The combination of cabozantinib and atezolizumab improved radiographic progression-free survival (rPFS) versus a switch to a second novel hormonal agent (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on a first NHT, according to findings from the phase 3 CONTACT-02 trial. Cabozantinib plus atezolizumab reduced the risk of progression or death by 35%, announced Neeraj Agarwal, MD, at the 2024 ASCO Genitourinary Cancers Symposium. Among patients assigned to cabozantinib-atezolizumab in the randomized trial, median rPFS was 6.3 months per a blinded independent radiology committee compared with 4.2 months assigned to a second NHT (hazard ratio [HR], 0.65; P=.0007).
CONTACT-02 is the first phase 3 study of a tyrosine kinase inhibitor plus an immune checkpoint inhibitor (ICI) to show a significant improvement in PFS in patients with mCRPC, said Dr Agarwal, of the Huntsman Cancer Institute at the University of Utah, Salt Lake City, adding that the findings support cabozantinib-atezolizumab as a potential new treatment option in this setting. “Cabozantinib-atezolizumab showed a statistically significant, and I'll argue, clinically meaningful, improvement in PFS versus second NHT in mCRPC, a patient population with a very poor prognosis,” he said.
Currently, median overall survival (OS) in patients with CRPC who have progressed on NHT is <2 years, with patients with visceral or liver metastases having the worst outcomes, noted Dr Agarwal. The median OS in CONTACT-02 was 14.6 months. Although the OS data were immature at the time of presentation, there was a trend for OS benefit with cabozantinib-atezolizumab versus second NHT, including in high-risk subgroups, such as those with liver metastasis, he observed. At an interim OS analysis in the intent-to-treat study population, OS favored the cabozantinib-atezolizumab arm at a median of 16.7 months compared with 14.6 months in the second NHT arm (HR, 0.79; P=.13).
CONTACT-02 evaluated cabozantinib plus atezolizumab versus a second NHT in 507 patients with mCRPC with measurable extrapelvic soft tissue metastasis (visceral or lymph node) after progression on a first NHT. Patients were randomized to oral cabozantinib once daily plus IV atezolizumab every 3 weeks or second-line NHT with either oral abiraterone plus prednisone or oral enzalutamide once a day. At baseline, the site of metastases was bone in about 80% of patients, visceral in about 40%, liver in 25%, and lymph nodes in approximately 75%. Twenty-three percent in each arm received prior docetaxel therapy.
The cabozantinib-atezolizumab combination was particularly effective in 2 prespecified subgroups of special interest: patients with liver metastases and those who had received docetaxel previously. Among patients with liver metastases, the median rPFS was 6.2 months in the doublet therapy arm versus 2.1 months in the NHT arm (HR, 0.43; 95% CI, 0.27-0.68). Among those with prior docetaxel treatment, the median rPFS was 8.8 versus 4.1 months, respectively (HR, 0.57; 95% CI, 0.34-0.97).
The safety profile of cabozantinib-atezolizumab was consistent with that reported for other cabozantinib-ICI combinations, “which are widely used and approved in the community, and we know how to manage them,” said Dr Agarwal. “We did not see any new safety signal.” Grade 5 treatment-emergent adverse events (AEs) occurred in 8% of the combination therapy arm and 12% of the switch NHT arm, and no grade 5 treatment-related AEs occurred in either arm. Treatment-related AEs led to the discontinuation of any treatment component in 13% of the combination arm and 2% of the second NHT arm.
Adequate control arm?
Invited discussant Kim N. Chi, MD, from the British Columbia Cancer Agency, Vancouver, Canada, said that the advantage of the combination on rPFS in CONTACT-02 was only modest, and referred to previous data from the COMET-1 study showing an improvement in rPFS of 6.6 months with cabozantinib monotherapy versus prednisone, with no difference in OS, in a more heavily pretreated population of patients with mCRPC. He then questioned the use of a second NHT for the control arm, noting that that it’s “not the best standard of care for this patient population with measurable disease and 40% visceral metastases.”