As reported in The New England Journal of Medicine by Rita S. Mehta, MD, and colleagues, the final overall survival results of the phase III SWOG S0226 trial show that the addition of first-line fulvestrant to anastrozole was associated with improved overall survival in postmenopausal women with hormone receptor–positive metastatic breast cancer. The improvement was observed despite a high degree of crossover to fulvestrant after progression on anastrozole alone. The initial report from the trial showed prolonged progression-free survival, the primary endpoint, and marginally prolonged overall survival with fulvestrant plus anastrozole.
Rita S. Mehta, MD
In the open-label trial, 694 eligible patients were randomly assigned to receive fulvestrant at a loading dose of 500 mg on day 1, with 250 mg on days 14 and 28, and then 250 mg as maintenance therapy every 28 days plus standard anastrozole (n = 349) or anastrozole alone (n = 345). Randomization was stratified according to adjuvant tamoxifen use.
Overall, 40% of patients had received adjuvant tamoxifen. Crossover to fulvestrant was encouraged at time of progression in the anastrozole group. Treatment was continued until disease progression, development of unacceptable toxicity, a delay in treatment of 4 weeks or longer, or patient withdrawal.
Median follow-up among the patients who did not have disease progression was 7 years, with a maximum follow-up of 12 years. Overall, there were 247 deaths (71%) among 349 women in the combination group and 261 deaths (76%) among 345 women in the anastrozole group. Median overall survival was 49.8 months vs 42.0 months (hazard ratio [HR] = 0.82, P = .03).
Among women who had received no prior tamoxifen, the combination group had significantly prolonged overall survival (median = 52.2 months vs 40.3 months; HR = 0.73, 95% confidence interval [CI] = 0.58–0.92). However, among women who had received tamoxifen, there was no significant difference between groups (median = 48.2 months vs 43.5 months; HR = 0.97, 95% CI = 0.74–1.27; P = .09 for interaction). Approximately 45% of patients in the anastrozole group crossed over to receive fulvestrant after progression.
Updated data on progression-free survival showed median progression-free survival of 15.0 vs 13.5 months (HR = 0.81, P = .007) among all patients; 16.7 vs 12.7 months (HR = 0.73, 95% CI = 0.60–0.89) among those who had not received prior tamoxifen; and 13.6 vs 13.9 months (HR = 0.93, 95% CI = 0.73–1.19) among those with prior exposure to tamoxifen.
As of the data cutoff for the current analysis, no new grade 4 or 5 adverse events had occurred since the initial report from the trial. Grade 3 adverse events occurred in 15% of the combination group and 13% of the anastrozole group, including musculoskeletal pain, fatigue, hot flashes, mood alterations, and gastrointestinal symptoms.
The investigators concluded, “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.”