Journal Article
. 2019 Mar;380(13).
doi: 10.1056/NEJMoa1811714.

Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer

Rita S Mehta 1 William E Barlow 1 Kathy S Albain 1 Ted A Vandenberg 1 Shaker R Dakhil 1 Nagendra R Tirumali 1 Danika L Lew 1 Daniel F Hayes 1 Julie R Gralow 1 Hannah H Linden 1 Robert B Livingston 1 Gabriel N Hortobagyi 1 
  • PMID: 30917258
  •     16 References
  •     19 citations


Background: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.

Methods: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.

Results: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.

Conclusions: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; number, NCT00075764.).

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.
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Lancet, 2016 Dec 03; 388(10063). PMID: 27908454
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Debu Tripathy, Seock-Ah Im, +23 authors, Yen-Shen Lu.
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Richard S Finn, John P Crown, +15 authors, Dennis J Slamon.
Lancet Oncol, 2014 Dec 20; 16(1). PMID: 25524798
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Maura N Dickler, William T Barry, +12 authors, Clifford A Hudis.
J Clin Oncol, 2016 May 04; 34(22). PMID: 27138575    Free PMC article.
Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study.
Miguel Martín, Sibylle Loibl, +16 authors, Juan R De la Haba-Rodriguez.
J Clin Oncol, 2015 Feb 19; 33(9). PMID: 25691671
Combination anastrozole and fulvestrant in metastatic breast cancer.
Rita S Mehta, William E Barlow, +8 authors, Gabriel N Hortobagyi.
N Engl J Med, 2012 Aug 03; 367(5). PMID: 22853014    Free PMC article.
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Lancet Oncol, 2013 Aug 02; 14(10). PMID: 23902874
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Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer.
Angelo Di Leo, Guy Jerusalem, +12 authors, Miguel Martin.
J Clin Oncol, 2010 Sep 22; 28(30). PMID: 20855825
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J Clin Oncol, 2012 Mar 01; 30(16). PMID: 22370325
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Angelo Di Leo, Guy Jerusalem, +5 authors, Miguel Martin.
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Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.
Dennis J Slamon, Patrick Neven, +18 authors, Guy Jerusalem.
J Clin Oncol, 2018 Jun 05; 36(24). PMID: 29860922
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Valentina Rossi, Paola Berchialla, +11 authors, Alessandra Fabi.
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M K Fink.
Ann Oncol, 2019 May 17; 30(8). PMID: 31095301    Free PMC article.
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Advances in endocrine and targeted therapy for hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
Le-Sang Shen, Xiao-Yan Jin, +2 authors, Jian Huang.
Chin Med J (Engl), 2020 Apr 09; 133(9). PMID: 32265426    Free PMC article.
ABC5 International Consensus Conference on Advanced Breast Cancer, Lisbon, 16 November 2019: Commentary by the German panel of experts on the ABC5 voting results.
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Geburtshilfe Frauenheilkd, 2020 Jun 23; 80(6). PMID: 32565549    Free PMC article.
Case report: 5-year progression free survival and complete liver response in a patient with metastatic breast cancer treated with everolimus plus exemestane.
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Half-dose fulvestrant plus anastrozole as a first-line treatment for hormone receptor-positive metastatic breast cancer: a cost-effectiveness analysis.
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Endocrine-Resistant Breast Cancer: Mechanisms and Treatment.
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