CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Livonia, LVHN, Sparrow, GenHur, Hurley, SJMO, Saginaw, Holy Cross

Eligibility Criteria:

Eligibility Criteria (see Section 3.2)

• Clinical stage II or III rectal adenocarcinoma defined as T4N0, or any T with node positive disease (any T, N+); also T3N0 requiring APR or coloanal anastomosis

• No prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer within the past 5 years

• Not pregnant and not nursing

• Age ≥ 18 years

• ECOG Performance Status 0-1

• No upper rectal tumors (distal margin of tumor > 12 cm from the anal verge)

• No recurrent rectal cancer; prior transanal excision, prior distal sigmoid cancer with a low anastomosis

• No known mismatch repair deficient rectal adenocarcinoma

**See most current version of the protocol for full eligibility list**

 *Credentialing required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED:
Livonia, Saginaw, Sparrow, St. Alphonsus, SJMH

*DTL Required- Physicians must sign toxicity grid CREDENTIALING REQUIRED. Please check your site's credentialing status.

-Histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract.
-Patient must fit into one of the following three categories:
--Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is ? pT2 and/or N+
--Patients who are not cisplatin-eligible
--Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is ? pT3 or pN+
-Patient must have had radical surgical resection of their bladder cancer ?4 weeks but ? 16 weeks prior to pre-registration.
-No invasive cancer at the surgical margins
-No evidence of residual cancer or metastasis after surgery
-No metastatic disease on cross-sectional imaging
-No postoperative/adjuvant systemic therapy.
-No prior treatment with any therapy on the PD-1/PD-L1 axis.
-ECOG Performance Status ? 2

Step 1:

-Histologically confirmed muscle-invasive urothelial carcinoma of the bladder.
-Clinical stage T2-T4aN0/xM0 disease
-Medically appropriate candidate for radical cystectomy as assessed by surgeon
-No concomitant multifocal carcinoma in situ; a single focus is allowed
-One focus of muscle-invasive bladder cancer and/or a tumor less than 5 cm in size
-No locally advanced or metastatic disease
-No prior anti-PD-1, anti-PD-L1 therapies, or systemic chemotherapy
-No prior radiation to the bladder
-ECOG PS must be 0-1
-No pre-existing sensory neuropathy grade 2 or greater

Step 2:
-Must have completed 4 or more cycles of protocol-directed chemotherapy

Step 3:
-Deleterious alteration within 1 or more of 9 pre-defined DDR genes within the pre-treatment TURBT DNA 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (AA), Livonia

Eligibility Criteria:

 Documentation of Disease

-Documented histologic or cytologic diagnosis of 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 CT, MRI, Tc-99m bone scan or PET (FDG or NaF) imaging. Patients with non-measurable bone-only disease are allowed. Patients may have received prior radiation therapy for bone metastases or other external radiation ≥14 days prior to registration, as long as they still have at least 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.

Prior Treatment

___ No prior treatment with cabozantinb.

___ No treatment with any type of small molecular kinase inhibitor (including investigational kinase inhibitors) within 2 weeks or 5 half-lives (whichever is shorter) of registration or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of registration.

___ No prior hemibody external radiotherapy.

___ No prior therapy with radium-223 dichloride or systemic radiotherapy (such as samarium, strontium).  

___ No major surgery within 6 weeks of randomization. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Moh’s or other topical skin surgery, Lasik eye surgery are not considered major surgery. Patients who have had a nephrectomy may be registered ≥3 weeks after surgery, providing there are no wound-healing complications. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.

___ Recovery to baseline or ≤ grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy.

___ The use of osteoclast targeted therapy including either bisphosphonates or denosumab is mandated on this study except in patients with contraindications as determined by the treating investigator, including:

• Hypocalcemia

• Hypophosphatemia

• Renal impairment including those with a GFR < 35 mL/min using the CockcroftGault 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 ONJ. Use of osteoclast targeted therapy or reason against use needs to be recorded in the 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). 

