Rita S. Mehta, MD
The frontline combination of fulvestrant (Faslodex) and anastrozole resulted in a sustained benefit in progression-free survival (PFS) and a significant improvement in overall survival (OS) compared with anastrozole alone in patients with postmenopausal, hormone receptor (HR)–positive metastatic breast cancer, according to long-term results of the SWOG S0226 trial (NCT00075764).1,2
The median OS in the combination arm was 49.8 months versus 42.0 months in the anastrozole-alone arm, resulting in an 18% reduction in the risk of progression or death (HR, 0.82; 95% CI, 0.69-0.98; P
= .03). Moreover, there were 247 total deaths among 349 women (71%) in the combination arm compared with 261 deaths among 345 women (76%) in the monotherapy arm. At 5 years, 42% of women in the combination arm were alive compared with 33% in the monotherapy arm.
The median rates of PFS were 15.0 months and 13.5 months in the combination and monotherapy arms, respectively (HR, 0.81; 95% CI, 0.69-0.94; P
Metastatic HR-positive breast cancer accounts for approximately 2 out of every third breast cancer diagnosis in the United States, underscoring the need for a life-extending frontline therapy, the investigators noted.
“These results are very exciting,” said Rita S. Mehta, MD, a member of the SWOG’s breast cancer research committee, a clinical professor at the University of California Irvine, and medical director of the Breast Center at Chao Family Comprehensive Cancer Center, in a press release.
Initial results from the phase III trial published in the New England of Medicine
in 2012 showed an improvement in median PFS and a marginal improvement in OS, which served as the primary and secondary endpoints of the trial, respectively.3
The previously reported rates of median PFS in the combination and monotherapy arms were 15.0 months and 13.5 months, respectively (HR, 0.80; 95% CI, 0.68-0.94; P
= .007). Moreover, at a median follow-up of 3 years, the rates of median OS were 47.7 months and 41.3 months, favoring the combination of fulvestrant and anastrozole (HR, 0.81; 95% CI, 0.65-1.00; two-sided P
Patients with estrogen receptor–positive or progesterone receptor–positive metastatic breast cancer with a Zubrod’s performance score of ≤2, who had not received prior chemotherapy, hormonal therapy, or immunotherapy were randomized 1:1 to anastrozole alone (n = 345) or fulvestrant plus anastrozole (n = 350). Adjuvant tamoxifen was allowed and served as a stratification criterion in the trial. If patients received neoadjuvant or adjuvant therapy with chemotherapy or an aromatase inhibitor, it had to be completed >12 months prior to enrollment.
Fulvestrant was given at a loading dose of 500 mg on day 1, followed by 250 mg on days 14 and 28, and 250 mg of maintenance therapy every 28 days. Crossover was permitted at the time of progression in the absence of visceral crisis. Towards the end of the trial, patients were allowed to supplant 250 mg of maintenance fulvestrant with 500 mg upon progression, per the FDA approval of the higher dose in 2010.
Among 707 patients who underwent randomization between June 2004 and June 2009, 694 were eligible for evaluation. Patients without progression were followed for a median 7 years after starting therapy. Additionally, the median age was 65 years. Forty percent of patients received prior adjuvant tamoxifen, and 33% received prior adjuvant chemotherapy. Approximately 10% of patients in both arms expressed HER2 positivity, and 45% of patients in the anastrozole-alone arm crossed over to the combination arm at the time of progression.
The OS benefit with the combination was observed in most subgroups, including age (≥65 versus ≤65 years), disease site (visceral metastases, nonvisceral metastases, and bone-only metastases), measurable disease, prior endocrine therapy, time between diagnosis of primary and metastatic disease (≥10 years; 5 to >10 years; 3 months to <5 years; none), and endocrine sensitivity.
However, patients who were diagnosed with metastatic disease 5 to >10 years from their primary diagnosis and those who were refractory to endocrine therapy experienced an OS benefit with anastrozole alone versus the combination (HR, 1.01; 95% CI, 0.69-1.48).
Patients with endocrine sensitivity, defined as tamoxifen-naivety or >6.5 years between the first diagnosis and enrollment or randomization, experienced an 8.4-month extension in median OS with the combination, at 50.7 months and 42.3 months (HR, 0.79; 95% CI, 0.65-0.95), respectively. Patients who were refractory to endocrine therapy, which was defined as <6.5 years between the first diagnosis and enrollment/randomization, experienced a worse survival with the combination; the median OS was 39.2 months with anastrozole alone versus 35.1 months with fulvestrant/anastrozole (HR, 1.08; 95% CI, 0.65-1.80; P
= .24 for interaction), respectively.