Novel Combination of Cabozantinib Plus Atezolizumab Shows Benefit in Patients With Advanced Prostate Cancer

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The combination of the small-molecule tyrosine kinase inhibitor cabozantinib (inhibits VEGF, AXL, MET, and others), plus the immune checkpoint inhibitor atezolizumab achieved encouraging activity in patients with metastatic castration-resistant prostate cancer, according to the results of COSMIC-021, a phase Ib trial presented at the 2020 Genitourinary Cancers Symposium.1 All of these patients had measurable and progressive soft-tissue metastasis, have had disease progression on prior enzalutamide and/or abiraterone treatment, and many had received prior chemotherapy. The objective response rate was 32%, and the disease control rate (objective response plus stable disease) was 80% at a median follow-up of 12.6 months.

“Given the poor prognosis for men with [metastatic castration-resistant prostate cancer], measurable visceral disease, and/or extrapelvic lymph node metastases who have had disease progression on novel hormone therapies, we are excited to observe clinically meaningful activity with the combination of cabozantinib and atezolizumab in this COSMIC-021 cohort,” said lead author Neeraj Agarwal, MD, of Huntsman Cancer Center, University of Utah, Salt Lake City.

“This magnitude of response has never been reported in the context of any immunotherapeutic combinatorial regimen in the metastatic castration-resistant prostate cancer setting.”
— Neeraj Agarwal, MD

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“This magnitude of response has never been reported in the context of any immunotherapeutic combination regimen in the metastatic castration-resistant prostate cancer setting,” he emphasized. Indeed, the results of COSMIC-021 accounted for the number 1 trending tweet reporting on the data presented in the symposium on Twitter.

“Emerging data suggest a tolerable safety profile and encouraging efficacy for this combination that may hold promise for these patients with limited treatment options, potentially buying more time before the need for treatment with chemotherapy. We look forward to additional results as the trial progresses,” Dr. Agarwal continued.

Emphasizing the need for a new therapy in this space, he said that the patient population represented in this cohort of ­COSMIC-021 would normally have only a modest benefit in survival with currently approved options such as novel hormonal agents, taxanes, radium-223, and sipuleucel-T.

“This is a patient population with a significant unmet need. We need better tolerated, more effective therapy,” Dr. Agarwal said.

Study Details

COSMIC-021 is a multicenter, phase Ib, open-label study with a dose-escalation phase and a multicohort expansion phase. The dose-escalation phase determined that the optimal dose of cabozantinib is 40 mg/d when used in combination with a 1,200-mg infusion of atezolizumab once every 3 weeks.

The expansion phase includes a total of 24 ­cohorts in 12 tumor types, including prostate cancer, and planned ­enrollment is for up to 1,720 patients. Dr. Agarwal’s presentation focused on an initial cohort of 44 patients with metastatic castration-resistant prostate cancer, which is being expanded to 130 patients after discussions with the U.S. Food and Drug Administration, he said. A phase III trial of the combination is planned and starting accrual soon.

The reported cohort enrolled patients with measurable disease by Response Evaluation Criteria in Solid Tumors, either with visceral metastases (34%) or extrapelvic lymphadenopathy (61%). Patients had to have had disease progression on one or two novel hormonal agents (such as abiraterone acetate or enzalutamide); 52% got both novel hormonal agents, and 27% received prior chemotherapy with docetaxel in the castration sensitive setting. Median age was 70 years.


  • Preliminary results suggest that the combination of cabozantinib plus atezolizumab may turn out to be an option for the treatment of metastatic prostate cancer that has progressed on other treatments.
  • The objective response rate was 32% and disease control rate was 80% at a median follow-up of 12.6 months.
  • A phase III study will be starting accrual soon.

The objective response rate was 32% (2 complete responses and 12 partial responses), and an additional 48% had stable disease, for an 80% disease control rate. Among the 36 patients with high-risk features, the objective response rate was 33%. Median duration of response for all responding patients was 8.3 months. Among 12 patients with an objective response and at least one postbaseline prostate-specific antigen (PSA) evaluation, 67% had a PSA decline of at least 50%.

“In this population, duration of response is typically 3 or 4 months, and this longer duration of response shows that the combination really helped patients,” Dr. Agarwal said. The median treatment duration was 6.3 months (range = 1–18 months), which speaks to the tolerability of this combination as well.

No new safety signals were identified in this cohort. The most common treatment-related adverse events of any grade were fatigue (57%), nausea (48%), decreased appetite (45%), diarrhea (39%), hand-foot syndrome (32%), and vomiting (32%). One treatment-related grade 5 adverse event (dehydration) was reported in a 90-year-old patient. The rate of discontinuation of study treatment for adverse events was 7%.

“The best part of these findings is that there were no new safety signals related to either drug. Grade 3 and 4 adverse events were minimal. Most adverse events were grade 1 or 2. This new combination has the potential to be highly effective and very well tolerated,” he said. 

DISCLOSURE: The study was funded by Exelixis. Roche is providing atezolizumab for the trial. Dr. Agarwal has served in a consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Exelixis, Foundation Medicine, Janssen Oncology, Lilly, Medivation/Astellas, Merck, Nektar, Novartis, and Pfizer and has received institutional research funding from Active Biotech, Amgen, AstraZeneca, Bavarian Nordic, Bayer, BN ImmunoTherapeutics, Bristol-Myers Squibb, Calithera Biosciences, Celldex, Eisai, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Merck, NewLink Genetics, Novartis, Pfizer, Prometheus, Rexahn Pharmaceuticals, Sanofi, Takeda, and Tracon Pharma.


1. Agarwal N, Loriot Y, McGregor BA, et al: Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results of cohort 6 of the COSMIC-021 study. 2020 Genitourinary Cancers Symposium. Abstract 139. Presented February 13, 2020.


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