Early Trial of Cabozantinib and Abiraterone Shows Promise in Prostate Cancer

A phase I trial that combined the investigational therapy cabozantinib with the already approved abiraterone acetate in metastatic castration-resistant prostate cancer (CRPC) patients shows that the two agents are tolerable, with the potential for improved efficacy.

Christopher Sweeney, MBBS, medical oncologist at Dana-Farber Cancer Institute in Boston, presented the results (abstract #5027) at the American Society of Clinical Oncology Annual Meeting, held May 30–June 3 in Chicago.

Patients received a fixed dose of 1,000 mg once daily of abiraterone acetate and 5 mg twice daily of prednisone, as well as escalating daily doses of cabozantinib at a 20-, 40-, or 60-mg dose.

The 21 patients enrolled in the trial had progressive disease, and 6 had prior chemotherapy treatment.

Fifty percent of the patients treated at the 20-mg cabozantinib dose had a greater than 90% decline in prostate-specific antigen (PSA) levels. Of the patients receiving the 40-mg dose of cabozantinib, 13% had a greater than 90% decline in PSA levels. According to Sweeney, the number of patients was too small to make any conclusions when comparing the outcomes of these two dose cohorts.

Patients on the 20-mg cabozantinib dose stayed on the regimen for a median of 7 months, with at least one patient receiving the combination for 22 months.

Those patients in the 40-mg cabozantinib cohort stayed on the regimen for a median of 8 months, with at least one patient receiving the combination for 23 months.

Nine patients, five in the 20-mg cohort and 4 in the 40-mg cohort, are still being treated.

In the 60-mg cabozantinib cohort, grade 2 adverse events included myalgias in two patients; fatigue in two patients; and deep vein thrombosis in a single patient in cycles 2 and 3, which required a dose reduction to 40 mg, after which no more patients were enrolled at this treatment dose.

Common low-grade adverse events included myalgias, nausea, fatigue, edema, hypertension, diarrhea, and hand-foot syndrome.

A total of six patients had cabozantinib-related grade 3 adverse events, including diarrhea, anemia, and increased aspartate aminotransferase and alanine aminotransferase levels for two at the 20-mg dose. Hypertension, low phosphate, and increased lipase were the documented grade 3 adverse events in the 40-mg dose group. Five 40-mg dose cohort patients required dose reductions.

“We did not see any evidence of additive toxicity in combining abiraterone and cabozantinib in this trial,” said Sweeney. “The challenge is that we want to develop a combination dose that is tolerable for patients in the long term, especially if this combination is moved into the chemotherapy-naïve patient population.”

According to Sweeney, both the 20-mg and the 40-mg doses of cabozantinib in combination with 1,000 mg of abiraterone daily are viable candidates for larger trials.

Preclinical data showed that combining cabozantinib with abiraterone decreased tumor volume more dramatically compared with each agent alone and also improved survival in a prostate cancer mouse model. “These are two drugs that have activity [in prostate cancer] and complementary mechanisms of action that hit multiple pathways,” Sweeney told Cancer Network.

“Several patients on this trial are staying on the therapy for longer than 1 year, so it will take at least another 12 months to have mature results from this trial,” said Sweeney.

A larger combination trial, also sponsored by Exelixis, the company developing cabozantinib, is currently ongoing, testing the combination in chemotherapy-naïve patients with bone metastatic CRPC.