Abstract
The MET/VEGFR2 inhibitor cabozantinib showed antitumor activity in men with metastatic CRPC.
Major finding: The MET/VEGFR2 inhibitor cabozantinib showed antitumor activity in men with metastatic CRPC.
Approach: The efficacy of cabozantinib was evaluated in a phase II randomized discontinuation trial.
Impact: Cabozantinib may improve the outcome and quality of life in patients with advanced CRPC.
Elevated tyrosine kinase receptor signaling has been implicated in the development of castration-resistant prostate cancer (CRPC), which is characterized by resistance to androgen deprivation and enhanced bone metastasis. Cabozantinib is an orally bioavailable MET and VEGFR2 inhibitor that has shown antitumor activity in mouse models of CRPC and in phase I trials. Smith and colleagues further investigated the efficacy and safety of this drug in a phase II randomized discontinuation trial in which 171 men with metastatic CRPC received open-label cabozantinib for an initial 12-week lead-in period, after which patients with stable disease were randomly assigned to cabozantinib or placebo; however, random assignment was stopped early based on evidence of drug efficacy. Although only 5% of the patients experienced a confirmed partial response, 75% had stable disease, and regression of soft tissue lesions was observed in 72% of patients, independent of prior treatment. In addition, among the 31 patients assigned to blinded treatment, median progression-free survival (PFS) was significantly increased with cabozantinib compared with placebo (23.9 weeks vs 5.9 weeks). Strikingly, drug treatment also resulted in complete or partial bone scan resolution in 68% of patients, which was correlated with soft tissue disease regression and longer PFS. Furthermore, this effect was associated with reductions in 2 bone turnover markers, serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen, and with bone pain relief and decreased narcotic use, suggesting that cabozantinib may improve quality of life. Importantly, the most common toxicities, including fatigue, hypertension, and dehydration, were manageable with dose reductions. Although phase III studies are ongoing and additional mechanistic studies are necessary, these findings suggest that cabozantinib targets both the microenvironment and cancer cells and may be an effective therapeutic strategy for men with metastatic CRPC.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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