A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer

Hideyuki Akaza, Hirotsugu Uemura, Taiji Tsukamoto, Seiichiro Ozono, Osamu Ogawa, Hideki Sakai, Mototsugu Oya, Mikio Namiki, Satoshi Fukasawa, Akito Yamaguchi, Hiroji Uemura, Yasuo Ohashi, Hideki Maeda, Atsushi Saito, Kentaro Takeda, Seiji Naito, Hideyuki Akaza, Hirotsugu Uemura, Taiji Tsukamoto, Seiichiro Ozono, Osamu Ogawa, Hideki Sakai, Mototsugu Oya, Mikio Namiki, Satoshi Fukasawa, Akito Yamaguchi, Hiroji Uemura, Yasuo Ohashi, Hideki Maeda, Atsushi Saito, Kentaro Takeda, Seiji Naito

Abstract

Background: The safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of enzalutamide were investigated in patients with castration-resistant prostate cancer (CRPC) in Japan through a multicenter phase I/II study.

Methods: In phase I, patients with progressive metastatic CRPC received single, then multiple, ascending doses of enzalutamide 80, 160 or 240 mg/day. After assessment of tolerability at multiple doses of 160 mg/day for 4 weeks, post-docetaxel patients with CRPC and measurable disease were enrolled into phase II; receiving long-term administration of enzalutamide 160 mg/day.

Results: Nine and 38 patients were enrolled in phase I and II, respectively. During phase I, enzalutamide was well tolerated in each cohort; PK parameters were similar to those of non-Japanese populations in other studies. By week 12, overall response rate was 5.3 % and clinical benefit rate was 47.4 %. Prostate-specific antigen response rate (≥50 % reduction from baseline) was 28.9 %. Treatment-emergent adverse events reported in >20 % of patients in phase II were decreased weight, decreased appetite and constipation. No seizures were observed.

Conclusion: Enzalutamide at 160 mg/day was well tolerated, with PK and safety profiles similar to the non-Japanese population. Anti-tumor activity was observed in post-docetaxel Japanese patients with metastatic CRPC. Apparent differences in anti-tumor activity compared with the AFFIRM study (a phase III trial in a diverse population of patients with CRPC post-docetaxel) may be attributed to differences in treatment history prior to starting enzalutamide. Particularly in Japan, the influence of sequence in hormone treatments, including combined androgen blockade therapy, should be considered.

Trial registration: ClinicalTrials.gov NCT01284920.

Keywords: Androgen receptor inhibitor; Enzalutamide; Metastatic castration-resistant prostate cancer.

Figures

Fig. 1
Fig. 1
Waterfall plot of maximum percent change from baseline of serum PSA in phase II. PSA, prostate-specific antigen
Fig. 2
Fig. 2
Comparison of individual enzalutamide Cmax and AUC∞ during single-dosing. aPhase I, open-label, dose-escalation safety and pharmacokinetic study of enzalutamide in patients with CRPC conducted overseas [19]
Fig. 3
Fig. 3
Individual trough plasma sum of enzalutamide and active metabolite concentration versus time plot in the Japanese phase I/II and AFFIRM (International, phase III, randomized, double-blind, placebo-controlled study of enzalutamide in patients with prostate cancer who had previously been treated with one or two chemotherapy regimens, at least one of which contained docetaxel [14]) studies, up to day 169

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Source: PubMed

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