San Francisco, CA—Combining cabozantinib (Cabometyx) with atezolizumab (Tecentriq) induced responses in 32% of patients with metastatic castration-resistant prostate cancer (CRPC) who had soft-tissue progression after previous novel hormonal therapy.
In an interim analysis of the expansion phase of the COSMIC-021 phase 1b study, the objective response rate (ORR) in 44 patients who received the combination was 32%, including 2 complete responses and 12 partial responses, said Neeraj Agarwal, MD, MBBS, Director, Genitourinary Oncology Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, who presented the data at the 2020 Genitourinary Cancers Symposium.
The response rates with either agent have been limited in this patient population, with ORRs of 0% to 5%, said Dr Agarwal.
“Cabozantinib promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors,” he said to explain the rationale for the combination.
The 32% ORR with the drug combination “is clearly indicative of synergy between these 2 drugs rather than merely additive actions,” Dr Agarwal pointed out. “The duration of response is also impressive at 8 months, and if you look at how soon responses were happening, most of them were within 6 weeks.”
The COSMIC-021 Study
The study’s patient population is challenging, unlike patients with metastatic castration-sensitive prostate cancer, for whom multiple drugs are already approved, he noted. The only viable option known to improve overall survival and progression-free survival in patients with measurable disease or soft-tissue metastases after novel hormonal therapy is taxane-based chemotherapy, said Dr Agarwal.
“This combination has the potential to allow a nonchemotherapy option for those patients who are progressing on these earlier therapies and have very limited options to date,” he said.
Dr Agarwal reported the results from the dose-expansion phase of COSMIC-021, a multicenter, open-label study. In this phase of the study, patients received cabozantinib 40 mg once daily and atezolizumab 1200 mg intravenously every 3 weeks. The cabozantinib dosage could be reduced to 20 mg daily and then to 20 mg every other day to manage the adverse events. Atezolizumab infusions could be delayed, to allow for the management of adverse events.
To be eligible, patients had to have measurable disease per RECIST version 1.1 and radiographic progression in soft tissue after receiving treatment with enzalutamide (Xtandi) and/or abiraterone (Zytiga). No previous chemotherapy was allowed, except for docetaxel for metastatic CRPC.
Tumors were assessed by computed tomography or magnetic resonance imaging at screening, every 6 weeks for the first 12 months, and every 12 weeks thereafter.
Of the 44 patients, 36 (82%) had high-risk features, defined as visceral and/or extra-pelvic lymph node metastases. A total of 25 (57%) patients had a Gleason score of ≥8 at diagnosis; 12 (27%) patients received previous treatment with docetaxel for metastatic CRPC; and all 44 patients had received abiraterone, enzalutamide, apalutamide, or darolutamide before enrollment.
With a median follow-up of 12.6 months, the time to objective response was a median of 1.6 months and the median duration of objective response was 8.3 months. Among the 36 patients with high-risk clinical features, the ORR was 33%.
Overall, 17 (50%) of 34 patients with a postbaseline assessment of prostate-specific antigen (PSA) level had a decrease in PSA level. In the 12 responders who had at least 1 postbaseline PSA assessment, 8 (67%) had a ≥50% decrease in the level of PSA.
A total of 14 (32%) patients were receiving the study treatment at the data cutoff. The median duration of exposure to study medications was 6.3 months. The study cohort is being expanded to include 130 patients.
“We did not see any new safety signals. The majority of side effects were grade 1 and 2. This tells you about the tolerability of the combination compared to chemotherapy. There were no grade 4 side effects except for fatigue in 1 patient,” said Dr Agarwal.
A total of 17 (39%) patients had adverse events that led to dose reductions of cabozantinib. The only grade 3 immune-related adverse event that occurred in more than 1 patient was an increase in alanine aminotransferase levels (N = 2).
According to a press release from Exelixis, the company plans to file with the FDA for accelerated approval for cabozantinib plus atezolizumab for the treatment of metastatic CRPC as early as 2021. This filing is based on regulatory feedback from the FDA, and is supported by clinical data from the recently expanded existing study cohort and additional cohorts with metastatic CRPC.
A pivotal phase 3 trial of the combination of cabozantinib and atezolizumab for the treatment of patients with metastatic CRPC is planned.