Abstract IA11: Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent

Abstract

Abstract The evolving understanding of the biology of prostate cancer has fueled therapeutic research with agents targeting androgen signaling, bone microenvironment, apoptosis, and immune modulation amongst others that are being evaluated in clinical trials and an expanding portfolio of FDA approved agents. Metastasis particularly to bone is a hallmark of prostate cancer and reflects the lethal phenotype of the disease. This process is complex and involves interactions between the cancer cell and several elements of the bone microenvironment including osteoblasts, osteoclasts, endothelial cells and cortical bone. The receptor tyrosine kinase MET and its ligand, hepatocyte growth factor (HGF), drive tumor cell invasion and metastasis. Bone metastases are associated with high levels of MET expression. MET and VEGFR2 synergize to promote angiogenesis, and HGF and VEGF direct crosstalk between tumor cells, osteoblasts, and osteoclasts. In prostate cancer, MET overexpression increases with progression and metastasis to bone and lymph nodes and overexpression of HGF has also been reported. Preclinical data suggest that androgen deprivation increases MET expression, and clinically increased plasma levels of HGF in castration resistant disease is associated with decreased overall survival. Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that simultaneously blocks MET and VEGFR in vivo. In transgenic mouse models it blocks metastatic spread from primary tumors and inhibits prostate xenograft tumor growth in bone. In cell culture studies, cabozantinib elicits a unique profile of effects on bone microenvironment cells, with dose-dependent inhibition of osteoclast differentiation, and biphasic effects on osteoblast differentiation and function. Results from a recently completed phase II trial in 171 patients with progressive metastatic castration resistant prostate cancer indicate that cabozantinib has moderate but manageable toxicities similar to other TKIs with the most common being fatigue, GI and hand and foot syndrome. Cabozantinib had substantial antitumor activity irrespective of prior docetaxel therapy. Specifically it resulted in 68% overall objective disease control at 12 weeks of therapy and 74% measurable disease regression. Of note is the unique and significant observation of a high rate of partial or complete resolution of bone scans which was observed in 76% of patients and was accompanied by pain improvement in patients with pain at baseline and decreases in bloodbased markers of osteoclast and osteoblast activity. The overall median progression free survival was 29 weeks. Several clinical trials are ongoing or planned to better characterize cabozantinib activity and effect. Citation Format: Maha H. Hussain. Cabozantinib (XL-184) and prostate cancer: Preclinical and clinical profile of a novel agent [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA11.