Age ≥ 18 years

- Karnofsky performance status ≥ 60%

-Comorbid conditions

___ No brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator.

___ No imminent or established spinal cord compression based on clinical symptoms and/or imaging. In patients with untreated imminent or established spinal cord compression, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration 

___ No imminent or impending pathologic fracture based on clinical symptoms and/or imaging. In patients with untreated imminent or impending pathologic fracture, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration.

___ No significant, uncontrolled intercurrent or recent illness, including but not limited to the following conditions:

• Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia; uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment; stroke (including transient ischemic attack), myocardial infarction, or other ischemic event, within 6 months before randomization; thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization; screening QTcF ≤500 msec.

• Gastrointestinal disorders: Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 3 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization.

• No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization.

• No lesions invading major pulmonary blood vessels.

• No other clinically significant disorders: - Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy (with no medications prohibited by this protocol [e.g. drugdrug 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:

o Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).

o 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.

- Required Initial Laboratory Values: Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 Platelet Count ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dl (transfusions allowed) Calc. Creatinine Clearance ≥ 30 mL/min using the Cockroft-Gault equation Total Bilirubin ≤ 1.5 x ULN, for patients with Gilberts disease ≤ 3.0 x ULN AST and ALT ≤ 3.0 x ULN UPC Ratio ≤ 1 mg/mg OR 24-hr urine protein < 1g  

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton), St. Mary's Livonia, GenesysHurley, LVHN, Sparrow, SJMO

Eligibility Criteria:

On-Study Guidelines This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All relevant medical and other considerations should be taken into account when deciding whether this protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of any therapy, and therefore only enroll patients for whom this treatment is appropriate. Physicians should consider whether any of the following may render the patient inappropriate for this protocol:

• Psychiatric illness which would prevent the patient from giving informed consent. • Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

• Patients with a “currently active” second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for ≥ 3 years.

• Patients who cannot swallow oral formulations of the agents. In addition:

• Men of reproductive potential should agree to use an appropriate method of birth control and not donate semen while taking rucaparib/placebo and for 6 months following the last dose of rucaparib/placebo due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom).

Pre-Registration Eligibility Criteria 

Documentation of Disease

-Histologic/cytologic documentation of prostate adenocarcinoma

- Adequate archival tumor specimen or archival slides must be available to be tested as part of the trial screening (most recent metastatic site biopsy preferred, but primary prostate biopsy allowed if metastatic biopsy is not available or inadequate. A new biopsy is not required for enrollment in the trial as long as sufficient archival tissue is available). Due to significant variability between tests, results from an existing targeted next-generation exome sequencing test may not be used for this trial. Progressive disease must be demonstrated at study entry while the patient is on continuous androgen deprivation therapy (ADT) or status post orchiectomy. Progressive disease is defined as one or more of the following criteria (choose all the apply):

- PSA progression, defined by at least 2 consecutive rising PSA values at a minimum of 1-week intervals with the most recent PSA value being 1.0 ng/mL or higher, if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen must have PSA progression after withdrawal of anti-androgen therapy.

- Radiographic progression per RECIST 1.1 criteria for soft tissue lesions \

- Bone metastasis progression per Prostate Cancer Working Group 3 (PCWG3) criteria.

- Measurable or non-measurable metastatic disease as defined in Section 11.0.

Prior Treatment

- No prior therapy for metastatic castration-resistant prostate cancer, defined as a treatment given for prostate cancer with radiographically-detectable metastasis and a serum testosterone level less than 50 ng/dl (1.73 nmol/L) at the time of pre-registration.

- ≥2 weeks or 5 half-lives (whichever is longer) since prior therapy with flutamide, dutasteride, bicalutamide, niltamide, finasteride, aminoglutethimide, estrogens, cytoproterone, chemotherapy, abiraterone, apalutamide, or darolutamide

- ≥4 weeks or 5 half-lives (whichever is longer) since any prior investigational therapy

- ≥4 weeks since a major surgery or radiation

- No prior therapy with enzalutamide, rucaparib or any other PARP inhibitor, or platinum chemotherapy.

