Zanzalintinib Efficacy Post Pluvicto® in Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer

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 \