SAN ANTONIO (FRONTLINE MEDICAL NEWS)Fulvestrant resulted in a 30% improvement in overall survival, compared with anastrozole as first-line therapy for postmenopausal women with hormone receptor–positive advanced or metastatic breast cancer in the randomized FIRST trial.

This new finding follows upon a previously reported 34% reduction in the risk of disease progression in an earlier FIRST analysis. Plus, significant improvements in both disease progression and overall survival were seen with fulvestrant at 500 mg as second-line endocrine therapy in the Phase III CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial (J. Natl. Cancer Inst. Jan 2014;106:djt337 [ doi:10.1093/jnci/djt337 ]). The clinical performance of fulvestrant in these two studies outpaces that of any other endocrine therapy for advanced breast cancer, Dr. John Robertson observed in presenting the new FIRST overall survival results at the San Antonio Breast Cancer Symposium.

“I don’t know of any other endocrine therapy where you can see both a time-to-progression and overall survival benefit in both the second- and first-line settings. So I think this is a new and exciting development in endocrine therapy for women with advanced breast cancer,” declared Dr. John Robertson, professor of surgery at the University of Nottingham, England.

FIRST (Fulvestrant First-line Study Comparing Endocrine Treatments) was a phase II, open-label study involving 205 women randomized to intramuscular fulvestrant (Faslodex) at 500 mg once monthly or the aromatase inhibitor anastrozole (Arimidex) at 1 mg/day orally. Aromatase inhibitors have been considered the standard therapy in this setting.

At a median follow-up of 48.8 months, the median overall survival was 54.1 months in the fulvestrant arm, compared with 48.4 months with anastrozole, for a 5.7-month advantage in favor of fulvestrant. This translated to a 30% reduction in the risk of death in the fulvestrant group (P = .041), which Dr. Robertson believes patients and their families will consider highly clinically meaningful.

“When I first started taking care of breast cancer patients like these 30 years ago, the average survival was 24 months. In this study, with fulvestrant it’s 54 months. We’re seeing step-by-step improvements,” he commented.

The advantage in overall survival seen with fulvestrant was consistent across all predefined subgroups based upon age, prior chemotherapy or endocrine therapy, visceral involvement status, and progesterone receptor status.

Both treatments were generally well tolerated, with no new safety concerns observed.

“Fulvestrant is a drug that’s really well tolerated. I can’t think of another medication in oncology where you can double the dose – from 250 to 500 mg – with no increase in side effects,” Dr. Robertson observed.

Now underway is the phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy–Naive Advanced Breast Cancer) trial, in which 450 hormone therapy–naive women with advanced breast cancer are being randomized to fulvestrant at 500 mg or anastrozole.

Dr. C. Kent Osborne commented, “Many people, including myself, have thought since the time fulvestrant was developed in the lab that it was the best endocrine therapy that we have.” But the drug “has had a checkered past,” he noted, citing the inconvenience of the required once-monthly intramuscular injections, plus the fact that early studies of fulvestrant as adjuvant therapy in early breast cancer yielded unimpressive results because they used fulvestrant at 250 mg, which turned out to be the wrong dose.

“In view of the data from CONFIRM and FIRST, are there plans to bring fulvestrant back into the adjuvant setting?” asked Dr. Osborne, professor of medicine and director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston.

Dr. Robertson replied that it’s now quite apparent that fulvestrant would likely outperform aromatase inhibitors or tamoxifen as adjuvant therapy in early breast cancer, but he doubts that AstraZeneca, which markets the selective estrogen receptor down-regulator, will sponsor the requisite clinical trials. It wouldn’t be commercially viable. Adjuvant breast cancer therapy trials take a long time to produce results, and the drug will be close to going off patent by then.

“It’s a study that’s crying out to be done given what we’ve seen here in the FIRST study, but I think it is unlikely to happen unless somebody like the NIH takes on the funding,” Dr. Robertson said.

Pharmaceutical companies are now developing next-generation selective estrogen receptor down-regulators that can be given orally. They’re so new that it’s not yet known whether they’re actually effective, but if they are, they’ll be the ones studied as adjuvant therapy in clinical trials, not fulvestrant, he predicted.

“I’m skeptical,” said Dr. Osborne. “Trying to develop a better fulvestrant might work, but remember that after tamoxifen came out many, many companies tried to develop a better tamoxifen – and here we are with tamoxifen 40 years later.”

The FIRST trial was funded by AstraZeneca. Dr. Robertson reported serving as a consultant to that company as well as Bayer HealthCare and receiving research funding from both companies along with Amgen and Novartis.


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