The CONFIRM trial, comparing two doses of fulvestrant, confirmed what clinicians already had seen: that the higher dose is associated with superior overall survival in postmenopausal women with advanced estrogen receptor (ER)-positive breast cancer who experienced progression after prior endocrine therapy.
Overall survival in the randomized, double-blind CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial was 26.4 months for the higher dose compared with 22.3 months for the lower dose, when 75 percent of the patients had died, representing a 19 percent reduction in the risk of death.
The report also confirmed the researchers' earlier report at the 2009 Symposium and published in 2010 (Di Leo et al: JCO 2010;28:4594-4600). At that analysis, with 50 percent maturity, overall survival was 25.1 months for patients receiving fulvestrant at 500 mg and 22.8 months for those receiving fulvestrant at 250 mg.
Angelo Di Leo, MD, PhD, Chair of the Department of Medical Oncology at Hospital de Prato, Istituto Toscano Tumori, in Italy, said that while the new data confirm earlier results, they also showed that the initial benefit for the higher dose was maintained.
Patients in the study received either 500 mg IM of fulvestrant in two infusions or 250 mg IM in one infusion, either dose on days 0, 14, and 28, and every 28 days thereafter.
The improvement in survival with the higher dose was also achieved without increasing toxicity, he reported. The trial included 736 women from 128 centers in 17 countries. Serious adverse events occurred in 8.9 percent of patients who had received the 500 mg dose and in 6.7 percent of patients in the 250 mg group.
Di Leo said the researchers will now study the 500 mg dose in combination with biological agents such as PI3K inhibitors or anti-HER2 agents that can reverse resistance to endocrine therapy.
In an interview after the presentation, moderator Kathy S. Albain, MD, Professor of Medicine in the Division of Hematology/Oncology at Loyola University Medical Center, said the report would probably not affect clinical practice very much “because we've already been pretty confident to switch the dose to 500 mg. But it was important to show to a large audience that the initial report of a benefit to the double-dose state was robust, and didn't go away.”
Better ER Down-Regulators Needed
Also asked for his opinion, Symposium Co-director Carlos Arteaga, MD, PhD, Associate Director for Clinical Research and Director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, said it was known that 250 mg of fulvestrant is inadequate to inhibit the estrogen receptor—“To me the 250 mg arm was almost like a control arm in this case,” he said.
What is really needed, he said, are better ER down-regulators. “And I'm very optimistic, because I know that there are companies making oral ER down-regulators, where we'll be able to dial up the drug, and hopefully, without the toxicity, get rid of that ER. With fulvestrant it's very hard to go higher on the dose because it's a large-volume injection every month. But in 10 years or less I think we're going to be using oral ER down-regulators.”
Arteaga also mentioned a presentation (P06-04-12) in the “Endocrine Therapy and Resistance” poster session at the meeting that described an orally bioavailable selective estrogen receptor degrader (SERD). The drug is a non-steroidal estrogen-receptor-alpha antagonist made by Aragon Pharmaceuticals that produces tumor regression in vivo in tamoxifen-resistant and tamoxifen-sensitive breast cancer, according to the abstract.
“They have an oral ER down-regulator that should be in Phase 1 next year, so stay tuned,” he said.