John Robertson, MD
Fulvestrant (Faslodex) improved overall survival (OS) by 5.7 months compared with anastrozole as a frontline treatment for postmenopausal women with HR-positive metastatic breast cancer, according to findings from the phase II FIRST trial presented at the 2014 San Antonio Breast Cancer Symposium.
In the open-label phase II trial, treatment with 500-mg fulvestrant reduced the risk of death by 30% compared with anastrozole. The median OS was 54.1 months with fulvestrant compared with 48.4 months with anastrozole (HR = 0.70; 95% CI, 0.50-0.98; P
= .041). Additionally, the benefit was seen across predefined subgroups of patients by age, tumor size, prior treatments, and other stratification factors.1
The phase III FALCON study is comparing the two drugs as frontline treatments for patients with HR-positive metastatic breast cancer. The primary endpoint of this study is progression-free survival (NCT01602380).
"We showed that the drug fulvestrant is better than the current standard of care, which is the third-generation aromatase inhibitor anastrozole," John Robertson, MD, 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."
In the phase II open-label study, postmenopausal patients with ER-positive primary breast cancer were randomized to receive fulvestrant at 500 mg on day 0, 14, and 28 followed by every 28 days (n = 102) or continuous anastrozole at 1 mg (n = 103). Patients who received prior adjuvant therapy were permitted to enroll in the trial. The median age of patients was 67 years.
The primary endpoint of the study was clinical benefit rate (CBR), defined as objective response or stable disease for ≥24 weeks. Secondary outcome measures focused on objective response rate (ORR) and time to progression (TTP). OS was not defined as an original endpoint of the study.
An earlier analysis of the study revealed a 72.5% CBR with fulvestrant compared with 67% for anastrozole (odds ratio = 1.30; P
= .386). The ORR was 36% with fulvestrant and 35.5% with anastrozole. The TTP with fulvestrant was 23.4 versus 13.1 months with anastrozole (HR = 0.66; 95% CI, 0.47-0.92; P
Serious adverse events in the trial were similar between fulvestrant (23.8%) and anastrozole (21.4%). The incidence of side effects coincided with the known toxicity profiles for both agents.
"The side effect profile is as good if not better than any other endocrine agents," Robertson said.
The FDA initially approved fulvestrant in 2002 at a 250-mg dose following progression on an antiestrogen therapy, such as tamoxifen. This approval was based on similar response rates to the already approved agent anastrozole. However, pharmacokinetic findings from the phase III EFECT trial in 2008 prompted researchers to explore a 500-mg dose of fulvestrant.
Initial data comparing the 250-mg and 500-mg dose from the phase III CONFIRM study were published in 2010 showing a clear advantage for the larger dose. In the final analysis of the study, the median OS in the 500-mg fulvestrant arm was 26.4 months compared with 22.3 months in the 250-mg fulvestrant arm (HR = 0.81; 95% CI, 0.69-0.96; P
"For something to be practice changing and to change the standard of care, we normally wait for a phase III trial," said Robertson. "However, if you see this in context, the FIRST trial is the second trial to show a survival advantage with fulvestrant."
Other promising evidence has offered clues to an optimal frontline therapy for women with HR-positive metastatic breast cancer. Recent findings have implicated alterations in ESR1 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% of patients with breast cancer.
Authors of a paper that was published at the 2014 SABCS 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 fulvestrant, with stable metastatic disease for greater than 13 months.3
Robertson JFR, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: overall survival from the phase II ‘first’ study. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S6-04
Di Leo A, Jerusalem G, Petruzelka L, et al. Final analysis of overall survival for the phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg. Presented at: 2012 San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, TX. Abstract S1-4.
Palma NA, Ali S, Frampton G, et al. Profiling of ESR1-mutated metastatic breast cancers by FoundationOne allows a broad genomic understanding for potential clinical implications. Presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract PD6-5.