title: Fulvestrant in postmenopausal women with advanced breast cancer.
abstract: OBJECTIVE
  Patients with hormone-sensitive breast cancer who have responded to tamoxifen (TAM) may receive additional benefit from a second endocrine agent after progression or relapse after TAM therapy. Fulvestrant (FVT; Faslodex; i.m. injection, ICI 182,780; AstraZeneca Pharmaceuticals, Wilmington, DE) was developed as a selective antagonist of estrogen. In postmenopausal women, FVT is reported to inhibit the proliferative effects of estrogen on sensitive tissues and has no apparent measurable estrogenic activity. In this report, we describe the data and analyses supporting marketing approval for FVT by the United States Food and Drug Administration (FDA).
  
  
  METHODS
  The FDA review of 16 clinical trials and 6 pharmacokinetic trials, as well as preclinical pharmacology and chemistry data, are described. The bases for marketing approval are summarized.
  
  
  RESULTS
  Toxicology studies in the mouse, rat, and dog showed minimal toxicity except for antiestrogenic effects. Because of FVT aqueous insolubility, an i.m. formulation, given at monthly intervals, was selected for clinical studies. Pharmacokinetic studies demonstrated sustained concentrations with monthly injection. In in vitro studies FVT was extensively metabolized, primarily by hepatic cytochrome P450 3A4. Phase I studies showed minimal toxicity, and the maximal dose (250 mg) was limited by FVT solubility. In two Phase III trials, 851 patients were randomized to either 250 mg FVT i.m. monthly or to anastrozole (ANZ) 1 mg p.o. daily. Ninety-six percent of patients had received TAM previously for early (adjuvant treatment) or advanced breast cancer. Response rates (RR) were 17% for both FVT and ANZ study arms in the North American trial, and were 20% versus 15% for FVT versus ANZ, respectively, in the European trial. There were no observed differences between study arms with respect to time to progression or survival. The most common FVT adverse events reported as potentially treatment-related were injection site reactions and hot flashes.
  
  
  CONCLUSIONS
  FVT was approved on April 25, 2002 by the FDA for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy. The recommended dose is 250 mg i.m. monthly as a single 5 ml injection or as two concurrent 2.5 ml injections into the buttocks. Approval was based on results of two randomized trials comparing response rates and time to progression of FVT- and ANZ-treated patients. Complete prescribing information is available on the FDA website.
authors.affiliation: Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Bross
authors.forename: Amy
authors.initials: A
authors.lastname: Baird
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Jee
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lostritto
authors.forename: David E
authors.initials: DE
authors.lastname: Morse
authors.forename: Liliam A
authors.initials: LA
authors.lastname: Rosario
authors.forename: Gene M
authors.initials: GM
authors.lastname: Williams
authors.forename: Peiling
authors.initials: P
authors.lastname: Yang
authors.forename: Atiqur
authors.initials: A
authors.lastname: Rahman
authors.forename: Grant
authors.initials: G
authors.lastname: Williams
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002986:Clinical Trials as Topic; D017277:Drug Approval; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009570:Nitriles / Q000627:therapeutic use; D017698:Postmenopause; D015996:Survival Rate; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol