Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) causes approximately 307,500 deaths annually worldwide. mCRPC has been defined as a clinical state in which, despite suppressed circulating testosterone levels lower than 50 ng/dL, the androgen receptor axis is reactivated. This reactivation is mainly due to the multiple signaling mechanisms in prostate cancer cells along with their microenvironment. Thus, research efforts aimed at identifying new strategies to inhibit the androgen receptor axis. Abiraterone acetate (ABI) is a first-in-class inhibitor of cytochrome (CYP) 17A1, a critical enzyme for extra-gonadal and testicular androgen syntheses. ABI has shown impressive efficacy in treatment of mCRPC. ABI plus low-dose prednisone was first shown to improve survival in mCRPC patients pre-treated with docetaxel, and the combination therapy has since been approved for this purpose. Moreover, ABI plus low-dose prednisone resulted in prolonged overall survival (OS) as compared with placebo plus prednisone in docetaxel-naive patients. In these patients, ABI was associated with a median progression free survival of 16 months and median overall survival of 35 months. However, around 40% of patients do not experience PSA response to ABI therapy at 3 months. This parameter has been consistently identified as a surrogate parameter of time to progression. As ABI is an oral agent that is subject to both inter- and intra-individual variability in bioavailability, its pharmacokinetics might be a critical parameter for its anticancer activity. Investigators first established a simple method to mesure plasma ABI concentration by HPLC. They then conducted a prospective observational study in which they aimed to explore the relationship between ABI trough concentration and PSA response in mCRPC patients and to identify the critical determinants for its activity. 73 mCRPC patients, in whom treatment with ABI was indicated, were recruited from December 2012 to December 2014 in the oncology department of Cochin Hospital in Paris, France. The plasma concentration of ABI was determined at baseline, and then one (M1), two (M2) and three (M3) months after treatment initiation. The primary study objective was to investigate the relationship between ABI mean plasma trough concentration (ABI Cmin) and PSA response. PSA response was defined as a PSA decline of at least 50% after receiving ABI for 3 months. In multivariate analysis, ABI Cmin was the only factor independently associated with PSA response: OR=1.12, \[1.0-1.3\], P=0.03. Based on these results, they established an optimal threshold of ABI C min by building a ROC curve. The treshold value of 8.45 ng/mL was associated with a specificity of and sensitivity of 70% \[49-84\] and 79% \[63-81\], respectively. As plasma ABI exposure is a key element of PSA response, it supports the exploration of benefits of a pharmacokinetically-guided dosing strategy for ABI. In a phase I trial, the recommended dose of ABI was 1000 mg per day as a plateau of endocrine effects was reported at doses greater than 750 mg. However, to their knowledge, no data regarding the effect of ABI on tissue androgens are available, and no dose limiting toxicity was identified up to 2000 mg per day which support the rational of a dose-escalation strategy. In a phase 2 study, 41 mCRPC patients received 1000 mg twice a day of ABI (2000 mg/day) and the tolerance profile appeared similar than with lower dose. In this phase II trial, investigators aim to confirm the preliminary results presented above in a larger population. Moreover, their objective is to test whether a dose escalation up to 2000 mg per day is feasible and lead to disease stabilization in progressive patients within the first 6 months of treatment.