title: A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer.
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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01284920.
authors.affiliation: Strategic Investigation On Comprehensive Cancer Network, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan. akazah@med.rcast.u-tokyo.ac.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Akaza
authors.affiliation: Department of Urology, Kinki University Faculty of Medicine, 377-2 Ono-Higashi, Osakasayama, 589-8511, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
authors.affiliation: Department of Urology, Sapporo Medical University School of Medicine, S1 W17 Chuo-ku, Sapporo, 060-8556, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ozono
authors.affiliation: Department of Urology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.affiliation: Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
authors.affiliation: Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Namiki
authors.affiliation: Department of Urology, Chiba Cancer Center, 666-2 Nitona-Cho, Chuo-ku, Chiba, 260-8717, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukasawa
authors.affiliation: Division of Urology, Harasanshin Hospital, 1-8 Taihakumachi, Hakata-ku, Fukuoka, 812-0033, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Department of Urology and Renal Transplantation, Yokohama City University Medical Center, 4-57 Urafune, Minami-ku, Yokohama, 232-0024, Japan.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Uemura
authors.affiliation: Department of Integrated Science and Engineering for Sustainable Society, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo, 112-8551, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ohashi
authors.affiliation: Astellas Pharma Inc, 2-5-1 Nihonbashi-Honcho, Chuo-Ku, Tokyo, 103-8411, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Astellas Pharma Inc, 2-5-1 Nihonbashi-Honcho, Chuo-Ku, Tokyo, 103-8411, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.affiliation: Astellas Pharma Inc, 2-5-1 Nihonbashi-Honcho, Chuo-Ku, Tokyo, 103-8411, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Urology, Harasanshin Hospital, 1-8 Taihakumachi, Hakata-ku, Fukuoka, 812-0033, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood; D004334:Drug Administration Schedule; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D017430:Prostate-Specific Antigen
keywords: Androgen receptor inhibitor; Enzalutamide; Metastatic castration-resistant prostate cancer