Cabozantinib/atezolizumab improves PFS, shows no significant OS benefit in mCRPC

Data from the final overall survival (OS) analysis from the phase 3 CONTACT-02 trial (NCT04446117) favored the combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) vs a second novel hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC), though the trend did not achieve statistical significance.¹

Neeraj Agarwal, MD, FASCO

The data were presented at the 2024 European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain.

Preliminary findings from the CONTACT-02 trial were presented earlier this year at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California, showing that the trial met the co-primary end point of progression-free survival (PFS) in patients with mCRPC.² In the intent-to-treat (ITT) population, the median PFS was 6.3 months (95% CI, 6.2-8.8) in the cabozantinib/atezolizumab (cabo/atezo ) arm vs 4.2 months (95% CI, 3.7-5.7) in the second NHT arm (HR, 0.65; 95% CI, 0.50-0.84; P = .0007).

In patients with liver metastasis, the median PFS was 6.2 months in the combination arm vs 2.1 months in the control arm (HR, 0.43; 95% CI, 0.27-0.68). In patients with bone metastasis, the median PFS was 6.3 months in the combination arm vs 4.1 months in the control arm (HR, 0.67; 95% CI, 0.50-0.88).

The data presented at ESMO focused on findings from the trial’s second co-primary end point of OS. At a median follow-up of 24 months, OS in the ITT population was 14.8 months (95% CI, 13.4-16.7) in the cabo/atezo arm vs 15.0 months (95% CI, 13.0-18.5) in the second NHT arm (HR, 0.89; 95% CI, 0.72-1.10; P = .30). In total, there were 175 OS events among patients who received cabo/atezo compared with 179 among patients who received a second NHT.

Neeraj Agarwal, MD, FASCO, who presented the data on behalf of the CONTACT-02 investigators, added during the presentation, “If you look at the forest plots for subgroups, which were pre-specified, we can see that patients with liver metastasis and bone metastasis seem to derive survival advantage with cabo/atezo.”

Specifically, in patients with liver metastasis, the combination of cabozantinib and atezolizumab was associated with a 32% reduction in the risk of death vs a second NHT (HR, 0.68; 95% CI, 0.47-1.00; P = .051). In this subgroup, the median OS was 12.2 months (95% CI, 8.8-13.8) with cabo/atezo vs 7.1 months (95% CI, 5.3-10.4) with a second NHT.

In patients with bone metastasis, the median OS was 13.8 months (95% CI, 11.9-16.3) in the cabo/atezo cohort vs 11.6 months (95% CI, 10.5-14.1) in the second NHT cohort, translating to a 21% reduction in the risk of death in the treatment arm (HR, 0.79; 95% CI, 0.63-1.00; P = .046).

Regarding the trial’s other clinically relevant end points, the time to chemotherapy was 19.6 months (95% CI, 16.2-26.9) among patients who received cabo/atezo compared with 10.4 months (95% CI, 8.3-15.3) among those who received a second NHT (HR, 0.59; 95% CI, 0.45-0.77). The median time to deterioration in EORTC QLQ-C30 Global Health Status was 4.1 months (95% CI, 2.6-4.2) in the cabo/atezo arm vs 4.2 months (95% CI, 3.0-4.3) in the second NHT arm (HR, 1.19; 95% CI, 0.94-1.51). The time to symptomatic skeletal events was 24.0 months (95% CI, 16.3-NE) in the cabo/atezo arm and 17.3 months (95% CI, 13.2-NE) in the second NHT arm (HR, 0.73; 95% CI, 0.44-1.20).

According to the investigators, the safety profile for cabozantinib plus atezolizumab was consistent with other CONTACT trials and other ICI/TKI combinations. Grade 3-4 treatment-related adverse events (AEs) were experienced by 40% of patients in the cabo/atezo arm and 8% of patients in the second NHT arm.

“Despite recent advancements, outcomes remain poor for patients with metastatic castration-resistant prostate cancer whose disease progresses after novel hormonal therapy–particularly those with liver metastases,” said Agarwal, who is the senior director for clinical research at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, in a news release on the data.³ “I believe there is a critical need for novel agents with a new mechanism of action that are broadly accessible to patients and can delay disease progression. The positive results from CONTACT-02, especially in the subset of patients with liver metastasis, reinforce the therapeutic potential of cabozantinib in combination with atezolizumab for these patients.”

In total, the global, multicenter, open-label, phase 3 CONTACT-02 trial enrolled 575 patients with mCRPC who had measurable extrapelvic soft tissue metastasis and had progressed on 1 prior NHT. Patients were randomly assigned 1:1 to receive cabozantinib, 40 mg PO QD plus atezolizumab 1200 mg IV Q3W (n = 289) or to a second NHT of either abiraterone (Zytiga), 1000 mg PO QD plus prednisone 5 mg PO BID or enzalutamide (Xtandi), 160 mg PO QD (n = 286).

The trial’s co-primary end points were PFS and OS in the ITT population. Other key end points included time to chemotherapy and symptomatic skeletal events, quality of life, and safety.

Overall, the authors wrote, “Cabo/atezo, a treatment option with a novel mechanism of action, may be useful for selected patients with mCRPC who have progressed on an NHT.”

According to the news release from Exelixis, the company plans to submit a new drug application to the FDA later this year for the combination of cabozantinib plus atezolizumab in mCRPC.²

However, in a news release from Ipsen, who holds exclusive rights for the commercialization and further clinical development of cabozantinib outside of the US and Japan, the company announced that they would not be pursuing "regulatory submissions for the combination regimen in countries where we have commercialization rights (outside of the US and Japan)."⁴

References

1. Agarwal N, Azad AA, Galceran JC, et al. Cabozantinib (C) plus atezolizumab (A) versus 2nd novel hormonal therapy (NHT) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Final overall survival (OS) results of the phase 3, randomized, CONTACT-02 study. Presented at: 2024 ESMO Congress. September 13-17, 2024. Abstract LBA67. https://esmocongress.esmo.org/esmo/esmo2024/en-GB/presentation/641313

2. Agarwal N, Azad A, Carles J, et al. CONTACT-02: 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). J Clin Oncol. 2024;42(suppl 4):18. doi:10.1200/JCO.2024.42.4_suppl.18

3. Exelixis presents final overall survival results from phase 3 CONTACT-02 pivotal study evaluating cabozantinib in combination with an immune checkpoint inhibitor in metastatic castration-resistant prostate cancer at ESMO 2024. News release. Exelixis. September 15, 2024. Accessed September 17, 2024. https://ir.exelixis.com/news-releases/news-release-details/exelixis-presents-final-overall-survival-results-phase-3-contact

4. Ipsen provides update on CONTACT-02 Phase III trial in metastatic castration-resistant prostate cancer following final overall survival analysis. News release. Ipsen. September 15, 2024. Accessed September 17, 2024. https://www.ipsen.com/press-releases/ipsen-provides-update-on-contact-02-phase-iii-trial-in-metastatic-castration-resistant-prostate-cancer-following-final-overall-survival-analysis-2946293/