The combination of the tyrosine kinase inhibitor cabozantinib (multiple targets, including MET, AXL, VEGFR2, RET, and FLT ) plus the monoclonal antibody atezolizumab achieved statistically significant improvement in progression-free survival compared with second-line novel hormonal therapy in patients with previously treated metastatic castration-resistant prostate cancer, according to an analysis of the phase III CONTACT-02 trial presented at the 2024 ASCO Genitourinary Cancers Symposium.¹

The median progression-free survival, according to an intention-to-treat analysis by blinded independent review, was 6.3 months with cabozantinib plus atezolizumab vs 4.2 months with the novel hormonal therapy, representing a 35% reduction in the risk of disease progression or death favoring the tyrosine kinase inhibitor and PD-L1 inhibitor combination (P = .0007). Median progression-free survival rate at 6 months was 60% vs 42%, and at 12 months, it was 25% vs 18%, respectively.

“These data support cabozantinib plus atezolizumab as a potential new treatment option for patients with metastatic castration-resistant prostate cancer who have experienced disease progression on a novel hormone therapy....”

— Neeraj Agarwal, MD, FASCO

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“CONTACT-02 is the first phase III trial of a [tyrosine kinase inhibitor and immune checkpoint inhibitor] combination to show statistically significant and clinically meaningful improvement in progression-free survival in patients with metastatic castration-resistant prostate cancer,” said lead author Neeraj Agarwal, MD, FASCO, of the Huntsman Cancer Institute of the University of Utah. “These data support cabozantinib plus atezolizumab as a potential new treatment option for patients with metastatic castration-resistant prostate cancer who have experienced disease progression on a novel hormonal therapy, including these patients with a very poor prognosis who have extrapelvic nodal or visceral metastases.”

Despite these results favoring the combination of cabozantinib plus atezolizumab, the formal discussant of CONTACT-02, Kim N. Chi, MD, of the British Columbia Cancer–Vancouver Center, Canada, had some reservations and did not consider it to be a practice-changing therapy (see Expert Point of View).

Study Details

The CONTACT-02 study randomly assigned 507 patients 1:1 to receive treatment with cabozantinib at 40 mg orally once a day plus atezolizumab at 1,200 mg intravenously every 3 weeks (n = 253) or second-line novel hormonal therapy (n = 254; abiraterone at 1,000 mg/d plus prednisone twice a day or enzalutamide at 160 mg orally once a day). The median duration of first novel hormonal therapy was around 12 months.

The trial’s dual primary endpoints were progression-free survival and overall survival in the intention-to-treat population. Secondary endpoints included objective response rate, radiographic progression–free survival, prostate-specific antigen (PSA) response rate, and safety. Other key endpoints included time to PSA disease progression, symptomatic skeletal events, chemotherapy, and pain progression.

Participants had adenocarcinoma histology and disease progression after prior treatment, including novel hormonal therapy. Additional eligibility criteria included having measurable extrapelvic soft-tissue metastasis and an Eastern Cooperative Oncology Group performance status of 0 or 1. Previous treatment with docetaxel for locally advanced or metastatic castration-sensitive prostate cancer was allowed. The median patient age was 71; the median PSA level at baseline was between 25 and 34 ng/mL. The proportion of patients with bone metastases (around 80%), visceral metastases (around 40%), and liver metastases (around 24%) was similar in both arms.

Key Findings

Median follow-up was 14.3 months. In addition to the progression-free survival data previously reported here, mean radiographic progression–free survival was 6.3 months with the combination therapy vs 4.1 months with the novel hormone therapy with a hazard ratio of 0.65, translating into a 35% reduction in the risk of disease progression or death favoring the novel combination.

The progression-free survival benefit favoring the combination was evident in most prespecified subgroups. For example, a 57% reduction in the risk of disease progression or death in patients with liver metastases, a 43% reduction in the risk of progression or death in patients previously treated with docetaxel, and a 33% reduction in the risk of progression or death in patients with bone metastases were demonstrated.

