Combination Treatment for Metastatic Breast Cancer Superior to Anastrozole Alone

Combination therapy with anastrozole and fulvestrant was found to be superior to treatment with anastrozole alone in a recent randomized study of postmenopausal women with hormone-receptor(HR)-positive metastatic breast cancer. The findings from this latest trial were recently published in the New England Journal of Medicine [2012;367(5):435-444].

Anastrozole, a selective aromatase inhibitor, is often used as a first-line endrocrine treatment for breast cancer patients with HR-positive metastatic disease because it acts by lowering the estrogen level. It can be used alone to treat the disease; however, researchers in this latest study wanted to explore whether adding fulvestrant, a medication that binds and accelerates the degradation of estrogen receptors, would improve treatment effectiveness. According to the study's authors, the combination of the 2 drugs could delay the development of resistance.

To test their hypothesis, they conducted a phase 3 randomized trial of postmenopausal women who had been diagnosed with previously untreated HR-positive metastatic breast cancer to determine whether the combination therapy had an impact on progression-free survival. In the trial, 707 participants were randomly assigned to either receive 1 mg of anastrozole orally each day or to receive a combination of anastrozole and fulvestrant. Those patients in the combination group were given an initial dose of 500 mg of fulvestrant on day 1, followed by 250-mg intramuscular doses on days 14, 28, and every additional 28 days after the first cycle, along with 1 mg of anastrozole given orally each day.

During the study, treatment was continued until the disease progressed, unacceptable toxic events were developed, there was a delay in treatment of ³4 weeks, or the patient chose to withdraw from the trial. Once progression of the disease had occurred, the physicians were able to select their next course of action; however, according to the study's authors, patients in the anastrozole-alone group were highly encouraged to cross over to fulvestrant. 

Researchers identified the study's primary outcome as progression-free survival and designated overall survival as a secondary outcome.

After assessing the study's results, researchers found that those patients in the combination therapy group had significant improvement in progression-free survival compared with those taking anastrozole alone. Based on the findings, those in the anastrozole-only group had a median progression-free survival of 13.5 months  (95% confidence interval [CI], 12.1-15.1), whereas those patients receiving the combination of drugs had a median progression-free survival of 15.0 months (95% CI, 13.2-18.4). Researchers reported a hazard ratio for progression or death with the combination therapy of 0.80 (95% CI, 0.68-0.94), and noted that the superiority of the combination therapy group when measuring progression-free survival emerged over time during the study.

Researchers also found that the median overall survival was longer for those patients in the combination therapy group, even though they noted that 41% of those patients who were taking anastrozole alone crossed over to fulvestrant once the disease had progressed. They found that the median overall survival for the anastrozole-alone group was 41.3 months (95% CI, 37.2 to 45.0), compared to 47.7 months (95% CI, 43.4 to 55.7) in the combination group. Using a stratified Cox regression analysis, they found that the estimated hazard ratio for death with the combination therapy was 0.81 (95% CI, 0.65 to 1.00).

The study's authors also collected data on toxic effects for both groups and found that most of the toxic effects were mild and did not differ significantly between the 2 groups. The rates of grade 3 to 5 toxic effects were also not significantly different between the 2 treatment groups; however, researchers did report that 3 of the deaths that occurred in the combination therapy group could have been associated with treatment.