Development of cabozantinib for the treatment of prostate cancer

Abstract

Cabozantinib (XL184) is a multitargeted receptor tyrosine kinase with predominantly MET and vascular endothelial growth factor inhibition properties. It is currently approved by the US Food and Drug Administration for the treatment of progressive metastatic medullary thyroid cancer. The agent has a convenient once-daily oral dosing schedule and has demonstrated encouraging activity in metastatic castrate-resistant prostate cancer (CRPC). A Phase I/II trial demonstrated responses in soft tissue, visceral disease, and bone metastases in CRPC. An objective response rate of 5%, a stable disease rate of 75%, and a median progression-free survival of 6 months was observed. As compared with the 140 mg daily dose used in thyroid cancer, a lower dose of 60 mg daily is currently being utilized in prostate cancer studies due to the fact that toxicity could be reduced without compromising efficacy. Randomized trials are ongoing in comparison with prednisone or with mitoxantrone and prednisone in pretreated metastatic CRPC. Cabozantinib has demonstrated a unique mechanism of action and preliminary efficacy in the crowded therapeutic field of prostate cancer. Since multiple therapies have recently demonstrated overall survival benefit in metastatic CRPC, cabozantinib will likely face some challenges in clinical application. At present, in this rapidly evolving field, it is unclear what proportion of patients with prostate cancer will be eligible to receive this therapy. The cost of cabozantinib is likely to be another deterrent, especially if it remains more expensive than other oral therapies, such as abiraterone and enzalutamide. Defining the role of MET overexpression and RET mutations as biomarkers in prostate cancer may help to guide patient selection, and enrich and enhance the future applications of this targeted novel agent.