The overall survival data, one of the dual primary endpoints, were not yet mature. In the intention-to-treat population, the interim analysis of survival showed a median overall survival of 16.7 months with cabozantinib plus atezolizumab compared with 14.6 months with the novel hormonal therapy, a 21% risk reduction that was not significant. The rate of overall survival at 6 months was 87% vs 79%, respectively; at 12 months, the rates were 62% and 57%, respectively.

After a follow-up of at least 6 months, the objective response rate was 14% with cabozantinib plus atezolizumab vs 4% for novel hormonal therapy. The disease control rate was 73% vs 55%, respectively. Partial responses were reported in 13% and 4% of patients; and 1% of those in the cabozantinib arm had a complete response. More patients in the cabozantinib arm experienced a reduction in the size of target lesions.

The median time to chemotherapy was not reached with both cabozantinib plus atezolizumab and novel hormonal therapy. The median time to symptomatic skeletal events was 16.3 months vs 13.2 months, respectively, and the median time to pain progression was identical in both arms. The median time to deterioration in quality of life was 2.2 months in both treatment arms. A PSA response was observed in 10% and 12% of patients, respectively.

“Patient-reported outcome measures were similar between arms, suggesting that the combination therapy did not adversely impact quality of life while improving outcomes,” Dr. Agarwal said.

Toxicity

Treatment-related adverse events that led to discontinuation of any study component were observed in 13% of patients given cabozantinib plus atezolizumab compared with 2% of those given novel hormone therapy. Any-grade treatment-emergent adverse events occurred in 97% of those who received cabozantinib vs 87% of those who received novel hormonal therapy. Grade 3 and 4 toxicities were reported in 48% vs 23%, respectively. The most common grade 3 or 4 treatment-related adverse events were diarrhea (4% vs < 1%), fatigue (4% vs 1%), anemia (6% vs 7%), and hypertension (7% vs 2%). The most common any-grade treatment-emergent adverse events 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 treatment-related adverse events occurred in 8% and 12%, respectively. 

DISCLOSURE: Dr. Agarwal has received research funding from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, Telix, and Tracon.

REFERENCE

1. Agarwal N, Azad A, Carles J, et al: CONTACT-2. 2024 ASCO Genitourinary Cancers Symposium. Abstract 18. Presented January 25, 2024.

EXPERT POINT OF VIEW

“CONTACT-02 is a positive trial. It is a first for the tyrosine kinase inhibitor plus immunotherapy combination in metastatic castration-resistant prostate cancer,” stated formal discussant, Kim N. Chi, MD, of the British Columbia Cancer–Vancouver Center, Canada. “There is a rationale for this combination in both preclinical and clinical research, suggesting cabozantinib may potentiate the immunomodulatory effects of immunotherapy.”

That said, the study had its limitations, Dr. Chi continued. “There was a 40% screen failure rate, the difference in radiographic progression–free survival is modest, and it was a small trial. Of note, there is no difference in overall survival, and the patient-reported outcomes were not improved with the combination of a tyrosine kinase inhibitor plus immunotherapy. Pain progression deteriorated within 4 months, and quality of life deteriorated within 2 months.”

Kim N. Chi, MD

Dr. Chi also said there are now better options for an androgen receptor pathway inhibitor switch for patients with measurable disease and visceral metastasis than the two novel hormone therapies used in the control arm of the trial. “However, an androgen receptor pathway inhibitor may be appropriate in selected patients,” he noted.

“Did the patients in the control arm lose an opportunity to get a better therapy than the second novel hormone therapy used in the trial? I cannot recommend this as a practice-changing trial at this time,” Dr. Chi stated. 

DISCLOSURE: Dr. Chi has received honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche; has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Bayer, Janssen, Merck, POINT Biopharma, and Roche; and has received institutional research funding from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, ESSA Pharma, Janssen, Merck, Novartis, Pfizer, Roche, and Sanofi.