Upfront Faslodex Improves Survival Over Anastrozole in Estrogen-Positive Metastatic Breast Cancer

Faslodex (fulvestrant) improved overall survival by nearly six months compared with anastrozole as initial hormone therapy for postmenopausal women with estrogen receptor-positive advanced breast cancer, according to findings from the phase 2 FIRST trial. Faslodex is currently approved for second-line therapy after cancer progression on anti-estrogen therapy.

The median survival was 54.1 months with 500-mg Faslodex compared with 48.4 months with anastrozole. Additionally, the benefit was seen across predefined subgroups of patients by age, tumor size, prior treatments and other factors.

"We showed that the drug fulvestrant is better than the current standard of care, which is the third-generation aromatase inhibitor anastrozole," John Robertson, professor of surgery at the University of Nottingham, Royal Derby Hospital in the United Kingdom, said in an interview with OncLive. "This is now the second randomized controlled trial where fulvestrant 500 has shown a time to progression and then now a survival advantage over the control arm. I don't know of any other endocrine therapies where you can see a time to progression and a survival benefit in both the second- and the first-line setting."

The primary endpoint of the study was clinical benefit rate, defined as objective response or stable disease for at least 24 weeks. Secondary outcome measures focused on objective response rate and time to disease progression. Overall survival was not defined as an original endpoint of the study.

An earlier analysis of the study revealed a 72.5 percent benefit with Faslodex compared with 67 percent for anastrozole. The overall response rate was 36 percent with Faslodex and 35.5 percent with anastrozole. The time to disease progression with Faslodex was 23.4 versus 13.1 months with anastrozole.

Serious adverse events in the trial were similar between the two arms. "The side effect profile is as good if not better than any other endocrine agents," Robertson said.

The Food and Drug Administration initially approved Faslodex in 2002 at a 250-mg dose following progression on an anti-estrogen therapy, such as tamoxifen. This approval was based on similar response rates to the already approved agent anastrozole. However, pharmacokinetic findings from the phase 3 EFECT trial in 2008 prompted researchers to explore a 500-mg dose of Faslodex.

Initial data comparing the 250-mg and 500-mg dose from the phase 3 CONFIRM study were published in 2010 showing a clear advantage for the larger dose; Faslodex was approved at the 500-mg dose later that year. "For something to be practice changing and to change the standard of care, we normally wait for a phase 3 trial," said Robertson. "However, if you see this in context, the FIRST trial is the second trial to show a survival advantage with fulvestrant."

The phase 3 FALCON study is now comparing the two drugs as front-line treatments for patients with metastatic hormone-positive breast cancer, and those results could lead to approval in the first-line setting. The primary endpoint of the study is progression-free survival (NCT01602380).

Other promising evidence has offered clues to an optimal front-line therapy for women with metastatic estrogen receptor-positive breast cancer. Recent findings have implicated alterations in the ESR1 gene in endocrine therapy resistance. A number of tests are available to ESR1 alteration. Findings from a study involving next-generation sequencing uncovered that aberrations in ESR1 occur in approximately 7.9 percent of patients with breast cancer.

Authors of a paper that was published at the symposium anecdotally described a case study from a single-patient experience that examined a case study from an ESR1 Y537-positive patient who was resistant to adjuvant tamoxifen and letrozole. In this scenario, the patient went on to respond to single-agent Faslodex, with stable metastatic disease for greater than 13 months.