SAN ANTONIO — Overall survival results are "impressive" for the selective estrogen-receptor down-regulator (SERD) fulvestrant (Faslodex, AstraZeneca) as a first-line therapy in postmenopausal women with hormone receptor (HR)-positive locally advanced or metastatic breast cancer, according to results from the phase 2 FIRST trial, presented here at the San Antonio Breast Cancer Symposium 2014.
As well as overall survival, the time to disease progression was significantly better with fulvestrant, which is administered by intramuscular injection, than with the current standard of care, the oral aromatase inhibitor anastrozole (Arimidex, AstraZeneca).
"This is an exciting and promising finding given that CONFIRM, our earlier phase 3 trial to test 500 mg fulvestrant in a second-line setting, also showed a survival advantage over anastrozole," said lead investigator John Robertson, MD, professor of surgery at Graduate Entry Medicine and Health School, University of Nottingham, Royal Derby Hospital, United Kingdom, in a press release.
"I don't know any other endocrine therapy where you can see a time-to-progression and survival benefit in both the second- and the first-line settings," he said during a press conference.
The FIRST phase 2 results bode well for the ongoing phase 3 FALCON study, which is necessary for regulatory approval of fulvestrant in the first-line setting, and "would be practice-changing," said Dr Robertson.
Superior to Anastrozole
The FIRST trial involved 205 women with advanced HR-positive disease from 62 centers in nine countries.
Patients were randomized to first-line therapy with fulvestrant 500 mg on days 0, 14, and 28, and every 28 days thereafter (n = 102), or to oral anastrozole 1 mg per day (n = 103).
The previously reported primary end point of the study — the clinical benefit rate (the number of patients whose disease is controlled at the end of the first 6 months) — was not significantly different between the groups.
However, time to progression, the previously reported secondary end point, was 34% longer with fulvestrant than with anastrozole (23.4 vs 13.1 months; hazard ratio [HR], 0.66).
Overall survival was not a defined end point in the original protocol, but, according to the newest data, median overall survival was longer in the fulvestrant group than in the anastrozole group (54.1 vs 48.4; HR, 0.70; P = .041), Dr Robertson reported.
"To put that in context in terms of the additional benefits we're seeing, when I first started treating breast cancer 30 years ago, average survival was 24 months; in this study, we're at 54 months," he said.
The survival benefit appeared to be consistent in all the predefined subgroups, irrespective of age, HR status, site of disease, and previous treatments.
There were no new safety issues. As expected, serious adverse events were similar in the fulvestrant and anastrozole groups (23.8% vs 21.4%). "These drugs have been given over many years and the extended follow-up of this study did not show any new safety concerns," Dr Robertson reported.
"This is a tremendously impressive result," said Kerin Adelson, MD, a medical oncologist at the Yale Cancer Center in New Haven, Connecticut, who was not involved in the study.
"Most drugs approved for the treatment of metastatic breast cancer only show a benefit in terms of time to progression or progression-free survival. It is much harder to demonstrate a benefit in terms of the overall survival," she told Medscape Medical News.
"I believe this result is extremely significant," she noted. "More and more evidence is accumulating to suggest that fulvestrant is superior to aromatase inhibitors and should be used earlier in the course of disease. These updated results of the FIRST trial are the most convincing of that evidence," Dr Adelson explained.
Dr Robertson said that the FIRST trial "cries out for an adjuvant study," but suggested this is unlikely to happen. "It's really a commercial issue; the drug is about to go off patent," he noted. "Unless the [National Institutes of Health] takes over and says they will fund such a study, I think it's unlikely the company will."
"What we're going to see is, almost certainly, that in the adjuvant setting, it will be the next generation of SERDs," Dr Robertson said.
There is a sense of regret about that, said press conference moderator and conference cochair Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine in Houston.
"Many of us, including myself, have thought, since development of the drug in the lab, that this was the best endocrine therapy that we have, but then we met with problems," he explained, referring to fulvestrant's inconvenient intramuscular administration and it's "checkered past" in terms of dosing. Initial studies using half the current dose failed to show the superiority of fulvestrant over anastrozole and tamoxifen in the second- and first-line settings, essentially putting a halt to an adjuvant trial, said Dr Osborne.
The study was sponsored by AstraZeneca. Dr Robertson reports serving as a consultant for AstraZeneca and Bayer HealthCare; receiving research funding from Amgen, AstraZeneca, Bayer HealthCare, and Novartis; and receiving speaking honoraria from AstraZeneca and GlaxoSmithKline. Dr Adelson has disclosed no relevant financial relationships. Dr Osborne is on the advisory boards of Pfizer, AstraZeneca, and NanoString.
San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S6-04. Presented December 12, 2014.
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Cite this: Fulvestrant Survival Advantage in Advanced Breast Cancer - Medscape - Dec 15, 2014.