Association of changes in biomarkers with treatment with cabozantinib (Cabo) in metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the 100mg nonrandomized expansion cohort of a randomized discontinuation trial.

Abstract

196 Background: Cabo, an oral inhibitor of receptor tyrosine kinases (RTK) including MET and VEGFR2, showed activity in early clinical studies in mCRPC, and is being investigated in phase 3 trials. Our primary aim was to retrospectively study the potential association between plasma concentrations of known markers of hypoxia, RTK cell signaling, inflammation, bone metabolism, chemo-attraction and epithelial-mesenchymal transition with response to Cabo in patients (pts) who received 100mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). Methods: Our cohort of mCRPC pts with available plasma samples comprised of 81 pts with bone lesions assessed for bone scan response (BSR, defined as ≥30% decrease in lesion area compared to baseline). Thirty three pts also had measurable disease and were assessed for RECIST response. Plasma samples were available for all pts at baseline, at 6 weeks and at time of best response. Levels of 27 plasma biomarkers were measured in duplicate using ELISA. Spearman correlation coefficients were calculated for the association between response and biomarker levels at each time point. Results: Sixty six of 81 pts (81%) had a BSR, and 6 of 33 pts (18%) had a partial response by RECIST. No significant associations were found between the levels of any of the biomarkers at baseline or subsequent time points and either BSR or response by RECIST. Over time, the plasma concentrations of soluble VEGFR2 were significantly decreased during treatment with Cabo, consistent with the known effects of VEGFR inhibition on soluble VEGFR2. The plasma concentrations of nine markers (VEGFA, CA9, clusterin, FLT3L, Gas6A, Bone Alkaline phosphatase, and the soluble forms of the RTKs MET, IGF1R and AXL) were significantly increased during treatment with Cabo irrespective of response. Conclusions: These results demonstrate that metabolic alterations occur following treatment with Cabo in pts with mCRPC. Changes in certain biomarkers during treatment with Cabo could suggest potential co-targeting approaches with Cabo or other RTK inhibitors in mCRPC.