SAN ANTONIO—Adding everolimus to exemestane increased progression-free survival in the Phase III BOLERO-2 trial, which researchers say validates targeting the oral mammalian target of rapamycin (mTOR) pathway in patients with hormone receptor-positive (HR+) advanced breast cancer whose disease has progressed during or after nonsteroidal aromatase inhibitor (AI) therapy.
Median progression-free survival was 11.0 months for the combination vs. 4.1 months for exemestane plus placebo, according to the final progression-free survival analysis presented here at the CTRC-AACR San Antonio Breast Cancer Symposium (Abstract P6-04-02).
The first author of the poster study, Martine Piccart-Gebhart, MD, PhD, Director of Medicine at Institut Jules Bordet in Brussels, had reported an interim analysis a few months before at the ESMO meeting, the results of which were also published simultaneously in the New England Journal of Medicine (2012;366:520-529) and showed that combining the mTOR inhibitor everolimus with the steroidal aromatase inhibitor exemestane significantly prolonged progression-free survival in this patient population.
The Phase III, double-blind trial of 724 patients randomly assigned 485 postmenopausal women with HR+ breast cancer progressing or recurring after nonsteroidal aromatase inhibitors (letrozole or anastrozole) to everolimus (10 mg once daily) plus exemestane (25 mg once daily), and 239 similar patients to placebo plus exemestane.
At a median follow-up of 18 months, 510 progression-free survival events were reported at the San Antonio meeting, showing that the addition of everolimus to exemestane significantly prolonged median progression-free survival versus exemestane monotherapy as per local assessment—7.8 vs. 3.2 months, respectively, with a hazard ratio of 0.45.
These data, the researchers said, were consistent with results based on central assessment—11.0 vs. 4.1 months, respectively, for a hazard ratio of 0.38.
The improvements in progression-free survival were seen in patients regardless of bone involvement or visceral metastases. And fewer deaths were reported at 18 months with the everolimus-exemestane regimen, 25.4 percent, vs. 32.2 percent for placebo-exemestane.
Analysis of progression-free survival based on central radiologic assessment resulted in an estimated 62 percent risk reduction for progression or death, the researchers reported.
The safety profile of everolimus-exemestane was consistent with that reported at the interim analysis and with data for everolimus from other oncology settings.
Baselga: Results Represent Paradigm Shift
In an interview, the first author of the NEJM report, José Baselga, MD, Physician-in-Chief of Memorial Sloan-Kettering Cancer Center, said the trial's outcomes represent a paradigm shift at several levels.
“This is one of the first therapies that address the issue of endocrine resistance,” he said. “What we've done with ER-positive tumors has been to adjust for neoadjuvant hormonal therapies. That actually has been fruitful to a point, and so we've had tamoxifen, the AIs, and then fulvestrant. But for the first time we are talking about a different pathway, one that is responsible for resistance.”
The doubling of progression-free survival in BOLERO-2 shows it is one of the most positive studies—“and this just on our first try, so now we can refine things tremendously,” he said, adding that an analysis of gene sequencing from BOLERO-2 will be presented this spring at the American Association for Cancer Research Annual Meeting.
“Now imagine if we can begin to refine the whole approach by trying to identify who responds better,” he said.
And there are new agents. Baselga said the alpha-specific PI3-kinase inhibitors are believed to be more potent than mTOR inhibitors, “and we are seeing huge, huge response rates [with them] in the Phase I setting.”
The next steps in this research, he said, will be to compare everolimus in different lines of therapy, in the first-line and adjuvant settings and to develop PI3-kinase inhibitors.
He also mentioned an ongoing Phase III registration study of the orally bioavailable PI3-kinase inhibitor BKM120 plus fulvestrant in women with advanced breast cancer, for which he is principal investigator.
“I anticipate a number of trials that will change the way we treat ER-positive breast cancer,” he said.