In an interview with The ASCO Post, Charles G. Drake, MD, PhD, expounded on the results of the COSMIC-021 trial. Dr. Drake is Division Director for GU Oncology, Co-Director of the Cancer Immunotherapy Program, and Co-Leader of the Tumor Biology and Microenvironment Program at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York.

Charles G. Drake, MD, PhD

“Cabozantinib has had a checkered history in prostate cancer. Early studies in metastatic prostate cancer showed that bone scans would go from positive to negative after treatment with cabozantinib at 60 mg. ­Although the phase III trial showed that cabozantinib improved progression-free survival, the trial was negative for overall survival, and no one knows why. The forest plots from the phase III trial suggested that patients with visceral metastasis many have had a trend toward a survival benefit, although the data are nonsignficant,” he said.

“Cabozantinib is a ‘dirty’ drug—that is, it is a broadly active kinase inhibitor. There are animal data suggesting that cabozantinib inhibits the function of suppressive immune cells, such as myeloid-derived suppressor cells and M2 macrophages. Based on the negative phase III trial, most folks in the field  would say that cabozantinib is not active in prostate cancer. Atezolizumab and anti-[programmed cell death ligand 1 (PD-L1)] agents have also not shown much activity in prostate cancer,” Dr. Drake continued.

“However, this study provides a signal that this combination has activity in prostate cancer, and it is one of the few times that potential synergy has been shown in prostate cancer. The biology is super interesting. These data are exciting, showing the possibility of synergy between a broad-spectrum tyrosine kinase inhibitor and anti-[programmed cell death protein 1 (PD-1)]/PD-L1 in prostate cancer,” Dr. Drake said.

Dr. Drake expressed concern about the rate of adverse events seen in this preliminary look at the prostate cancer cohort. “The poster showed a rate of grade 3 or higher adverse events of around 40%, which is similar to what you get with chemotherapy, which puts us in ‘chemoland.’ With enzalutamide and abiraterone acetate, the rate of grade 3 or higher adverse events is around 20%.”

“The bottom line is that when a patient has disease progression on first- or second-line androgen-deprivation therapy, this combination might be a good option to switch to [instead of chemotherapy] if the adverse events are tolerable,” Dr. Drake stated.

A phase III trial is planned to compare cabozantinib/atezolizumab vs a switch to enzalutamide or abiraterone in patients with metastatic prostate cancer whose disease progresses on androgen-deprivation therapy. “If future studies hold up, this will be exciting for our patients,” Dr. Drake said. 

DISCLOSURE: Dr. Drake owns stock or other ownership interests in Compugen, Harpoon Therapeutics, Kleo Pharmaceuticals, Tizona Therapeutics, UroGen Pharma, and Werewolf; has served in a consulting or advisory role for AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Compugen, F-Star, Ferring, Genocea Biosciences, Janssen Oncology, Kleo Pharmaceuticals, Merck, Merck/Serono, Pierre Fabre, Pfizer, Roche/Genentech, Shattuck Labs, Tizona Therapeutics, UroGen Pharma, and Werewolf; has received institutional research funding from Bristol-Myers Squibb; holds institutional patents licensed to Bristol-Myers Squibb and Potenza Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by AACR, ASCO, Merck Sharp & Dohme, Pfizer, and Roche/Genentech.