Fulvestrant/Anastrozole Combo Improves Survival in Metastatic HR+ Breast Cancer

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 = .007).

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 = .005).

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.

Moreover, OS among women who had not previously received tamoxifen (60%) was longer with the combination compared with anastrozole alone, with median OS rates of 52.2 months and 40.3 months, respectively (HR, 0.73; 95% CI, 0.58-0.92). Similarly, the combination was superior in terms of PFS, at 16.7 months and 12.7 months with the combination and monotherapy, respectively (HR, 0.73; 95% CI, 0.60-0.89).

Median OS was also longer with the combination versus monotherapy among women with prior exposure to tamoxifen (40%) at 48.2 months and 43.5 months, respectively (HR, 0.97; 95% CI, 0.74-1.27; P = .09 for interaction). The rates of median PFS were similar between both arms, at 13.6 months with the combination and 13.9 months in the anastrozole-alone arm (HR, 0.93; 95% CI, 0.73-1.19).

“Women who received fulvestrant, right upfront, lived longer based on this new long-term analysis. This is credible evidence that combination endocrine therapy should be considered an option for first-line treatment of advanced HR-positive breast cancer,” said Mehta in the press release.

Regarding safety, the rate of long-term grade ≥3 adverse events (AEs) was similar between arms and consistent with previously reported findings. As of the data-cutoff, grade 3 AEs were seen in 15% of patients in the combination arm and 13% of patients in the monotherapy arm (P = .47), the most common of which were musculoskeletal pain, fatigue, hot flashes, mood alterations, and gastrointestinal symptoms. However, 12 patients in the combination arm and 5 in the monotherapy arm discontinued therapy due to AEs.

“Women who are treated with fulvestrant upfront live about 8 months longer,” Mehta said in the press release. “That’s a lot of extra time to do the things you love with the people you love.”

References

1. Mehta R, Barlow W, Albain K, et al. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer [published online ahead of print March 28, 2019]. N Eng J Med. doi: 10.1056/NEJMoa1811714
2. Combo Better for HR+ Breast Cancer Patients. SWOG Cancer Research Network. Published March 27, 2019. https://bit.ly/2JJwnDq. Accessed March 28, 2019.
3. Mehta R, Barlow W, Albain K, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. [published online August 2, 2012]. N Eng J Med. doi: 1056/NEJMoa1201622.