- Prior docetaxel and/or novel antiandrogen use is allowed only if given in the hormone-sensitive disease setting

- Patient must have discontinued all previous treatments for cancer (except ADT and bone anti-responsive therapies such as denosumab or zoledronic acid) and must have recovered from all acute side effects of prior therapy or surgical procedures to ≤ Grade 1 or baseline prior to randomization, with the exception of fatigue, alopecia or peripheral neuropathy 

-Age ≥ 18 years

-  ECOG Performance Status 0-2

- Required Initial Laboratory Values

-Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

-Platelet Count ≥ 100,000/mm3 Hemoglobin ≥ 10 g/dL

-Serum testosterone ≤ 50 ng/dl (≤ 1.73 nmol/L)

-Serum Creatinine ≤ 1.5 x upper limit of normal (ULN)

-Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)

-AST / ALT ≤ 2.5 x upper limit of normal (ULN) 

Comorbid conditions

-No clinically suspected CNS (leptomeningeal or parenchymal) metastases. Patients with a history of CNS metastasis(s) will be allowed as long (1) as the metastatic site(s) were adequately treated as demonstrated by clinical and radiographic improvement, AND (2) the patient has recovered from the intervention (no residual adverse events > CTCAE grade 1), AND (3) the patient has remained without occurrence of new or worsening CNS symptoms for a period of 28 days prior to pre-registration.

- No known or suspected history of cytopenia (low WBC, hemoglobin or platelet count) of greater than 3 months duration with an unknown cause, myelodysplastic syndrome, or hematologic malignancies.

-No blood product transfusion, granulocyte/granulocyte-macrophage-colony stimulating factor (G-CSF/GM-CSF), or erythropoietin/thrombopoietin use within 14 days of pre-registration.

- No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New York Heart Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within 3 months prior to pre-registration on A031902.

- No history of seizure or any condition that may increase the patient’s seizure risk (e.g., prior cortical stroke, significant brain trauma) within 2 years prior to pre-registration on A031902.

- No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh Class B or C), ascites, coagulopathy or bleeding due to liver dysfunction.

-No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of pre-registration.

-No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery.

- No untreated spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression.  

-No known or suspected contraindications or hypersensitivity to enzalutamide, rucaparib, or to any of the excipients.

- No known or suspected gastrointestinal disorder affecting absorption of oral medications.

- No prior malignancy for which the last treatment was given within the past 2 years prior to pre-registration on A031902, or any active concurrent malignancy with the exception of non-melanomatous localized skin cancers (such as squamous or basal cell carcinoma of the skin).

Concomitant medications

- Any concomitant medications that are strong inhibitors of CYP2C8 or inducers of CYP3A4 cytochrome enzymes must be discontinued prior to registration. Dose adjustments per FDA label or clinical judgement should be considered for any concomitant medications that are moderate inhibitors of CYP2C8 or inducers of CYP3A4 cytochrome enzymes.

- Any concomitant medications that are substrates of CYP3A4, CYP2C8 and CYP2C19 cytochrome enzymes should be monitored closely per clinical judgement of the treating physician. An indicative list of medications with drug-drug interactions is provided in Appendix III.

 Registration Eligibility Criteria

- Results of HRR testing available HRR testing results from the central laboratory (Tempus Labs) are required before registering. Tempus will forward the HRR results to the statistical center, and the statistical center will notify the site that the result is available. Since the results will be blinded to the site the notification from the Alliance registration/randomization office will serve as a confirmation of this eligibility criteria. After the site receives this confirmation e-mail from Alliance they can register the patient. Patients with known HRR test results may not use the known result for A031902, tissue must still be sent to Tempus Labs for testing.  

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED:  SJMH (AA, Brighton, Canton, Chelsea), Livonia, SJMO, GenHur, Sparrow

Eligibility Criteria: 

Diagnosis

• Histologically or cytologically-confirmed diagnosis of advanced or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies except for small-cell histology), including N3 only disease prior to start of first-line platinum-based chemotherapy.

- Prior Treatment Required:

• Prior first-line treatment must have consisted of 4-6 cycles of 1st-line therapy (platinum-based chemotherapy; gemcitabine-cisplatin, gemcitabine-carboplatin, MVAC or ddMVAC).

• No more than 1 line of prior chemotherapy for metastatic or locally advanced disease (neoadjuvant or adjuvant chemotherapy will be allowed if given 12 or more months prior to registration).

