The phase 3 CONTACT-02 study, presented at the 2024 ESMO Congress, revealed that cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) did not significantly improve overall survival (OS) compared to a second novel hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on a prior NHT. Although the combination met its other co-primary endpoint of improved progression-free survival (PFS), the OS results raise questions about its broad applicability in this patient population.
Overall Survival Analysis
At a median follow-up of 24 months, the combination of cabozantinib and atezolizumab showed an 11% reduction in the risk of death (HR, 0.89; 95% CI, 0.72–1.10; P = .30) compared to the second NHT in the intention-to-treat (ITT) population (n = 289). The median OS was 14.8 months with the combination (n = 253; 95% CI, 13.4-16.7) and 15 months with the second NHT (n = 254; 95% CI, 13.0-18.5).
Subgroup Analysis
Subgroup analyses indicated a trend favoring the cabozantinib combination in patients with liver metastases (n = 132) and bone metastases (n = 446). In the liver metastases subgroup, the combination reduced the risk of death by approximately 32% (HR, 0.68; 95% CI, 0.47–1.00; P = .051), with a median OS of 12.2 months (95% CI, 8.8-13.8) compared to 7.1 months (95% CI, 5.3-10.4) with the second NHT. For patients with bone metastases, the hazard ratio was 0.79 (95% CI, 0.63–1.00; P = .046), with median OS of 13.8 months (95% CI, 11.9-16.3) vs 11.6 months (95% CI, 10.5-14.1) for the combination and second NHT arms, respectively.
Progression-Free Survival
Previously presented at the 2024 Genitourinary Cancers Symposium, the primary analysis of CONTACT-02 demonstrated a statistically significant and clinically meaningful improvement in PFS with cabozantinib plus atezolizumab. At a median follow-up of 14.3 months, the median PFS per blinded independent review committee (BIRC) assessment was 6.3 months (95% CI, 6.2-8.8) in the combination arm versus 4.2 months (95% CI, 3.7-5.7) in the NHT arm (HR, 0.65; 95% CI, 0.50-0.84; P = .0007).
The PFS benefit was particularly notable in patients with liver metastases, with a median PFS of 6.2 months (95% CI, 4.0-9.1) with the combination versus 2.1 months (95% CI, 2.0-2.3) with the second NHT (HR, 0.43; 95% CI, 0.27-0.68). For patients with bone metastases, the median PFS was 6.3 months (95% CI, 6.0-8.6) versus 4.1 months (95% CI, 2.8-5.7) in the respective arms (HR, 0.67; 95% CI, 0.50-0.88).
Study Design
CONTACT-02 enrolled patients with mCRPC who had progressed following one prior NHT. Patients were randomized 1:1 to receive either 40 mg of oral cabozantinib daily plus 1200 mg of intravenous atezolizumab every 3 weeks, or a second NHT (abiraterone acetate plus prednisone or enzalutamide). The primary endpoints were PFS and OS. Secondary endpoints included overall response rate, radiographic PFS, PSA response rate, and safety.
Safety Profile
All safety-evaluable patients in the cabozantinib combination arm (n = 284) experienced any treatment-emergent adverse event (TEAE) compared with 92% in the second NHT arm (n = 284). The frequency of grade 3/4 TEAEs was higher with the cabozantinib combination (56%) versus the second NHT (26%). Common any-grade TEAEs included diarrhea, decreased appetite, fatigue, and anemia.
Expert Commentary
According to lead study author Neeraj Agarwal, MD, a professor of medicine at the University of Utah, Huntsman Cancer Institute, the combination may be useful for selected patients with mCRPC who have progressed on an NHT, especially those with liver metastasis whose disease may be evolving to an androgen receptor–indifferentiated phenotype. "OS, the second primary end point, favored cabozantinib plus atezolizumab, but did not achieve statistical significance. However, a strong survival advantage was seen in patients with liver metastasis... Cabozantinib plus atezolizumab, a treatment option with a novel mechanism of action, may therefore be useful for selected patients with mCRPC who have progressed on an NHT,"
