Abstract 1099: Testosterone abolishes cabazitaxel efficacy in an in vivo model of prostate cancer and affects intratumoral concentrations

Abstract

Abstract Introduction Docetaxel combined with castration provides a major survival benefit in newly diagnosed metastatic PCa. Conversely, docetaxel without castration in high-risk localized PCa is not active. Cabazitaxel is a new taxane retaining its activity in tumors resistant to docetaxel and new hormonal therapies. We aimed at better characterizing in vivo the relationship between cabazitaxel and circulating androgens in a preclinical human-derived xenograft model of castration-resistant prostate cancer (CRPC). Material and methods Athymic nude mice were inoculated with the androgen receptor wt, PSA secreting CRPC cell line PC346C-DCC-K. Mice were surgically castrated when tumors were established (tumor volume (TV) of 150 mm3). After 7 days, mice were randomized to receive testosterone (40 mg) or empty pellet. The following day mice were injected with one bolus injection of cabazitaxel (33 mg/kg) or NaCl intraperitoneally. Mice were sacrificed when tumors exceeded a volume of 1,500 mm3 or the maximum follow-up of 90 days after cabazitaxel treatment. Blood was sampled biweekly for PSA and testosterone and analyzed by an immunoassay. In a second in vivo experiment intratumoral uptake of cabazitaxel was determined in the presence and absence of testosterone using a similar experimental set-up, with the exception that mice were sacrificed 7 days after cabazitaxel treatment. Here, intratumoral cabazitaxel concentrations were determined in snap frozen tumors by LC/MS-MS and corrected for tumor weight. Results Cabazitaxel treatment of castrated male mice bearing PC346C-DCC-K tumors resulted in a complete or near-complete antitumor response. In contrast, in mice supplemented with testosterone the anti-tumor effect of cabazitaxel was not significantly different from placebo (median time till TV 1,500 mm3 48 and 45 days resp.). Importantly, testosterone supplementation alone did not significantly affect tumor growth, confirming the CRPC nature of the (PC346C-DCC-K) xenograft. Interestingly, in tumors of testosterone supplemented castrated mice the intratumoral cabazitaxel concentrations were significantly decreased compared to mice that did not receive testosterone (0.39 ng cabazitaxel per mg tumor tissue vs. 1.36 ng/mg, t-test p=0.0032). Conclusions These findings indicate that circulating testosterone significantly impairs the efficacy of cabazitaxel. Testosterone supplementation may alter the metabolism of cabazitaxel, or may interfere with uptake and/or accumulation of cabazitaxel in PCa cells. We will further investigate the relationship between circulating androgens and intratumoral cabazitaxel accumulation as well as anti-tumor efficacy. The study was supported by a research grant from Sanofi Citation Format: Lisanne Mout, Corrina de Ridder, Debra Stuurman, Peter Bruijn, Ron H. Mathijssen, Ronald de Wit, Martijn P. Lolkema, Wytske M. Weerden. Testosterone abolishes cabazitaxel efficacy in an in vivo model of prostate cancer and affects intratumoral concentrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1099. doi:10.1158/1538-7445.AM2017-1099