• Tumor objective response of CR, PR, or SD upon completion of first line platinumbased chemotherapy.

• The last dose of first-line chemotherapy must have been received no less than 3 weeks, and no more than 10 weeks, prior to randomization in the present study.

- Prior Treatment:

• No prior immunotherapy with IL-2, IFN-a, or an anti-PD-1, anti-PD-L1, anti-PDL2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways 

 -Age ≥ 18 years

- ECOG Performance Status of 0 or 1

_- Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

- Women of childbearing potential must have a negative pregnancy test ≤ 14 days prior to registration. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea ≥12 consecutive months.

Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason.

- No use of immunosuppresive medication within 7 days prior to randomization except:

a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);

b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent;

c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).

- HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

- Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

- None of the following: No known symptomatic central nervous system (CNS) metastases. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for at least 2 weeks, and are neurologically stable. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility. No major surgery within 4 weeks prior to randomization. Subjects must have complete wound healing from surgery before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. No palliative radiotherapy within 48 hours prior to patient randomization. No hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood, clinically significant hematuria, hematemesis, coagulopathy, or other history of significant bleeding (eg. Pulmonary hemorrhage) within 3 months before randomization.

No known cavitating pulmonary lesion(s) or known endobronchial disease manifestation.

No administration of a live, attenuated vaccine within 30 days prior to randomization. The use of inactivated (killed) vaccines for the prevention of infectious disease is permitted. The use of COVID-19 vaccines is permitted. No uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

1. Cardiovascular disorders including:

a) Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening.

b) Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment.

c) The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤500 ms, the subject meets eligibility in this regard.

d) Any history of congenital long QT syndrome.

e) Stroke, transient ischemic attack (TIA), myocardial infarction, or other symptomatic ischemic event or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism (DVT/PE) within 6 months before randomization. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if asymptomatic and stable at screening and treated with LMWH or the direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before randomization. Non-symptomatic white matter disease in the brain is acceptable.

2. No significant gastrointestinal disorders, particularly those associated with a high risk of perforation or fistula formation including unresolved active peptic ulcer disease, cholecystitis, diverticultis, symptomatic cholangitis or appendicitis, or malabsorption syndrome within 28 days of randomization.

3. No other clinically significant disorders such as:

a) Any active infection requiring systemic treatment within 14 days before randomization. Subjects receiving oral (including prophylactic) antibiotics with no symptoms of infection at randomization are eligible.

b) serious non-healing wound/ulcer/bone fracture within 28 days before randomization

c) history of organ or allogeneic stem cell transplant

4. No persisting toxicity related to prior therapy Grade >2 constituting a safety risk based on the investigator’s judgment.

5. No diagnosis of any other malignancy within 3 years prior to randomization, except for locally curable cancers that have been adequately treated such as basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, Gleason < 7 prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms and no indication for treatment.  

6. 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 are the following:

o 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.

- Required Initial Laboratory Values:

Absolute Neutrophil Count (ANC) ≥ 1,000/mm3

Platelet Count ≥ 100,000/mm3 Hemoglobin ≥ 8 g/dL Calc.

Creatinine Clearance ≥ 30 mL/min Total Serum Bilirubin ≤ 1.5 x upper limit of normal (ULN)

AST / ALT ≤ 2.5 x ULN (or ≤5 x ULN for patients with liver metastases or Gilbert’s disease)

UPC Ratio ≤ 1 or 24-hour protein < 1 g  

Eligibility Criteria:

- Documentation of Disease 

Histologic or clinical diagnosis of metastatic prostate cancer 

- Must have had evidence of metastatic disease by bone scan, or nodal or visceral lesions on CT or MRI prior to starting on intense ADT. 

• Radiographic evidence of disease is not required at the time of enrollment.

• No metastases to liver or to brain,as these represent aggressive variant disease biology for which intermittent treatment may not be favored.

Prior Treatment

• Must currently be receiving intense ADT for metastatic hormone sensitive prostate cancer (mHSPC)

o Testosterone suppression (TS) with luteinizing hormone releasing hormone (LHRH)-agonist or LHRH-antagonist AND

o An approved secondary androgen receptor pathway inhibitor (ARPI) abiraterone, enzalutamide, or apalutamide ( or darolutamide if approved for this indication).

