Cabozantinib Prolongs PFS in Advanced Prostate Cancer

A new study is reporting "unprecedented" results in the treatment of castration-resistant prostate cancer (CRPC) with the new drug cabozantinib (Cometriq, Exelixis).

Results were published online November 19 in the Journal of Clinical Oncology.

Cabozantinib is an oral inhibitor of multiple receptor tyrosine kinases, including RET, MET, and vascular endothelial growth factor 2 (VEGFR2). It was recently approved by the US Food and Drug Administration for the treatment of medullary thyroid cancer.

Cabozantinib demonstrated "dramatic and rapid effects" on bone scan lesions in a high proportion of patients, the study authors report. These effects are "echoed in other measures of antitumor effect," they add.

Of the patients randomized to cabozantinib, 72% experienced regression in soft tissue lesions, and 68% of evaluable patients showed improvement on bone scan. In addition, there was complete resolution in 12%.

However, lead author David C. Smith, MD, professor of internal medicine and urology at the University of Michigan Medical School in Ann Arbor, said the study should not change clinical practice at this time. "Cabozantinib should not be used for CRPC outside of clinical trials at this point, but the data should prompt referrals for clinical trials such as the phase 3 trials referred to in the paper, as well as institutional trials listed on ClinicalTrial.gov," he said.

"Dosing is still being assessed and the side-effect profile requires that patients be closely monitored to limit major toxicities," Dr. Smith told Medscape Medical News. "I would not recommend off-label use at this time."

Increasing Evidence

Cabozantinib demonstrated antitumor activity in 12 of 13 tumor types studied, as reported last year at the American Society of Clinical Oncology annual meeting.

Particularly high rates of disease control were observed for advanced prostate, ovarian, and liver cancers. Treatment with the agent also completely or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Improved Progression-Free Survival

The study by Dr. Smith and colleagues involved 171 men with CRPC. All patients initially received cabozantinib 100 mg daily. Those with stable disease at 12 weeks, according to Response Evaluation Criteria in Solid Tumors (RECIST), were randomized to cabozantinib or placebo. However, randomization was stopped early because of the observed activity of cabozantinib.

The majority of patients (87%) had bone metastases and 46% had received previous chemotherapy (94% with docetaxel-based therapy). In addition, 39% of patients had received previous and ongoing bisphosphonate treatment.

In the first 12 weeks of treatment, 127 patients (75%) had stable disease and 18 (11%) had disease progression. Four patients with stable disease had a confirmed partial response after the lead-in stage.

There were 154 patients evaluable for best change in measurable disease, and 111 (72%) underwent at least 1 assessment that showed a decrease of soft tissue tumor lesions. These changes in measurable disease were independent of previous treatment.

The primary study end point was progression-free survival in patients with stable disease at week 12. Before randomization was suspended, 14 patients were randomized to cabozantinib and 17 to placebo. There was a marked increase in progression-free survival with cabozantinib, compared with placebo (23.9 vs. 5.9 weeks; hazard ratio, 0.12; P < .001).

Median overall progression-free survival for the entire treatment period was estimated to be 29.4 weeks in cabozantinib-treated patients, 29.7 weeks in docetaxel-naïve patients (n = 97), and 23.9 weeks in patients who previously received docetaxel-based therapy (n = 74).

Decreased Pain, Improved Markers

The authors conducted a post hoc analysis of the effects of cabozantinib on factors such as bone scan, bone markers, pain, and narcotic use. Bone pain improved in 67% of evaluable patients, with an accompanying decline in narcotic use by 56% of patients.

All patients experienced at least 1 adverse event, and the majority experienced more, the authors report. The most common events were a "variable cluster" that included fatigue, decreased appetite, taste alterations, nausea, diarrhea, weight loss, and hand–foot syndrome, which resulted in dose reductions in 62% of patients. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand–foot syndrome (8%). The most common serious adverse events were pulmonary embolism (6%), dehydration (5%), and vomiting (5%).

The study was funded by Exelixis. Several of the authors report relationships with industry, as noted in the paper.

J Clin Oncol. Published online November 19, 2012. Abstract