Cabozantinib is a multikinase inhibitor that targets VEGFR2 and MET; however, it also inhibits RET, KIT, AXL, ephrins, and others. In a phase II randomized discontinuation trial, 103 patients who completed the 12-week lead-in period for evaluation had bone metastatic CRPC.4 Only 3 patients (3%) had new lesions on bone scan, 23 (21%) were stable, 61 (56%) had partial resolution, and 21 (19%) had complete resolution of all lesions. The dramatic effects on bone scans correlated with improvement in bone pain and bone turnover markers (i.e., alkaline phosphatase and C-telopeptide) but not prostate- specific antigen (PSA). Of 151 evaluable patients by response evaluation criteria in solid tumors (RECIST), 79% had stable disease at week 12, while 4% had a confirmed partial response; however, 74% showed some evidence of tumor regression in soft tissue. As a result of fatigue, anorexia, weight loss, and gastrointestinal (GI) side effects, efforts are underway to discover efficacious yet more tolerable doses of cabozantinib. Lower doses are likely to be brought into upcoming phase III trials evaluating pain palliation and OS. There is strong preclinical rationale that supports MET as a major target of cabozantinib. MET expression is negatively regulated by the androgen receptor (AR), and androgen deprivation (AD) increases MET expression in tumor cells.5 AD also increases tumor and stromal expression of hepatocyte growth factor (HGF), the ligand for MET.METis also more frequently expressed in bone metastases and poorly differentiated prostate cancers.6 MET and HGF may contribute directly to cellular proliferation, invasion, metastasis, and androgenindependent growth.7 Higher levels of plasma HGF are associated with shorter survival in men with CRPC.8 MET is also expressed on osteoblasts and osteoclasts, although the exact role is currently unknown.9 VEGF binding to neuropilin-1 may result in HGF-independent activation of MET and may tie angiogenesis and MET pathways together.10
One quote made me sit up (although we've known this for a while):
"The dramatic effects on bone scans correlated with improvement in bone pain and bone turnover markers (i.e., alkaline phosphatase and C-telopeptide) but not prostate- specific antigen (PSA)."
Is the lack of improvement in PSA something that is likely to affect the FDA's reaction CRPC test results for pain and/or OS ? PSA is the traditional marker for the potential onset of prostate cancer but I'm not sure if it has any effect on patients already fighting prostate cancer in it's final stages. Obviously I am not medically trained and the mavens on this board would certainly know better than I whether the lack of improvement in PSA matters. Perhaps we can hear from one or more of them.
The Stand Up 2 Cancer video supplied by biglabowski earlier this week is worthy of review, as the concept of the "mutational landscape" is sure to become the new lingo in ascertaining "best" biomarkers for any given patient. Imagine entering a treatment center from an initial PC diagnosis with your genome in your back pocket. Your personal chromosomal sequence, family history, select predictive & prognostic biomarkers, and your personal chemistry will create the guidelines for your personalized therapy. PSA is not necessarily to be considered the final assay. And...It's really not that far in the future... GLTA
Good stuff! If CABO can continue to carry this measure of academic acceptance, transform it successfully into clinical acceptance, and finally gain the acceptance of the insurors... Well...we got no worries...do we?