This is a multi-center single arm phase II study of zanzalintinib after Pluvicto in chemotherapy-naïve mCRPC. Subjects will receive zanzalintinib 60mg orally (PO) once daily. Zanzalintinib may continue until evidence of radiographic progression, intolerable adverse events, or withdrawal of consent. Two interim analyses will be performed; a safety interim analysis to be performed for the first 5 evaluable subjects, and a futility interim analysis to be performed for the first 15 evaluable subjects.

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0-2.

4. Metastatic Castrate Resistant Prostate Cancer (mCRPC) with histologically/cytologically confirmed adenocarcinoma without small cell histology.

5. Prior cancer treatment must be completed at least 14 days prior to registration NOTE: Antiandrogen agent, against LHRH axis, such as Leuprolide or institutional equivalent, Relugolix, Degarelix etc. are to be continued during the course of the treatment.

6. Must have recovered from adverse effects of any prior oncologic treatment (e.g. prior surgery, radiotherapy, or other antineoplastic therapy). CTCAE adverse events ≤ grade 1 are acceptable. CTCAE adverse events grade 2 or greater may be acceptable as determined by the treating Investigator.

7. Patients must have had at least one dose of prior Pluvicto therapy for prostate adenocarcinoma. Patients must have received PARP inhibitor if the tumor has BRCA 1 or 2 pathogenic mutations prior to enrolling on this study unless intolerant or contraindicated per treating investigator.

8. Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 14 days prior to registration.

   • Platelets (Plt) ≥ 100,000 /mm3 without transfusion within 14 days of sample collection

   • Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3 without granulocyte colony-stimulating factor support within 14 days of sample collection

   • Hemoglobin (Hgb) ≥ 9g/dL without transfusion within 14 days of sample collection

   • Serum Creatinine OR Calculated creatinine clearance (Cockcroft-Gault formula will be used to calculate creatinine clearance) ≤ 1.5 x ULN

     ≥ 40 mL/min (≥ 0.67 mL/sec)

   • Urine protein OR Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine or 24-hour urine protein <1.5 g.

   • Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) ≤ 3 × ULN for subjects with Gilbert's disease

   • Aspartate aminotransferase (AST) ≤ 3 × ULN

   • Alanine aminotransferase (ALT) ≤ 3 × ULN

   • Alkaline Phosphatase (ALP) ≤ 3 × ULN; ≤ 5x ULN for subjects with documented bone metastasis; ≤ 10 x ULN for subjects with CRPC and bone metastasis if predominantly bone-specific ALP

   • International Normalized Ratio (INR) ≤ 1.5 x upper limit of normal (ULN)

   • Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x upper limit of normal (ULN)

9. Males able to father a child who are sexually active with female of childbearing potential and their partners must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception as outlined in Section 5.3.

10. Ability of the subject to understand and comply with study procedures for the entire length of the study, as determined by the enrolling physician or protocol designee.

Exclusion Criteria:

1. Receipt of chemotherapy in the mCRPC disease state. NOTE: Prior exposure and any number of lines of chemo (including docetaxel) during hormone naïve or castrate sensitive state of the cancer is allowed.

2. Any other active malignancy or diagnosis of another malignancy within 2 years before first dose of study treatment requiring systemic treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.

   NOTE: Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial as approved by the Principal Investigator.

3. Known central nervous system (CNS) metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 28 days before the first dose of study treatment.

   NOTE: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of registration. Base of skull lesions without definitive evidence of dural or brail parenchymal involvement are allowed.

4. Treatment with any investigational drug within 14 days prior to registration.

5. History of severe allergic anaphylactic reactions or hypersensitivity to zanzalintinib or any of their excipients such as Cabozantinib.

6. Prior treatment with Zanzalintinib.

7. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before first dose of study treatment.

8. Receipt of any type of cytotoxic, biologic (such as systemic Immune Checkpoint Inhibitors) or other systemic anticancer therapy (including investigational) within 28 days before the first dose of study treatment. NOTE: The antiandrogen abiraterone is permitted up to 7 days prior to the first dose of study treatment. Concomitant use of megestrol acetate or leuprolide/Relugolix/ Degarelix/ Equivalent drugs such as Eligard etc. per institutional guidelines is permitted. Other types of hormonal therapies with similar use require prior approval from the sponsor-investigator.

9. Radiation therapy for bone metastasis within 14 days, any other radiation therapy within 28 days before the first dose of study treatment. Systemic treatment with radionuclides within 42 days before the first dose of study treatment.

10. 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

11. Uncontrolled, significant intercurrent or recent illness including, but not limited to the following conditions:

    a. Unstable or deteriorating cardiovascular disorders: i. Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (eg. ventricular flutter, ventricular fibrillation, Torsades de pointes).

    ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.

    iii. Stroke (including transient ischemia attack [TIA]), myocardial infection, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before the first dose of study treatment.

    iv. Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before the first dose of study treatment.

    NOTE: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before the first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen.

    NOTE: Subjects who do not require prior anticoagulation therapy may be eligible but must be discussed and approved by the sponsor-investigator.

    b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. Tumor invading the GI tract from external viscera. ii. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis.

    iii. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before the first dose unless cause of obstruction is definitively managed and subject is asymptomatic.

    iv. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before the first dose. NOTE: Complete healing of an intra-abdominal abscess must be confirmed before the first dose of study treatment.

    v. Known gastric or esophageal varices. vi. Ascites, plural effusion, or pericardial fluid requiring drainage in the last 28 days.

12. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g. pulmonary hemorrhage) within 84 days (12 weeks) before the first dose of study treatment.

13. Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed).

14. Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. NOTE: Subjects with intravascular tumor extension (eg. Tumor thrombus in renal vein or inferior V. cava) may be eligible following sponsor-investigator approval.

15. Other clinically significant disorders that would preclude safe study participation.

    1. Active infection requiring systemic therapy. NOTE: Subjects receiving prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are eligible for the study.
    2. Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. NOTE: Subjects with HIV/AIDS may be eligible if they meet all of the following criteria:

    i. On stable anti-retroviral therapy ii. CD4+ T cell count ≥ 200/µL iii. Undetectable viral load NOTE: To be eligible, participants taking CYP inhibitors (eg. zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 28 days (4 weeks) prior to the first dose. CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider.

    c. Serious non-healing wound/ulcer/bone fracture. NOTE: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions.

    d. Malabsorption syndrome. e. Pharmacologically uncompensated, symptomatic hypothyroidism. f. Moderate to severe hepatic impairment (Child-Pugh B or C). g. Requirement for hemodialysis or peritoneal dialysis. h. History of solid organ or allogenic stem cell transplant.

16. Major surgery (eg. GI surgery, removal or biopsy of brain metastasis) within 56 days (8 weeks) prior to the first dose of treatment. Minor surgery (eg. simple excision, tooth extraction) within 5 days before the first dose of study treatment. Complete wound healing from major or minor surgery must have occurred at least prior to the first dose of study treatment.

    NOTE: Fresh tumor biopsies should be performed at least 5 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.

17. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment.

    NOTE: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility.

18. Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube.

19. Other conditions, which in the opinion of the investigator, would compromise the safety of the patient or the patient's ability to complete the study.