S1-1: A Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226.

Abstract

Background: Anastrozole inhibits the aromatase enzyme-induced estrogen synthesis, and fulvestrant down-regulates estrogen receptors in hormone receptor-positive breast cancer. We hypothesized that the simultaneous disruption of the ligand-receptor axis with concurrent use of these agents may be potentially additive or synergistic in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women. Materials and Methods: A total of 707 patients were randomized to either 1 mg anastrozole P.O. daily (Arm 1) or to the combination of anastrozole and fulvestrant (Arm 2). Fulvestrant was given as an intramuscular injection as follows: loading dose of 500 mg on day 0, followed by 250 mg on days 14, 28 and 250 mg maintenance monthly thereafter. The primary endpoint was progression-free survival (PFS), with a power of 90% and one-sided alpha of 0.025 to detect an expected median PFS of 10 months in Arm 1 versus 13 months in Arm 2. Randomization was stratified by adjuvant tamoxifen use with the possibility of differential benefit of fulvestrant in the two strata. Patients were encouraged to crossover to fulvestrant after progression on the anastrozole alone arm (40% did), if they were not candidates for immediate chemotherapy. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Two interim analyses were performed with the final analysis using a 2-sided p-value of 0.04. Results: There were 548 events (287 and 261 by arms, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for anastrozole and 15.0 months for the combination of fulvestrant and anastrozole (log-rank p=0.0145; HR=0.81 (95% CI 0.68−0.96). In a subset analysis of tamoxifen-naive women (60%, n=414), median PFS was 12.6 months and 17.0 months for Arms 1 and 2, respectively (log-rank p=0.0069; HR=0.74 (95% CI 0.60−0.92)), and 14.1 months and 13.5 months for Arms 1 and 2, respectively, in the 40% of tamoxifen-pretreated women (log-rank p = 0.56; HR=0.93 (95% CI 0.71−1.20)). A trend for improved overall survival (OS) in the combination arm was seen (median OS was 42 and 48.6 months based on 152 and 137 deaths respectively, log-rank p = 0.094; HR=0.82 (95% CI 0.65−1.03)). On the combination arm, three treatment-related deaths occurred: due to pulmonary embolism (2) or cerebrovascular ischemia (1); one Grade 4 thrombosis/embolism and one Grade 4 neutropenia and lymphopenia were reported. On the anastrozole arm, four patients experienced Grade 4 toxicities: thrombosis/embolism, arthralgia, thrombocytopenia, and dyspnea. In general, Grade 3 or higher toxicity was rare (12.7% vs. 14.5% for Arms 1 and 2, respectively) and did not differ significantly. Discussion: The combination of anastrozole and fulvestrant was associated with improved PFS compared to anastrozole alone as well as a trend in OS despite substantial crossover, thus offering a new standard in the first-line treatment of hormone receptor-positive breast cancer in postmenopausal women, specifically in tamoxifen-naive patients. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI CA32102, CA38926 and AstraZeneca. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-1.

Breast Cancer 2012 - New Aspects

“…In the recently presented SWOG-S0226 trial which tested the combination of anastrozole and fulvestrant vs. anastrozole alone for metastatic breast cancer, surprisingly, significant differences were found both in progression-free survival (HR 0.8, 95 % CI: 0.68-0.94; p = 0.007, l " Fig. 6) and, above all, also in overall survival (HR 0.81; 95 % CI: 0.65-1.00; p = 0.049) [62]. This success was achieved almost exclusively in those patients who had not previously received tamoxifen.…”

“…Taking the health-care costs into consideration differentiated according to the various types of care offered, there are especially 3 major cost factors: for physiciansʼ services the expenditure in 2008 was 71.5 billion € (27.2 %), for nursing and thera-S0226 trial -Evaluation of the primary endpoint progression-free survival. Adapted after Mehta et al[62].…”

Optimizing Endocrine Therapy for Metastatic Breast Cancer

“…These results are in contrast to the earlier FACT trial, which was similar in design but may have included a larger proportion of "endocrine-insensitive" subjects, as 60% of women enrolled in S0226 had no adjuvant endocrine therapy. Although the results of S0226 are compatible with preclinical observations, the value of the benefit will need to be assessed from a clinical and cost-effectiveness perspective [47].…”

Metastatic Breast Cancer, Version 1.2012

“…13 In the second study (S0226), the progression-free survival (hazard rate, 0.80; 95% CI, 0.68–0.94, stratified log-rank P = .007) and overall survival (hazard rate, 0.81; 95% CI, 0.65–1.00; stratified P = .049) were superior with combination anastrozole plus fulvestrant. 14 An unplanned subset analysis of this trial suggested that patients without prior adjuvant tamoxifen experienced the greatest benefit with the combination endocrine therapy. The reason for the divergent outcomes in the 2 studies is not known.…”

“…Because of the contradictory results of the FACT 13 and S0226 14 trials, the NCCN Breast Cancer Panel has not made specific recommendations for including combination endocrine therapy in the main algorithm of the guidelines. However, the panel included a footnote on algorithm page BINV-18 (see page 823) stating, “A single study (S0226) in women with hormone receptor–positive breast cancer and no prior chemotherapy, biological therapy, or endocrine therapy for metastatic disease demonstrated that the addition of fulvestrant to anastrozole resulted in prolongation of time to progression (hazard rate for recurrence, 0.80; 95% CI, 0.68–0.94; stratified log-rank P =.007) and improvement in overall survival (hazard rate, 0.81; 95% CI, 0.65–1.00; stratified log-rank P = .049).…”