Zanzalintinib in Men With Aggressive Variant Prostate Cancer

Inclusion Criteria: 1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 2. Age ≥ 18 years at the time of consent. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 within 14 days prior to registration. 4. Histological or cytologically proven prostate cancer 5. Must have had evidence of metastatic disease (AJCC v.8 M1 disease) based on conventional CT/MRI and/or bone scan. This will be defined as: * Bone metastases detected by CT, radionuclide 99Tc- methylene bisphosphonate bone scan, or MRI as defined by PCWG3 criteria, OR * Non-pelvic lymph node metastases (measurable lymph nodes above the aortic bifurcation; lymph nodes are measurable if the short axis diameter is ≥15 mm) detected on CT or MRI as defined by RECIST version 1.1. Subjects with regional lymph node metastases only (N1, below the aortic bifurcation) will not be eligible for the study; OR * Visceral or soft tissue metastases detected on CT or MRI as defined by RECIST version 1.1. Soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm. 6. Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or medical castration), with serum testosterone \< 50 ng/ dL (\< 1.73 nmol/L) at screening. 7. Must have progressed during or after at least one second-generation androgen receptor pathway inhibitor (abiraterone acetate, enzalutamide, apalutamide, darolutamide) given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 castrate- resistant prostate cancer (CRPC), or metastatic CRPC. Note: Subjects may have previously received taxane-based chemotherapy for metastatic castration-sensitive prostate cancer (mCSPC), and sipuleucel-T, olaparib, Pluvicto (Lutetium (177Lu) vipivotide tetraxetan), and/or radium-223 for castrate -resistant prostate cancer. The number of patients who have received both taxanes and/or platinum in a CRPC setting will be limited to 5/15 in the first stage and thereby sponsor investigator approval is required prior to enrollment of patients who meet above criteria. 8. Presence of at least one of the following: * Presence of visceral metastases or high-volume disease (\> 4 sites of metastases) on conventional imaging (CT/MRI/bone scan) with a PSA ≤ 5. * Predominantly lytic bone metastasis. * Bulky (≥5 cm) lymphadenopathy OR bulky (≥5 cm) high-grade (Gleason ≥8) tumor mass in the prostate/pelvis. * Serum chromogranin A level ≥ 5× upper limit of normal (ULN) and/or serum neuron specific enolase (NSE) ≥ 2× ULN. * Prostate adenocarcinoma with IHC staining for neuroendocrine markers (positive staining of chromogranin A or synaptophysin). * Alterations in at least two of the three tumor suppressor genes: TP53, RB1 and PTEN on genomic testing. * Progression to CRPC within 6 months or less of initiation of hormonal therapy. * Poorly differentiated or transdifferentiated carcinoma. * PSMA negative/FDG avid disease on PET scan. 9. Recovery of adverse events (AEs), including immune-related adverse events (irAEs), to baseline or ≤ Grade 1 severity (CTCAE v5) related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy (eg, physiological replacement of corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ Grade 2 hypomagnesemia, ≤ Grade 2 neuropathy are permitted. 10. 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 2 weeks of sample collection * Absolute Neutrophil Count (ANC) ≥ 1500/mm3 without granulocyte colony-stimulating factor support within 2 weeks of sample collection * Hemoglobin (Hgb) ≥ 9 g/dL without transfusion within 2 weeks of sample collection. * Calculated creatinine clearance1 ≥ 40 mL/min * Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine * 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; ≤ 5 × 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 × ULN * Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 × ULN 11. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception during the course of the study and for 96 days after the last dose of study drug. 12. Projected life expectancy of at least 6 months as determined by treating investigator. 13. 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. Pure small cell carcinoma of the prostate. 2. Prior treatment with zanzalintinib. 3. Imminent or established spinal cord compression based on clinical and/or imaging findings. 4. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study drug. 5. Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 2 weeks of start of investigational agent and during the study. Concomitant use of megestrol acetate or leuprolide is permitted. The anti-androgen abiraterone is permitted up to 1 week prior to the first dose of study drug. Other types of hormonal therapies with similar use require prior approval of the Sponsor Investigator. 6…

Reproduced word-for-word from the public registry record — the study team can answer questions about it.