Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. It is designed to target the men with castration resistant prostate cancer (CRPC). Results from a phase II randomized discontinuation trial with an expansion cohort of XL184 have recently been released.

The trial included men with castrate resistant prostate cancers who were given 100 mg of XL185 daily. The men who demonstrated stable disease at 12 weeks were randomly assigned to either cabozantinib or to placebo. The trial’s primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.

The trial enrolled one hundred seventy-one men (171) with CRPC (phase II trials are designed with smaller numbers than phase III trials). The randomizations were halted early because of the positive activity of the investigational treatment, cabozantinib. The researchers found that seventy-two percent of men had a regression in soft tissue lesions and 68% of the evaluable men had improvements on bone scan, including complete resolution in 12% of the subjects.

The objective response rate at 12 weeks was 5%, with stable disease in 75% of men. Thirty-one (31) men with stable disease at week 12 were randomly assigned to either the investigation treatment or to placebo.

Median progression free survival was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and only 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ? 50% in 57% of evaluable patients. On retrospective review of the study they found that bone pain improved in 67% of evaluable men, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). The researchers concluded that Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in progression free survival, resolution of bone scans, and reductions in bone turnover marker, as well as pain and narcotic use by the treated men. Look for the soon to come phase III trial. We will hopefully be looking for another blockbuster treatment for men with advanced prostate cancer who are castrate resistant. XL185, another new potential treatment that is “On The Horizon.” Smith, DC, Smith MR, Sweeney C, et al. J Clin Oncol 19 Nov 2012; Epub Joel T. Nowak, M.A., M.S.W.