• Must have remained on testosterone suppression for metastatic disease continuously (without treatment breaks) for 540-750 days (approximately 18 to 24 months) from time of first dose of LHRH agonist or antagonist by time of registration. A period of anti-androgen treatment prior to LHRH agonist or antagonist initiation is not included in the 540- 750 days (approximately 18 to 24 months).

• Must have received treatment with ARPI for at least 360 days in total by time of A032101 registration. Treatment breaks from ARPI ofup to 28 days are permitted (for example peri-procedural or for management of a temporary adverse event) as long as PSA did not rise while holding therapy.

• Prior TS in the context of neoadjuvant/concurrent/adjuvant treatment with local therapy is permitted. Prior course(s) of intermittent TS for biochemical-only recurrence is permitted. However, if the patient previously received TS, metastatic progression for which intense ADT was initiated must have occurred during an off­treatment interval and with testosterone 2'. 150 ng/dL.

• Prior local therapy for prostate cancer ( either before or after diagnosis of metastatic disease) is permitted. Prior treatment with docetaxel chemotherapy for up to 6 cycles is permitted. Prior radiation therapy to metastatic sites ( either for symptom palliation or for ablation of oligometastatic disease) is permitted.

• No history of surgical castration.

• No history of ARPI use prior to diagnosis of mHSPC for which the patient is currently receiving intense ADT (such as in the neoadjuvant setting with prior local therapy).

• No current or prior treatment with experimental agents for metastatic hormone­sensitive prostate cancer.

- ECOG Performance Status 0-2 

***Please see the current version of the protocol for the complete eligibility criteria list.** 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health SJMH IHA (Brighton, Ann Arbor, Chelsea, Canton), Livonia, Sparrow

Eligibility Criteria:

3.2 Pre-Registration Eligibility Criteria

3.2.1 Documentation of Disease: Histological or cytological evidence of prostate cancer. Patients with variant histologies including neuroendocrine, small cell and sarcomatoid prostate cancer are allowed to enroll and these will not be used as selection criteria for individual arms. Central pathology review is not required.

3.2.2 Measurable disease and/or non-measurable metastatic disease per RECIST version 1.1. 

3.2.3 Tissue procured within 12 months of pre-registration (metastatic disease preferred over primary tissue, though both are acceptable) available for submission per Section 6.2. For patients who have progressed on A032102 and are pre-registering again, repeat tissue procurement will not be mandated.  3.2.4 Molecular report available performed as part of standard of care testing via any CLIA-certified next generation sequencing (NGS) assay. Patients may be assigned based on pre-determined qualifying molecular/DNA alterations as stated in section 4.8 after receipt of local molecular testing by the A032102 molecular tumor board (MTB). Final determination of arm assignment will be determined by the MTB. For qualifying DNA alteration determined by the MTB, testing may be from tumor tissue collected at any time or ctDNA within 12 months of pre-registration. If no qualifying DNA alteration is identified based on the CLIA-certified next generation sequencing assay and MTB review, Caris testing, should be performed for both DNA/RNA profiling. Arm assignment based RNA requires testing of tumor tissue collected within 12 months of pre-registration and MTB review.

3.2.5 Age ≥ 18 years

3.3 Registration Eligibility Criteria 

3.3.1 Progressive mCRPC as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND one or more of the following criteria (choose all the apply):

• PSA progression, defined by at least 2 consecutive rising PSA values at a minimum of 1-week intervals with the most recent PSA value being 2.0 ng/mL or higher, if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen must have PSA progression after withdrawal of anti-androgen therapy.

