticholinergics, antispasmodics or tricyclic antidepressants) affecting bladder function, 18. Inability to stop taking anticoagulants and/or antiplatelets for at least 3 days prior to the procedure or coumadin for at least 5 days prior to the procedure (Note: low dose aspirin therapy (81 mg) is permitted), 19. Taking 5-alpha-reductase inhibitors within 3 months of baseline evaluation, 20. Taking one of the following within 2 weeks of baseline evaluation: 1. alpha-blockers, 2. imipramine, 3. anticholinergics, 4. cholinergic gonadotropin releasing hormonal analogues, 5. Phosphodiesterase-5 Enzyme Inhibitors (Tadalafil) in doses for BPH, 6. Beta-3 adrenergic receptor agonist (Mirabegron), 21. Taking androgens, unless eugonadal state for at least 3 months or greater as documented by the Investigator, 22. Taking one of the following within 24 hours of pre-treatment (baseline) evaluation: 1. phenylephrine, or, 2. pseudoephedrine, 23. Future fertility concerns, or, 24. In the Investigator's opinion, the subject has a physical, psychological, or medical impairment that might prevent study completion or would confound study results (including subject questionnaires).

• 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.

Participants eligible for inclusion in this study must meet all of the following criteria: 1. Signed informed consent must be obtained prior to participation in the study 2. Patients must be adults ≥18 years of age 3. Patients must have an ECOG performance status of 0 to 2 4. Patients must have a life expectancy >9 months as determined by the study investigator 5. Patients must have metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic site) 6. Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT scan, and eligible as determined by the sponsor's central reader 7. Patients must have at least one documented metastatic bone and/or soft tissue/visceral lesion documented in the following manners within 28 days prior randomization: 1. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone scintigraphy on either pre-ADT scans or baseline scans AND/OR 2. Lymph node metastases of any size or distribution. If lymph nodes are the only site of metastasis, then at least one must be at least 1.5 cm in short axis AND outside of the pelvis AND/OR 3. Visceral metastases of any size or distribution. If a participant has a history of visceral metastases at any time prior to randomization, he should be coded as having visceral metastases at baseline (i.e., patients with visceral metastases prior to ADT that disappear at baseline will be counted as having visceral metastases and would therefore have high volume disease for stratification purposes). 8. Patients must have adequate organ function:
• Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL
• Hepatic Total bilirubin ≤2 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
• Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation 9. Albumin ≥2.5 g/dL 10. Human immunodeficiency virus (HIV)-infected patients who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial 11. Patients must be: Treatment naïve OR minimally treated with:
• Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist /antagonists or bilateral orchiectomy with or without first generation anti-androgen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation anti-androgen must be discontinued prior to start of study therapy or after 45 days whatever happens first.
• If received, prior LHRH agonist/antagonist with or without first generation anti-androgen use in the adjuvant/neo-adjuvant setting must have been discontinued > 12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy.
• Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. No CYP17 inhibitor or ARDT exposure for earlier stages of prostate cancer is allowed. Participants meeting any of the following criteria are not eligible for inclusion in this study. 1. Participants with rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy 2. Any prior systemic anti-prostate cancer therapy (with the exception of the drugs listed on inclusion criteria 11), including chemotherapy, Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biological therapy (including monoclonal antibodies). 3. Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy 4. 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 5. Ongoing participation in any other clinical trial 6. Use of other investigational drugs within 30 days prior to day of randomization 7. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes 8. Transfusion for the sole purpose of making a participant eligible for study inclusion 9. Participants with CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with epidural disease, canal disease and prior cord involvement are allowed if those areas have been treated, are stable, and not neurologically impaired. Participants with parenchymal CNS metastasis (or a history of CNS metastasis), that have received prior therapy and are neurologically stable, asymptomatic and not receiving steroids for CNS metastases, are allowed, baseline and subsequent radiological imaging must include evaluation of the brain (magnetic resonance imaging (MRI) preferred or CT with contrast). 10. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free, treatment free for more than 3 years prior to randomization, or participants with adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible. 11. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, 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. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance). 12. Active clinically significant cardiac disease defined as any of the following:
• NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class < 3.
• History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)
• History of familial long QT syndrome or known family history of Torsades de Pointes
• Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature 13. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study 14. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression 15. Any condition that precludes raised arms position 16. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed. 17. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF

• 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 1 metastatic bone lesion 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 >= 7 days prior to registration, as long as they still have at least 1 metastatic bone lesion not treated with radiation. Patients with visceral metastases are allowed, as long as they have at least one untreated bone metastases
• No prior treatment with cabozantinib
• 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%
• 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
• 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 >= 9 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 =< 2 mg/mg OR 24-hr urine protein < 2 g

• Ability to understand and the willingness to sign a written informed consent that includes study interventions (PET/CT and, if cohort 2, mandatory biopsy).
• Ability to lie still for a 30- to 60-minute PET/CT scan.
• One of the following: 1. Cohort 1. Patients with suspected RCC planned for surgery. 2. Cohort 2. Patients with metastatic ccRCC or VHL syndrome and RCC. Biopsy is required (planned resection for treatment reasons of a metastatic site is acceptable in lieu of the biopsy). 3. Cohort 3. Patients with VHL syndrome with RCC, CNS hemangioblastoma, and/or pancreatic neuroendocrine tumor(s) planning to start belzutifan.
• Women of child-bearing potential must agree to undergo and have documented a negative pregnancy test on the day of [18F]PT2385 administration. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or celibate by choice) who meets the following criteria: 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).
• Uncontrolled severe and irreversible intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements.
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
• Claustrophobia or other contraindications to PET/CT.
• Subjects must not weigh more than the maximum weight limit for the table for the PET/CT scanner where the study is being performed (>200 kilograms or 440 pounds).
• For cohort 2 patients, lack of suitable sites for mandatory biopsy. For example, patients with metastatic disease restricted to the lungs that would require percutaneous biopsies with associated risk of bleeding and pneumothorax will be excluded.