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New Combination Treatment for mCRPC Heads to Phase 3 Trial

At the GU-ASCO meeting held earlier this year, Dr. Neeraj Agarwal of the Huntsman Cancer Center at the University of Utah presented results of a Phase 1b trial of combination therapy with two drugs (cabozantinib + atezolizumab) in metastatic castration resistant prostate cancer (mCRPC).

Many treatments for mCRPC exist, but the cancer progresses in almost all men despite therapy, and more options are needed. Cabozantinib is an inhibitor of multiple proteins called tyrosine kinases that are involved in cancer processes (tumor growth, angiogenesis, and immune cell regulation). Atezolizumab is an immune checkpoint inhibitor that targets the immune-suppressive protein PD-L1 – in other words, the drug prevents the cancer from blocking the body’s immune response, allowing the immune system to kill the cancer cells.

These drugs had not been effective on their own, but data suggested that the combination might be beneficial, leading to a multinational phase 1b trial across many cancer types. Dr. Agarwal presented the results of one specific cohort of 44 patients: men with mCRPC who had cancer in soft tissues that progressed while on treatment with abiraterone or enzalutamide or both. These men had significant disease: 82% were classified as “high risk” mCRPC based on the extent and location of the metastases.

The overall response rate was 32% among all 44 CRPC patients and an additional 48% of patients experienced stable disease. Thus, the clinical benefit rate (response or stabilization of disease) was seen in 80% of patients. The median duration of treatment was 6.3 months, and the median duration of response was 8.3 months. This waterfall plot shows changes in tumor burden for each patient. Most patients showed a decrease in the amount of tumor as measured on scans.


The side effect profile of the combination was primarily associated with known effects of cabozantinib. 59% of patients had a Grade 3 or 4 treatment-related adverse event (AE) and 9.1% of patients had an immune-related Grade 3 AE. One grade 4 AE of diverticular perforation was reported. One patient had a Grade 5 AE (dehydration).

The overall response rate of 32% was highly promising. These results have led to the initiation of an international phase 3 trial to test the combination of cabozantinib + atezolizumab in men with mCRPC. The trial has already been approved by the FDA and is opening at several sites. The investigators hope to enroll the first patient within months.

Andrea Miyahira
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.