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original article

Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer
Rita S. Mehta, M.D., William E. Barlow, Ph.D., Kathy S. Albain, M.D., Ted A. Vandenberg, M.D., Shaker R. Dakhil, M.D., Nagendra R. Tirumali, M.D., Danika L. Lew, M.A., Daniel F. Hayes, M.D., Julie R. Gralow, M.D., Robert B. Livingston, M.D., andGabriel N. Hortobagyi, M.D.

A BS T R AC T
Background

The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)–positive metastatic breast cancer.
Methods

Postmenopausalwomen with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrantwas administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progressionfree survival, with overall survival designated as a prespecified secondary outcome.
Results

The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combinationtherapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P = 0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P = 0.05 bythe log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.
Conclusions

From the University of California Irvine Medical Center, Chao Family Comprehensive CancerCenter, Orange (R.S.M.); SWOG Statistical Center (W.E.B., D.L.L.) and Puget Sound Cancer Consortium/ Seattle Cancer Care Alliance (J.R.G.) — both in Seattle; Loyola University Chicago Stritch School of Medicine, Maywood, IL (K.S.A.); London Health Sciences Center/ National Cancer Institute of Canada Clinical Trials Group, London, ON, Canada (T.A.V.); Wichita Community Clinical Oncology Program (CCOP),Wichita, KS (S.R.D.); Northwest CCOP/Northwest Permanente, Portland, OR (N.R.T.); University of Michigan, Ann Arbor (D.F.H.); University of Arizona/Arizona Cancer Center, Tucson (R.B.L.); and University of Texas M.D. Anderson Cancer Center, Houston (G.N.H.). Address reprint requests to Dr. Mehta at the University of California Irvine Medical Center, Chao Family Comprehensive Cancer Center, 101The City Dr., Bldg. 23, Orange, CA 92868, or at rsmehta@uci.edu.
N Engl J Med 2012;367:435-44. DOI: 10.1056/NEJMoa1201622
Copyright © 2012 Massachusetts Medical Society.

The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant thatwas below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.)

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