Osteoblasts and osteoclasts are the process that the body uses to breakdown old bone and then to rebuild it with new bone.
c-Met is a tyrosine kinase expressed by osteoblasts and osteoclasts, and overexpressed by prostate cancer cells. This over expression leads to the eventual development of bone metastases.
The experimental treatment known as Cabozantinib (XL-184) is a c-Met and vascular endothelial growth factor receptor-2 inhibitor. It has been tested in men with mCRPC yielding impressive results from a phase II study that enrolled 171 men. The results showed n a partial or complete improvement in the bone scans in 68% of the subjects and pain improvement in 67% of the patients.(1)
Median PFS was 23.9 weeks (95% CI 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI 5.4 to 6.6 weeks) with a placebo (HR 0.12; p < 0.001).However, it is expected that there will be toxicity from a tyrosine kinase inhibitor. Toxicities will include fatigue, hypertension, and palmar-plantar syndrome. These side effects constitutes a challenge for the original 100 mg/day dose for further development.Two phase III trials were recently initiated: one with pain as the primary endpoint (COMET-2, NCT01522443) and a global phase III trial with overall survival as the primary endpoint in men with mCRPC in whom docetaxel and abiraterone failed (COMET-1, NCT01605227). What is really interesting is the exact mechanism of action of cabozantinib remains to be understood as a another c-Met inhibitor, rilotumumab, failed to demonstrate efficacy in a randomized phase II trial. (2)Another potential future target for therapy in mCRPC is Src, which is expressed by osteoclasts and by some prostate cancer cells. A prior trial of Dasatinib, a Src inhibitor, was tested in men with mCRPC as a single agent and also in combination with chemotherapy (3). The results of this very large phase III trial with and without dasatinib (NCT00744497) was very recently reported to be negative.Targeting bone metastasis is vital in the treatment of advanced prostate cancer as it is by far the most common tumor type in prostate cancer. Bone metastasis cause the following problems:
• severe pain
• bone fractures
• spinal cord compression
• spinal instability
• decreased mobilitySuccessful treatment of bone mets will improve the life of many of us and future treatments will have to find better ways to deal with our bone issues.(1) – Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412-419.
(2) – Ryan CJ, Rosenthal M, Ng S, et al. Targeted MET inhibition in castration-resistant prostate cancer: a randomized phase II study and biomarker analysis with rilotumumab plus mitoxantrone and prednisone. Clin Cancer Res. 2013;19:215-224.
(3) – Yu EY, Massard C, Gross ME, et al. Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. Urology. 2011;77:1166-1171.
Joel T Nowak, M.A., M.S.W.