Cabozantinib plus atezolizumab delays disease progression in mCRPC

Findings from the phase 3 CONTACT-02 trial (NCT04446117) showed that the combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) significantly reduced the risk of disease progression or death compared with treatment with a second novel hormonal therapy (NHT; abiraterone [Zytiga] or enzalutamide [Xtandi]) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received an initial NHT.¹

Neeraj Agarwal, MD

Results from the study presented at the 2024 ASCO Genitourinary Cancers Symposium showed that, across the progression-free survival (PFS) intent-to-treat (ITT) population, the median PFS per blinded independent reviewee committee (BIRC) assessment was 6.3 months (95% CI, 6.2-8.8) with the cabozantinib combination vs 4.2 months (95% CI, 3.7-5.7) in the NHT arm (HR, 0.65; 95% CI, 0.50-0.84; P = .0007). Additionally, the PFS rate in each respective arm was 60% vs 42% at 6 months and 25% vs 18% at 12 months.

The median PFS per BIRC across the ITT population was 6.3 months with cabozantinib plus atezolizumab vs 4.2 months with NHT (HR, 0.64; 95% CI, 0.50-0.81; P = .0002). Moreover, data highlighted a median radiographic PFS (rPFS) of 6.3 months vs 4.1 months in each respective arm in the PFS ITT population (HR, 0.62; 95% CI, 0.48-0.81).

The PFS benefit with the cabozantinib-based regimen extended to patients across most prespecified subgroups. Of note, the experimental combination led to a PFS improvement in those with liver metastases (HR, 0.43; 95% CI, 0.27-0.68), patients who previously received docetaxel (HR, 0.57; 95% CI, 0.34-0.97), and those with bone metastases (HR, 0.67; 95% CI, 0.50-0.88).

Findings from the interim overall survival (OS) analysis in the ITT population indicated a median OS of 16.7 months (95% CI, 15.1-20.9) in the cabozantinib arm compared with 14.6 months (95% CI, 11.6-22.1) in the NHT arm (HR, 0.79; 95% CI, 0.58-1.07; P = .13). The 6-month and 12-month OS rates in each arm, respectively, were 87% vs 79% and 62% vs 57%.

In the cabozantinib and NHT arms, respectively, the objective response rate (ORR) was 14% vs 4%, and the disease control rate (DCR) was 73% vs 55%. Partial responses were reported in 13% and 4% of patients; 1% of those in the cabozantinib arm had a complete response. Additionally, more patients in the cabozantinib arm experienced a reduction in the size of target lesions.

“CONTACT-02 is the first phase 3 trial of a [tyrosine kinase inhibitor and immune checkpoint inhibitor] combination to show statistically significant improvement in PFS in patients with [metastatic] CRPC,” presenting author Neeraj Agarwal, MD, a professor of medicine, presidential endowed chair of cancer research, and director of both the Genitourinary Oncology (GU) Program and the Center of Investigational Therapeutics at the Huntsman Cancer Institute (HCI) of the University of Utah, said. “These data support [cabozantinib plus atezolizumab] as a potential new treatment option for patients with [metastatic] CRPC who have progressed on an NHT.”

In the CONTACT-02 study, 507 patients were randomly assigned 1:1 to receive cabozantinib at 40 mg orally once a day plus atezolizumab at 1200 mg intravenously every 3 weeks (n = 253) or second-line NHT (n = 254). Treatment with NHT included abiraterone acetate (Zytiga) at 1000 mg orally once a day plus 5 mg of prednisone orally twice a day or enzalutamide (Xtandi) at 160 mg orally once a day.

The trial’s dual primary end points were PFS in the PFS ITT population—which included the first 400 patients to be randomly assigned—as assessed by BIRC per RECIST v1.1 guidelines and OS in the ITT population. Secondary end points included ORR per RECIST v1.1 criteria, PFS in the ITT population, rPFS, prostate specific antigen (PSA) response rate, and safety. Time to PSA progression, symptomatic skeletal events, chemotherapy, and pain progression were other key end points.

Patients 18 years and older with adenocarcinoma histology who had disease progression following prior treatment including NHT were able to enroll on the trial. Additional eligibility criteria included having measurable extrapelvic soft tissue metastasis per RECIST v1.1 guidelines and an ECOG performance status of 0 or 1. Those who were previously treated with docetaxel for locally advanced or metastatic castration-sensitive prostate cancer were also eligible for enrollment.

The median age was 71 years in the cabozantinib arm (range, 48-91), and the NHT arm (range, 45-89). Additionally, a comparable proportion of patients in each respective arm had bone metastases (81% vs 77%), visceral metastases (39% vs 41%), and liver metastases (23% vs 24%).

The median time to chemotherapy was not reached (NR) in both the cabozantinib (95% CI, 17.3-not evaluable [NE]) and NHT arms (95% CI, 11.6-NE; HR, 0.56; 95% CI, 0.39-0.82). The median time to symptomatic skeletal events was 16.3 months (95% CI, 11.5-NE) compared with 13.2 months (95% CI, 11.9-22.0) in each respective arm (HR, 0.62; 95% CI, 0.33-1.16), and the median time to pain progression was 4.3 months (95% CI, 3.1-4.7) vs 4.3 months (95% CI, 3.0-6.3; HR, 1.06; 95% CI, 0.80-1.39). Investigators also reported a median time to deterioration of 2.2 months (95% CI, 2.1-2.3) and 2.2 months (95% CI, 2.1-2.3) in each arm via European Organization for Research and Treatment of Cancer Quality of Life C30 questionnaire Global Health Status (HR, 1.10; 95% CI, 0.85-1.44). Additionally, 10% and 12% of patients in each arm had a PSA response.

The median dose intensity of cabozantinib, atezolizumab, and NHT, respectively, was 94.0% (range, 22.0%-100.0%), 83.0% (range, 21.0%-100.0%), and 100.0% (range, 50.0%-100.8%). Additionally, treatment-related adverse effects (TRAEs) leading to discontinuation of any study component affected 13% of patients in the cabozantinib arm compared with 2% in the NHT arm.

Any-grade treatment-emergent AEs (TEAEs) occurred in 97% of the cabozantinib arm vs 87% of the NHT arm, as well as grade 3/4 toxicities in 48% vs 23%, respectively. The most common any-grade TEAEs in each respective arm included diarrhea (40% vs 4%), decreased appetite (38% vs 12%), fatigue (27% vs 17%), nausea (25% vs 11%), and asthenia (25% vs 11%). Grade 5 TEAEs were reported in 8% and 12% of patients in each arm; there were no grade 5 TRAEs.

Reference

1. Agarwal N, Azad A, Carles J, 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). J Clin Oncol. 2024;42(suppl 4):18. doi:10.1200/JCO.2024.42.4_suppl.18