A phase 2 study of cabozantinib and nivolumab in metastatic castration resistant prostate cancer (CANOPY).

TPS302 Background: Advanced metastatic-castration-resistant prostate cancer (mCRPC) remains a lethal disease with limited treatment options. Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets VEGF, MET and AXL that has demonstrated activity in patients with mCRPC, particularly in individuals with bone and liver metastases. Studies have demonstrated anti-tumor activity of cabozantinib combined with atezolizumab, a programmed death ligand 1 targeting agent. In this study, we will investigate the efficacy of cabozantinib in combination with nivolumab, a programmed death 1 (PD-1) targeting agent, in patients with mCRPC. Methods: This is a prospective, multi-center, single arm, two-stage open label phase II study of cabozantinib combined with nivolumab in the treatment of patients with mCRPC. Eligible patients include those with histologically or cytologic evidence of prostate adenocarcinoma or mixed adenocarcinoma/neuroendocrine tumors, progressive mCRPC disease defined by PCWG3 criteria, exposure to one prior androgen receptor pathway inhibitor (ARPI), and one prior taxane chemotherapy (in hormone sensitive or castration resistant setting). Exclusion criteria include pure small cell carcinoma, received prior immune checkpoint inhibitor, received prior cabozantinib, and received >1 line of chemotherapy (including both hormone sensitive and castration resistant settings). Prior to treatment initiation, patients will receive a mandatory baseline biopsy. Eligible patients will receive treatment with cabozantinib (orally 40 mg daily) and nivolumab (intravenous 480 mg every 4 weeks). An on-treatment biopsy will be performed during cycle 2. Patients will continue on treatment until disease progression, unacceptable toxicity, death, or other reason (e.g., subject withdrawal). The primary endpoint is radiographic progression-free survival (rPFS) at 6 months by RECIST 1.1 for soft tissue and PCWG3 for bone metastasis. Secondary endpoints include PSA response per PCWG3, overall response rate (ORR), and overall survival (OS). For statistical analysis, a Simon’s two-stage MiniMax design will be used with 80% power and one-sided significance level of 5%, hypothesizing that the true 6-month rPFS rate is >30% and assuming the observed rate is 47%. Stage I of the trial will accrue 32 patients and the trial will proceed to stage II if > 9 patients are progression-free and living at 6 months. Stage II of the trial will accrue 18 more patients, and we will conclude that the study treatment is associated with a 6-month PFS rate > 30% if ≥ 21 subjects among 50 enrolled subjects are progression-free and alive at 6 months. This trial is conducted through the Hoosier Cancer Research Network and is actively accruing patients at the University of California San Diego, UT Southwestern, University of Chicago, and University of Wisconsin. Clinical trial information: NCT05502315 .