Abstract 735: Evaluation of cabozantinib in combination with abiraterone, enzalutamide or docetaxel in a castration-resistant prostate cancer xenograft in vivo
Authors: Nguyen Holly M. , Brown Lisha G. , Olson Jessica L. , Aftab Dana T. , Vessella Robert L. , Corey Eva 
Published: May 2015

Abstract
New second-generation hormonal therapy agents abiraterone (abi) and enzalutamide (enz), and standard chemotherapy docetaxel (doc) provide survival benefits for patients with castration-resistant prostate cancer (CRPC). However, despite these survival benefits, CRPC is still an incurable disease. Therefore, combination treatments with other agents are under consideration to potentially improve patient outcome. Cabozantinib (cabo), an inhibitor of tyrosine kinases including MET, VEGFR2, RET, KIT and AXL, has shown activity as monotherapy in clinical investigations in CRPC. Our objective was to evaluate effects of cabo in combination with abi, enz or doc on a CRPC xenograft tumors in vivo.
Mice with subcutaneous LuCaP 35CR CRPC patient-derived xenograft tumors were treated with abi (0.5 mmol/kg), enz (50 mg/kg), doc (10 mg/kg) or cabo (10 mg/kg) monotherapies or with combinations of cabo with abi, enz or doc. Mice were treated for 4 weeks (wks) and followed for additional 6 wks. After 4 wks of treatment abi and enz exhibited limited activity in this model (∼20% inhibition of tumor volume (TV), not significant), doc exhibited ∼40% TV inhibition (P=0.017), and cabo exhibited ∼60% TV inhibition (P&lt;0.001) vs untreated tumors. Combination of cabo with each of these agents provided reduction in TV vs single agent treatments: ∼40% inhibition vs abi only, P=0.0039; ∼60% inhibition vs enz only, P&lt;0.0001; and ∼70% inhibition vs doc only, P&lt;0.0001. When the tumors were followed for 6 wks after discontinuation of the treatment, all treated tumors started to grow at rates similar to the untreated tumors, indicating presence of viable tumor cells. At the end of the study (10 wks) there were survival benefits for monotherapies, and further survival benefits were detected for combination of enz+cabo vs enz as a monotherapy (medium survival 5.7 vs 3.5 wks, P=0.0087) and doc+cabo vs doc as monotherapy (medium survival 4.75 vs 3.5 wks, P=0.0003), however survival of animals treated with the combinations was not significantly different from the survival of animals treated with cabo monotherapy. In the second study, where mice were treated for up to 18 wks, there were significant survival benefits detected for enz+cabo vs enz (median survival 15.5 vs 6.5 wks; P=0.0039), and for doc+cabo vs doc (median survival 15 vs 6.8 wks; P=0.0008); however, the cabo combinations with enz and doc had survival times similar to cabo monotherapy (16 wks). No significant effects on survival were detected for abi+cabo vs abi as monotherapy. Cabo at 10 mg/kg administered long term did not result in decreased body weight in comparison to non-treated mice. These preliminary data indicate that combinations of cabo with enz, doc or abi are active in the subcutaneous LuCaP 35CR xenograft model. Further analyses of the data and tumors are ongoing.
Citation Format: Holly M. Nguyen, Lisha G. Brown, Jessica L. Olson, Dana T. Aftab, Robert L. Vessella, Eva Corey. Evaluation of cabozantinib in combination with abiraterone, enzalutamide or docetaxel in a castration-resistant prostate cancer xenograft in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 735. doi:10.1158/1538-7445.AM2014-735