Cabozantinib plus atezolizumab offers hope to patients with mCRPC who progress on novel hormonal therapy

Patients with metastatic castration-resistant prostate cancer (mCRPC) have a very poor prognosis, and a high unmet medical need. The CONTACT-02 study is the first phase III study of a tyrosine kinase inhibitor – immune checkpoint inhibitor (TKI-ICI) combination to show statistically significant improvement in progression-free survival, supporting the use of cabozantinib plus atezolizumab as a potential new treatment option in this patient population.  

Patients with mCRPC and extrapelvic nodal or visceral disease who have progressed on one prior line of novel hormonal therapy (NHT) comprise a population with a poor prognosis. Cabozantinib, a multi-targeted tyrosine kinase inhibitor, promotes an immune-permissive tumour environment and may enhance the response to immune checkpoint inhibitors, such as atezolizumab. Previously, one cohort of the ongoing phase Ib COSMIC-021 study showed promising efficacy of cabozantinib plus atezolizumab in patients with mCRPC that had progressed in soft tissue during or after treatment with enzalutamide and/or abiraterone for metastatic disease. The phase III CONTACT-02 study evaluates cabozantinib plus atezolizumab versus a second course of NHT in mCRPC with measurable extrapelvic soft tissue metastasis after progression on a first NHT.

Methods

Participants were randomised 1:1 to receive cabozantinib (40 mg PO QD) plus atezolizumab (1.200 mg IV Q3W) or second-line NHT, consisting of abiraterone (1000 mg PO QD) plus prednisone (5 mg PO BID) or enzalutamide (160 mg PO QD). Key eligibility criteria were mCRPC with disease progression on one prior line of NHT, measurable extrapelvic nodal or visceral disease, ECOG performance status ≤1, and ongoing androgen deprivation therapy. Treatment with docetaxel was allowed for metastatic castration-sensitive prostate cancer (mCSPC). Co-primary endpoints were radiographic progression-free survival (rPFS), assessed by a blinded independent radiology committee (BIRC) according to RECIST v1.1 in the first 400 randomised patients, and overall survival (OS) assessed in all randomised patients. The secondary endpoint was the overall response rate (ORR), assessed by a BIRC according to RECIST v1.1. All analyses were done on an intention-to-treat basis.

Results

At the data cut-off on February 28, 2023, 507 patients were randomised to receive cabozantinib plus atezolizumab (n=253) or second NHT (n=254). Baseline and clinical characteristics were balanced between treatment arms. Median follow-up was 12.0 months for all randomised patients and 14.3 months for the first 400 randomised patients. Median rPFS was significantly longer for patients treated with cabozantinib plus atezolizumab versus second NHT(6.3 vs. 4.2 months; HR [95% CI]: 0.65 [0.50-0.84], p= 0.0007), with similar results found for subgroups of patients with liver metastases (6.2 vs. 2.1 months; HR [95% CI]: 0.43 [0.27- 0.68]) and patients who previously received docetaxel for mCSPC (8.8 vs. 4.1 months; HR [95% CI]: 0.57 [0.34-0.97]). In patients with a follow-up ≥6 months, ORR was higher in the cabozantinib-atezolizumab group, compared with the second NHT group (14% vs. 4%). The median duration of response was 9.7 months in the cabozantinib-atezolizumab group and not reached in the second NHT group, and the time to response was 2.3 versus 4.6 months. OS data were immature but a trend for OS benefit with cabozantinib-atezolizumab vs. second NHT was observed, including in high-risk subgroups.

Treatment-emergent adverse events (TEAEs) occurred in 97% of patients in the cabozantinib-atezolizumab group and 87% of patients in the second NHT group. Furthermore, grade 3 or 4 TEAEs occurred in 48% of patients in the cabozantinib-atezolizumab group and 23% of patients in the second NHT group, while grade 5 TEAEs occurred in 8% and 12% of patients, respectively, none of them was treatment-related. TEAEs led to the discontinuation of all treatment components in 5% of patients in the cabozantinib-atezolizumab group and 2% of patients in the NHT group.

Conclusions

In patients with mCRPC and extrapelvic nodal or visceral disease who have progressed on one prior line of NHT, treatment with cabozantinib-atezolizumab resulted in a significant and clinically meaningful improvement in rPFS, compared with second NHT. The survival benefits were most pronounced in patients with liver metastases and patients who previously received docetaxel for mCSPC. Toxicities were manageable in both treatment arms.

Reference

Agarawal N, et al. CONTACT-2: phase 3 study of cabozantinib (C) plus atezolizumab (A) vs second novel hormonal therapy (NHT) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Presented at ASCO GU 2024; Abstract 18.