Introduction: Abi (CYP17A1 and lyase inhibitor) and cabo (multi-targeted receptor tyrosine kinase inhibitor including MET and VEGFR2) have complementary mechanisms of action and both have significant single agent activity in CRPC. Cabo decreases evidence of skeletal disease on 99mTc bone scans to a marked degree. Rationale exists for cabo to enhance abi efficacy.
Methods: In vitro proliferation experiments have been done with WST-1 assay to evaluate anti-cancer activity of abi and cabo as single agents and in combination in androgen receptor (AR) positive and negative, hormone sensitive and castration resistant cell lines (PC-3, VCaP, LAPC4 and LAPC4-CR). An in vivo established subcutaneous model of LAPC4-CR in female mice has been used to compare single agents and combination therapy. A phase 1 dose escalation trial using a 3 + 3 design with a fixed dose (1,000 mg) of abi and 5mg BID prednisone with escalating doses of cabo (20mg, 40mg and 60mg) is ongoing in pts who are castration resistant and pre or post chemotherapy. This study includes assessment of therapy response using 18F-NaF and 18F-FDG PET/CT combined with 99mTc bone scan and diagnostic CT abdomen and pelvis.
Results: In vitro proliferation studies demonstrated single agent activity between 2 and 10 μM for abi and cabo in all cell lines (including AR negative PC-3) and the ability of cabo to enhance abi activity. In LAPC4 and VCaP, abi plus cabo decreased AR and PSA protein levels to the same degree or more than abi or cabo alone. In vivo LAPC4-CR studies showed abi retarded growth until day 14 only, single agent cabo caused 66% growth suppression at day 25 with effect durable until day 39. At day 39, abi + cabo resulted in no growth from baseline. In the phase 1 trial, 8 pts have been enrolled and no dose limiting toxicities (DLT) have been observed in the first 28 days of therapy for the 3 patient cohorts treated at both 20 mg and 40 mg. Two patients have been treated at 60mg without DLT in the first cycle (third patient enrollment pending). The number of 4 week cycles for the 20mg cohort are: 9+, 9, 8+ (all post docetaxel); 40mg: 2, 3+, 3+; 60mg: 1+, 1+. Preliminary findings from PET/CT studies of 6 patients with baseline and follow-up after 8 weeks of therapy: extent of bone disease and change in SUVmax on NaF PET/CT show potential for better definition of disease burden and therapy response than 99m Tc bone scan plus CT; potential negative prognostic outcome for patients with 18F-FDG-avid disease.
Conclusion: Preclinical in vitro and in vivo studies show cabo enhances abi efficacy in prostate cancer. Mechanistic studies are being conducted to identify the biological basis for this finding. The ongoing phase 1 clinical trial with drug trough levels, CTC enumeration and bone turnover assessments will help define the recommended phase 2 dose of abi + cabo combination therapy.
Citation Format: Christopher J. Sweeney, Katherine Zukotynski, Xiaodong Wang, Andrew Wick, Amanda Fredericks, Bon Lam, Philip Kantoff. Cabozantinib (cabo) + abiraterone (abi) combination therapy in castration resistant prostate cancer (CRPC): preclinical evaluation and interim results of an investigator-sponsored phase 1 clinical study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-166. doi:10.1158/1538-7445.AM2013-LB-166