Phase‐1 study of abiraterone acetate in chemotherapy‐naïve Japanese patients with castration‐resistant prostate cancer

Abstract

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1–7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2–3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.

Efficacy and safety of abiraterone acetate plus prednisone in Japanese patients with newly diagnosed, metastatic hormone-naive prostate cancer: final subgroup analysis of LATITUDE, a randomized, double-blind, placebo-controlled, phase 3 study

“…This difference in the incidence rates of hypertension could partly be explained by the lower daily dose of prednisone used in LATITUDE (5 mg/day) ( 5 ) compared with the other studies that used 10 mg/day ( 4 , 9 , 11 , 13 ). The incidence of hepatotoxicity in this subgroup analysis was comparable with that of the IA of Japanese subgroup ( 17 ) and previous studies conducted in Japanese patients with mCRPC ( 10–13 ). Incidence of grade 3 or 4 AEs of cardiac disorders in this Japanese subgroup analysis was similar to that of the IA of Japanese subgroup ( 17 ), and a previous study was conducted in patients with chemotherapy-naïve mCRPC ( 21 ).…”

“…Abiraterone acetate (AA) is a selective inhibitor of CYP17α hydroxylase enzyme that irreversibly inhibits intra- and extra-tumoral androgen biosynthesis. Addition of abiraterone acetate plus prednisone (AAP) to ADT has demonstrated a significant improvement in overall survival (OS) in patients with mCRPC in both chemotherapy-naïve and post-chemotherapy setting, in the global ( 4 , 9 ) and Japanese populations ( 10–13 ). The addition of AAP to ADT was associated with lowering of prostate tissue androgens in men with localized prostate cancer (PC), which suggests its role in inhibiting the extra-gonadal androgen biosynthesis and preventing progression to castration resistance in mHNPC patients ( 14 ).…”

A multicenter retrospective analysis of sequential treatment of abiraterone acetate followed by docetaxel in Japanese patients with metastatic castration-resistant prostate cancer

“…The patient eligibility criteria for the clinical trials of AA have already been reported (13,14). The summary of eligibility is as follows: patients had mCRPC and had not received cytotoxic chemotherapy.…”

Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models

“…Interestingly, similar results were seen in abiraterone acetate‐treated cells as seen in SR‐treated cells (Supplementary Figure S3A‐D). This effect occurred at the pharmacologically relevant and non‐toxic concentration of 1 µM, similar to blood concentrations of patients after taking this medication; tissue concentrations would be expected to be higher . Cotreatment with SR media and abiraterone promoted formation of more projections than treatment with SR media alone ( P < 0.0005, one way ANOVA with Sidak's multiple comparisons).…”