Abstract 5750: Synergistic effects of everolimus and bicalutamide in castration-resistant prostate cancer: Results from a phase I/II clinical trial
Authors: Pan Chong-xian , Robles Daniel , D'Abronzo Leandro , Beggs Ryan E. , deVere-White Ralph , Lara Primo , Ghosh Paramita M. 
Published: August 2012

Abstract
Background: We previously showed that the mTOR pathway is activated in castrate resistant prostate cancer (CRPC) while inhibition of this pathway upregulated androgen receptor (AR) signaling. Based on these data, a phase I/II clinical trial was designed to determine the efficacy and tolerability of the combination of the AR inhibitor bicalutamide and the mTOR inhibitor everolimus in CRPC patients compared with bicalutamide alone. Methods: Eligible patients had histologically confirmed disease and disease progression (PSA or radiographically) while on androgen deprivation therapy (failed the therapy); and could have less than 2 months of bicalutamide at the initiation of androgen deprivation to prevent flare. The primary endpoint is PSA response. Complete response (CR) was defined as complete disappearance of all measurable and non-measurable disease. Results: In all, 19 patients were enrolled in the study, but data from only 18 have been included because one patient passed away before he could be started on the drugs. No unexpected toxicity was observed in the 18 patients enrolled in this study. 5 patients were on placebo+bicalutamide and 13 were on everolimus+bicalutamide. Of the 13 patients on everolimus+bicalutamide, nine (69.23%) had partial response (PR, a decline in PSA by at least 30%), one (7.69%) unconfirmed PR (patients have PSA response less than two cycles), and three (23.08%) had stable disease (SD, no symptomatic deterioration, PSA increase &lt;100%, and not CR/PR). In contrast, of the 5 patients on Placebo+bicalutamide, 1 (20%) had PR, 1 (20%) unconfirmed PR, 2 SD (40%) and one (20%) had disease progression. The mean time to relapse (days from start of treatment to patient withdrawal) was 220 days for patients on everolimus+bicalutamide and 109 days for patients on Placebo+bicalutamide. Recent publications indicate ErbB3 increases with mTOR inhibition. Therefore, to investigate the difference in the patients on everolimus+bicalutamide who responded to the treatment, vs those who did not, serum from 8 patients on everolimus+bicalutamide, of which 4 responded to this combination (PSA decrease &gt;50%) and 4 did not, were further analyzed for levels of ErbB3. Significantly, ErbB3 levels were increased in the serum from patients who did not show any decline or partial decline in PSA, but not in the ones who responded well to the drug combination. Conclusions: The combination of everolimus+bicalutamide doubled the time to relapse in patients who had failed androgen deprivation therapy, compared to bicalutamide alone. Relapse in these patients may be related to the increase in ErbB3, hence an ErbB3 inhibitor in combination with everolimus may further benefit this group of patients. We intend to investigate in the future whether expression of ErbB3 in the serum can be used to predict whether a patient will respond to the treatment or not.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5750. doi:1538-7445.AM2012-5750