Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm across many solid tumors. However, they have demonstrated limited activity as single agents in prostate cancer. Despite the advent of many new therapeutic agents in the last two decades, metastatic castration-resistant prostate cancer (mCRPC) remains a highly lethal disease. Preclinical studies suggested that cabozantinib could activate neutrophil-dependent anti-tumor activity in aggressive PTEN/p53-deficient prostate cancer. In early clinical studies, cabozantinib in combination with PD-L1 antibody has demonstrated encouraging activity in mCRPC. Building on these observations, this study aims to investigate the efficacy of cabozantinib plus nivolumab (PD-1 inhibitor) in patients with mCRPC. Methods: This is an investigator-initiated, phase II, multi-center, open-label, single-arm study of the combination of cabozantinib plus nivolumab in mCRPC. Patients diagnosed with mCRPC with histologically or cytologically confirmed prostate adenocarcinoma (without small cell or neuroendocrine component), and prior exposure to one taxane chemotherapy (or ineligible for taxane or refuse taxane) and one ARSI (in the castration-sensitive or castration-resistant setting) are eligible for enrollment. Enrollment of patients with only non-measurable disease will be capped at 50%. Patients who have received more than one line of chemotherapy (including both castration-sensitive and castration-resistant setting) are not eligible. Eligible patients will undergo a baseline biopsy and will subsequently receive treatment with cabozantinib 40 mg PO daily and nivolumab 480 mg IV every four weeks (cycle length=28 days). On-treatment biopsy will be performed during cycle 2. Patients will continue treatment until radiographic progression, intolerable toxicity, death, or withdrawal. The primary endpoint is 6-month radiographic progression-free survival (rPFS) by RECIST 1.1 for soft tissue, and PCWG3 criteria for bone metastases. The study will enroll 50 patients. A Simon’s two-stage MiniMax design is used with 80% power and one-sided significance level of 5%, hypothesizing that the true 6-month rPFS rate is >30%. Key secondary endpoints include PSA response, overall response rate, overall survival, and conversion of circulating tumor cell (CTC) count (from ≥5 cells/7.5 mL blood at baseline to <5 cells/7.5 mL). Key explorative objectives include evaluating the immunomodulatory effects of, and mechanisms of response/resistance to, cabozantinib/nivolumab via sequential assessments of biopsy tissue and blood correlates. Correlations between the presence of germline/somatic pathogenic alterations and treatment efficacy, baseline CTC count/tumor cfDNA and tumor burden on imaging will also be evaluated. This trial is enrolling through the Hoosier Cancer Research Network. Clinical trial information: NCT05502315.