Abstract PD5-07: A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226
Authors: Mehta RS , Barlow WE , Albain KS , Vandenberg TA , Dakhil SR , Tirumali NL , Lew DL , Hayes DF , Gralow JR , Linden HM , Livingston RB , Hortobagyi GN 
Published: February 2018

Abstract
Background: Anastrozole depletes estrogen via aromatase inhibition and fulvestrant binds and degrades estrogen receptor. In a Phase III trial we compared the concurrent use of these agents to anastrozole alone or sequential anastrozole and fulvestrant in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women, and demonstrated improved progression-free (PFS) and overall survival (OS)-NEJM 2012. Now we report PFS and OS five years after the initial positive findings. 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 administered as a loading dose of 500 mg on day 1, 250 mg on days 14, 28 and monthly thereafter. Randomization was stratified by adjuvant tamoxifen use. The primary endpoint was PFS with OS a secondary outcome. 40% patients not in visceral crisis crossed over to fulvestrant after progression on arm 1. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Subset analyses include treatment effect by adjuvant tamoxifen exposure, initial sites of metastases and time from diagnosis. Results: There were 646 PFS events (328 and 318 for arms 1 and 2, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for arm 1 and 15.0 months for the arm 2 (log-rank p=0.007; HR=0.81 (95% CI 0.69-0.94)). This benefit extended similarly in visceral and non-visceral subgroups. In subset analysis for Arms 1 and 2, respectively, in tamoxifen-naive women (60%, n=414), median PFS was 12.7 vs. 16.7 months (log-rank p=0.002; HR=0.73 (95% CI 0.60-0.89) while in women exposed to tamoxifen, median PFS was 13.9 vs. 13.6 months (log-rank p=0.57; HR=0.93 (95% CI 0.73-1.19)). An improved OS in the combination arm was seen, median OS 42 and 50 months in arms 1 and 2, based on 261 and 247 deaths, respectively (log-rank p=0.028; HR=0.82 (95% CI 0.69-0.98)). In subset analysis in tamoxifen-naive women, median OS was 40.3 vs. 52.2 months for Arms 1 and 2, respectively (log-rank p=0.007; HR=0.73 (95% CI 0.58-0.92)) while in women exposed to tamoxifen, median OS was 43.5 vs. 48.2 months (log-rank p=0.85; HR=0.97 (95% CI 0.74-1.27). Patients with initial diagnosis &gt;10 years benefitted most from the combination (HR=0.66 (95% CI 0.49-0.89)) regardless of tamoxifen exposure. Patients in Arm 1 who crossed over had post-progression survival similar to post-progression survival of Arm 2 patients. Conclusion: The addition of fulvestrant to anastrozole was associated with improved long-term PFS and OS compared to anastrozole alone, despite the use of fulvestrant at a dose lower than the approved, and despite the substantial cross over to fulvestrant after progression on anastrozole alone. The benefit was especially notable in those without recent exposure to adjuvant endocrine therapy. Ongoing translational medicine studies will further refine the need for up front fulvestrant. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI U10CA180888, U10CA180819 and AstraZeneca.
Citation Format: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NL, Lew DL, Hayes DF, Gralow JR, Linden HM, Livingston RB, Hortobagyi GN. A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-07.