Abstract
BackgroundApalutamide, 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.MethodsIn 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.ResultsAll 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.ConclusionApalutamide 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 registrationClinicalTrials.gov identifier: NCT02162836.
Highlights
Prostate cancer is the 6th leading cause of cancer death in men worldwide (307,000 deaths in 2012) [1]
In contrast to bicalutamide, apalutamide lacks significant androgen receptor (AR) agonist activity in preclinical models of castration-resistant prostate cancer (CRPC) and is unable to induce AR nuclear translocation and DNA binding in prostate cancer cells [6]
Patients who received first generation antiandrogen as part of an initial combined androgen blockade therapy or as second-line hormonal therapy for continuing disease progression, or who progressed after AR antagonists, 5-α reductase inhibitors, estrogens, and any other anticancer therapy, including chemotherapy given in the adjuvant/neoadjuvant setting were required to be off those medications for ≥ 4 weeks before first dose administration
Summary
Prostate cancer is the 6th leading cause of cancer death in men worldwide (307,000 deaths in 2012) [1]. Prostate cancer is estimated as one of the most common type of cancers in Japanese men and the sixth largest cause of cancerrelated death [2,3,4]. Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with nonmetastatic 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. In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. Conclusion Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients.
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