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Abstract
Over 80% of men with castration-resistant prostate cancer have bone metastases. This condition can dramatically impact quality of life and is associated with short-term survival. Consequently, the development of bone-targeted therapies is a relevant topic on prostate cancer management. Hepatocyte growth factor receptor and vascular endothelial growth factor signaling pathways have been identified to play a role in prostate cancer progression and bone metastasis and are potential targets for therapeutic intervention. Early-phase studies have shown encouraging responses in bone metastases and pain control with cabozantinib, a multi-tyrosine kinase inhibitor targeting hepatocyte growth factor receptor and vascular endothelial growth factor receptor. Despite striking responses seen in some patients, preliminary results from a pivotal Phase III study have failed to produce survival benefit. This review encompasses preclinical and clinical data of cabozantinib in metastatic castration-resistant prostate cancer highlighting future research options for this agent.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Metastatic castration-resistant prostate cancer is associated with poor prognosis and bone metastases remain a major cause of morbidity and mortality in this setting.
Especially at the level of bone metastases, hepatocyte growth factor receptor (MET) and VEGF signaling pathways have been identified to play a relevant role in prostate cancer progression.
Cabozantinib (XL-184) is a potent oral multi-tyrosine kinase inhibitor, targeting mainly MET and VEGF receptors.
Early-phase studies have shown encouraging responses in bone metastases and pain control with cabozantinib.
The pivotal Phase III trial (COMET-1) has unfortunately failed to meet its primary end point (OS), with median OS in patients treated with cabozantinib being 11 months versus 9.8.
Better understanding of its mechanism of action in bone metastases and new biomarkers-driven studies may be able to select a population to benefit from the dual inhibition of VEGF and MET signaling pathways.