title: [Enzalutamide-a novel androgen receptor inhibitor that provides treatment options for patients with castration-resistant prostate cancer].
abstract: The recent emergence of new hormonal or chemotherapeutic drugs has resulted in a paradigm shift in the treatment of castration-resistant prostate cancer(CRPC). Enzalutamide is a rationally designed, orally administered androgen receptor(AR)inhibitor. It inhibits multiple points in the androgen receptor signalling pathway, which is considered an important driver of CRPC, including the inhibition of androgen binding to the AR, nuclear translocation of the AR complex, and binding of the AR complex to deoxyribonucleic acid(DNA). Unlike other anti-androgens(such as bicalutamide), enzalutamide does not act as a partial AR agonist. The first in human phase I/II trial was conducted in the United States in both chemotherapy-naïve patients and postchemotherapy patients with progressive metastatic CRPC(mCRPC). The results showed encouraging antitumor activity of enzalutamide by considering all outcomes assessed in the trial. The first reported phase III trial was a randomized, double-blind, placebo-controlled, multinational study involving 1,199 patients with mCRPC that progressed even after docetaxel therapy(AFFIRM trial). Enzalutamide was associated with significant benefits over the placebo considering time-to-event outcomes(i.e. prolonged overall survival[OS], delayed time to prostatic specific antigen[PSA]progression[TTPP], prolonged radiographic progression free survival[rPFS], time to the first skeletal related event[SRE])as well as objective response outcomes(i.e. PSA, soft tissue, and quality of life[QOL]). On the basis of the AFFIRM results, Astellas and Medivation filed a new drug application with the United States Food and Drug Administration and the European Medicines Agency in 2012, and obtained their approval. Another phaseI/II enzalutamide trial was conducted in both chemotherapy-naïve patients and post-chemotherapy pa- tients with progressive mCRPC. Enzalutamide at a dose of 160mg/day was well tolerated, and it showed pharmacokinetic characteristics, adverse events, and anti-tumor activity profiles similar to that of the non-Japanese population. On the basis of the results of the studies summarized above, a new drug application was submitted to the Ministry of Health, Labour, and Welfare of Japan in May 2013 and obtained the approval in Mar 2014. The second phase III trial was a randomized, double-blind, placebo-controlled, multinational study of 1,717 chemotherapy- naïve patients with CRPC(PREVAIL trial). An interim analysis recently demonstrated the significant benefits of enzalutamide over the placebo considering both OS and rPFS. In light of these results, the Independent Data Monitoring Committee (IDMC)advised terminating the study early, and suggested treating the patients in the placebo group with enzalutamide. This paper reviews the developmental history of enzalutamide, its pharmacokinetic and pharmacodynamic characteristics, as well as available efficacy and tolerability data yielded in clinical trials of patients with CRPC.
authors.affiliation: Oncology, Clinical Development 3, Development, Astellas Pharma Inc.
authors.forename: Hideki
authors.initials: H
authors.lastname: Maeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
mesh_terms: D059002:Androgen Receptor Antagonists / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D001549:Benzamides; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide