Exemestane Plus Everolimus New Standard of Care for Postmenopausal Hormone Receptor-Positive Advanced Breast Cancer


The BOLERO-2 trial suggests that adding everolimus to hormonal therapy can overcome resistance in patients whose disease progressed.

Gabriel N. Hortobagyi

Gabriel N. Hortobagyi, MD

Although hormonal therapy can delay or prevent disease progression in hormone receptor-positive (HR+) breast cancer, resistance develops over time. Updated results of BOLERO-2 suggest that the addition of everolimus to hormonal therapy can overcome that resistance in patients whose disease progressed despite being treated with hormonal therapy.

Adding everolimus to exemestane extends progression-free survival (PFS) in postmenopausal women with HR+ breast cancer, as demonstrated in the original results and updated results of the phase III BOLERO-2 trial. Results were first presented at ECCO/ESMO in September 2011. Data based on an additional 5 months of follow-up were presented at the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) on December 8, 2011. Study results were published online in the New England Journal of Medicine to coincide with the formal presentation at SABCS.

“The addition of everolimus to exemestane markedly improves the duration of disease control. The difference between the two arms in PFS was highly significant in favor of the addition of everolimus. The trial was based on the original hypothesis that the combination would be of benefit, based on compelling preclinical experiments and preliminary results of earlier, smaller clinical trials. These results establish exemestane and everolimus as a new standard of care for postmenopausal HR+ breast cancer,” stated Gabriel N. Hortobagyi, MD, professor of medicine and director of the Multidisciplinary Breast Cancer Research Program at the University of Texas MD Anderson Cancer Center in Houston, TX.

Experts found the results of this trial exciting. In fact, when asked about FDA approval for everolimus in this setting, Jose Baselga, MD, Massachusetts General Hospital, Boston, MA, stated, “I’m looking forward to having everolimus [approved for this indication] to treat patients as soon as possible.”

The prospective, double-blind, placebo-controlled, phase III BOLERO-2 trial enrolled 724 postmenopausal women with HR+ metastatic breast cancer who had progressed on anastrozole or letrozole. Patients were randomized 2:1 to exemestane plus everolimus (n=485) versus exemestane plus placebo (n=279). At baseline, median age was 62 years, 56% had visceral metastases, and 84% had documented benefit from previous endocrine therapy with letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%).

At a median follow-up of 12.5 months, median PFS was 7.4 months for the combination versus 3.2 months for exemestane plus placebo. The rate of clinical benefit (complete response, partial response, stable disease, amount of pain, and overall benefit of the drug) was 50.5% for the combination versus 25.5% for exemestane plus placebo.

Overall survival data are not yet available. The combination of exemestane plus everolimus was well tolerated; the most common grade 3 or higher adverse events were stomatitis (8% for the combination versus 1% for exemestane plus placebo, respectively), anemia (7% versus 1%, respectively), hyperglycemia (5% versus <1%, respectively), dyspnea (4% versus 1%, respectively), and fatigue (4% versus 1%, respectively). Hortobagyi said that although adverse events were higher in the combination arm, they were manageable with dose interruption and/or reduction and did not appear to affect quality of life.

Everolimus inhibits the mTOR pathway, which is activated in hormone-resistant advanced breast cancer. Phase II clinical trials showed promise for everolimus as monotherapy and in combination with endocrine therapy in patients with estrogen-receptor advanced breast cancer.

“These results highlight the progress being made in understanding the evolving mechanisms of resistance to standard therapies,” Hortobagyi said.

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