An open-label, phase 1 study of androgen receptor antagonist, apalutamide in Japanese patients with metastatic castration-resistant prostate cancer

Abstract

Background: Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC.

Methods: In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1.

Results: All six patients received apalutamide. The most common treatment-emergent adverse events (TEAEs) were abdominal discomfort, nasopharyngitis, dysgeusia, rash, and hot flush [2/6 patients (33.3%) each]. No death or DLTs were reported. Grade 3 TEAEs were spinal-cord compression and renal disorder (1/6 patient each). In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. A significant accumulation of apalutamide was observed (mean accumulation index 3.55), based on AUC0-24. Median (range) serum prostate-specific antigen level decreased from 54.42 (8.92-310.11) ng/mL at baseline to 11.70 (0.37-47.74) ng/mL at week 12 with ≥ 50% reduction in 4/6 (66.7%) patients and 90% reduction in 2/6 (33.3%) patients.

Conclusion: Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients.

Trial registration: ClinicalTrials.gov identifier: NCT02162836.

Keywords: Androgen receptor antagonist; Apalutamide; Metastatic castration-resistant prostate cancer; Prostate cancer.

Conflict of interest statement

Dr. Hiroji Uemura received grants from Janssen Pharmaceutical K.K.(during the conduct of the study) and from Bayer Yakuhin, Limited, Takeda Pharmaceutical Company Limited, AstraZeneca K.K., TAIHO Pharmaceutical Company Limited, Astellas Pharma Inc. and Pfizer Inc (outside the research work, lecture, or subsidies). Dr. Katsuyoshi Hashine received grants from Janssen Pharmaceutical (during the conduct of the study) and from Takeda Pharmaceutical (subsidies). Dr. Tomohiro Tsuchiya and Dr. Akito Yamaguchi received grants from Janssen Pharmaceutical K.K. during the conduct of the study. Dr. Keiichiro Imanaka, Ms. Yuki Iwaki, and Mr. Ryo Oyama are employees of Janssen Pharmaceutical K.K.

Figures

Fig. 1

Schematic overview of the study. D1–D7 day 1 to day 7, DLT dose-limiting toxicity, PK pharmacokinetics, PSA prostate-specific antigen

Fig. 2

Waterfall plots of prostate-specific antigen percent change from baseline at week 12 (all-treated population)