title: Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial.
abstract: BACKGROUND
  The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation.
  
  
  METHODS
  In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea).
  
  
  RESULTS
  Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4-5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6-5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0-4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83-1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79-1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight).
  
  
  CONCLUSIONS
  After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane.
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK. stephen.johnston@rmh.nhs.uk
authors.forename: Stephen Rd
authors.initials: SR
authors.lastname: Johnston
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Kilburn
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
authors.forename: David
authors.initials: D
authors.lastname: Dodwell
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.forename: Larry
authors.initials: L
authors.lastname: Hayward
authors.forename: Young-Hyuck
authors.initials: YH
authors.lastname: Im
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: A Murray
authors.initials: AM
authors.lastname: Brunt
authors.forename: Kwok-Leung
authors.initials: KL
authors.lastname: Cheung
authors.forename: Rema
authors.initials: R
authors.lastname: Jyothirmayi
authors.forename: Anne
authors.initials: A
authors.lastname: Robinson
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wardley
authors.forename: Duncan
authors.initials: D
authors.lastname: Wheatley
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Gill
authors.initials: G
authors.lastname: Coombes
authors.forename: Nicole
authors.initials: N
authors.lastname: Sergenson
authors.forename: Hui-Jung
authors.initials: HJ
authors.lastname: Sin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Folkerd
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bliss
mesh_terms: D000077384:Anastrozole; D000730:Androstadienes / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000032:analysis; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; C056516:exemestane