• Radiographic progression per RECIST 1.1 criteria for soft tissue lesions

• Bone metastasis progression per Prostate Cancer Working Group 3 (PCWG3) criteria. Patients selected to receive lutetium Lu 177 vipivotide tetraxetan treatment are required to have PSMA positive mCRPC as determined by investigator assessment. For reference, in the VISION trial this was defined as at least 1 PSMA+ metastatic lesion (defined as uptake greater than that of liver parenchyma in lesions of any size in any organ system) and no PSMA- lesions (defined as uptake equal to or lower than that of liver parenchyma in any lymph node with a short axis of at least 2.5 cm, in any solid organ lesion with a short axis of at least 1.0 cm, or in any bone lesion with a soft-tissue component of at least 1.0 cm in the short axis) 

3.3.2 Prior Treatment

• Prior treatment with ARSI in either the metastatic hormone sensitive setting or mCRPC is required. Prior taxane therapy in either metastatic hormone sensitive setting or mCRPC is mandated unless patient is taxane ineligible or the patient refuses taxane therapy. Prior lutetium LU177 vipivotide tetraxetan treatment is permitted but not mandated. Patients with known germline or somatic deleterious BRCA 1/2 mutations must have received a prior PARPi.

• Resolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, Grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to registration and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, comprised of:

• Chemotherapy-induced neuropathy

• Fatigue

• Residual toxicities from prior treatment: Grade 1 or Grade 2 endocrinopathies which may include: Hypothyroidism/hyperthyroidism. type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo)

• No cytotoxic, biologic, radiopharmaceutical or other non-kinase inhibitor investigational agent within 4 weeks of registration. Treatment with any type of small molecular kinase inhibitor (including investigational kinase inhibitor) within 2 weeks of registration. Treatment with abiraterone acetate, apalutamide, or darolutamide within 2 weeks of registration. Treatment with enzalutamide within 4 weeks of registration. No treatment with radiation therapy within 2 weeks of registration.

• No major surgery within 4 weeks of registration.

• No prior treatment with EZH inhibitors.

• Prior treatment with cabazitaxel + carboplatin.

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST** 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health IHA (Ann Arbor, Brighton, Canton, Chelsea), Livonia, Genesys, Hurley, Sparrow, Lehigh

Eligibility Criteria:

3.3.1 Patient must have had radical cystectomy and lymph node dissection ≤ 18 weeks prior to registration. 

3.3.2 Must have evaluable ctDNA Signatera assay result [i.e., ctDNA(+) or ctDNA(- )] based on test performed as part of central testing after pre-registration to A032103. Central testing is defined as testing performed as part of the A032103. Local/commercial testing results may not be used for registration to A032103.

• Cisplatin-ineligible (or cisplatin-declining) patients with a pT2N0 urothelial cancer on cystectomy who were pre-registered based on routine standard care ctDNA(+) Signatera testing must have confirmed ctDNA(+) Signatera testing on central testing. If central Signatera testing yields a ctDNA(-) result, these patients are ineligible. NOTE: This is a distinct consideration from patients with ypT2-4 and/or ypN+ urothelial cancer (i.e., patients who had received neoadjuvant cisplatin-based chemotherapy) who are eligible with either ctDNA(+) or ctDNA(- ) central Signatera testing. 

3.3.3 All patients must have confirmed disease-free status defined as no measurable disease by RECIST 1.1, or definitive non-measurable radiographic metastatic disease, within 60 days prior to registration. Patients with equivocal nodes less than 15 mm in short axis, or < 10 mm in long axis for non-lymph node lesions, not considered by the investigator to represent malignant disease will be eligible. Attempts should be made to resolve the etiology of equivocal lesions with complementary imaging (e.g., PET scan) or biopsy.

3.3.4 No major surgery ≤ 3 weeks before registration. 

3.3.5 No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette– Gue´rin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccines are not live vaccines and are allowed.

 3.4 Eligibility Criteria for Cohort B Arm 4 patients initiating nivolumab after conversion of ctDNA assay from ctDNA(-) to ctDNA (+)

• Patient must have converted to ctDNA(+) during serial monitoring performed centrally in the setting of the A032103 study.

• No evidence of metastatic disease on the most recent scheduled imaging assessment as outlined in the study calendar [no repeat imaging is necessary specifically at the time of the conversion from ctDNA(-) to ctDNA(+)].

• No change in clinical condition and/or laboratory tests that would impact the safety of nivolumab in the opinion of the treating investigator.

• ≤ 6 weeks from reporting of ctDNA(+) result by Natera. 

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**