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

Abstract

187 Background: Advanced metastatic castration-resistant prostate cancer (mCRPC) remains a largely lethal disease with limited treatment options. Cabozantinib is a tyrosine kinase inhibitor targeting VEGFR, MET, and AXL that has demonstrated activity in mCRPC patients, particularly those with bone and liver metastases. The CONTACT-02 trial showed efficacy of cabozantinib combined with the PD-L1 inhibitor atezolizumab in mCRPC. Building upon this background, we investigated the efficacy of cabozantinib plus nivolumab, a PD-1 inhibitor, in patients with mCRPC (NCT05502315). Methods: This prospective, multi-center, single-arm, two-stage open-label phase II study enrolled patients with progressive mCRPC per PCWG3 criteria and prior androgen receptor pathway inhibitor exposure. Prior taxane was permitted. Patients received cabozantinib 40 mg daily orally plus nivolumab 480 mg IV every 4 weeks. The primary endpoint was radiographic progression-free survival (rPFS) at 6 months by RECIST 1.1/PCWG3. A Simon two-stage MiniMax design was used with 80% power, hypothesizing 6-month rPFS >30%. Stage 1 required ≥7 of 24 patients to be progression-free at 6 months to continue to Stage 2, which will enroll an additional 23 patients. Results: Twenty-four patients were enrolled in Stage 1 (median age 71 years). Baseline characteristics: 50% (12/24) had de novo metastatic disease, 91.7% (n=22) had bone metastases, 29.2% (n=7) bone-only disease, 16.7% (n=4) visceral metastases, 66.7% (n=16) received prior chemotherapy, and 25% (n=6) prior ¹⁷⁷Lu-PSMA-617 therapy. Eight patients remained progression-free at 6 months, meeting continuation criteria for Stage 2. Median rPFS was 5.5 months (95% CI >3.6 months). Objective response rate was 17.6% (3/17 evaluable patients). Median baseline PSA was 28.05 ng/mL and median time to PSA progression was 1.87 (95% CI 1.81-3.78) months. One patient experienced PSA 50 . Grade ≥3 treatment-related adverse events occurred in 52% (n=12) of patients, with 5 treatment-related serious adverse events. Most common adverse events were anorexia 58% (n=14), diarrhea 58% (n=14), fatigue 54% (n=13), nausea 46% (n=11), anemia 38% (n=9), AST increase 38% (n=9), ALT increase 33% (n=8), constipation 33% (n=8), and hypothyroidism 29% (n=7). Conclusions: The CANOPY trial met its interim efficacy threshold, demonstrating activity of cabozantinib plus nivolumab in mCRPC patients. The combination showed manageable toxicity. The study continues to Stage 2 enrollment to further evaluate this promising combination therapy. Clinical trial information: NCT05502315 .