Combining everolimus and exemestane improves progression-free survival in women with metastatic breast cancer

In an international phase III randomized study, everolimus, when combined with exemestane has been shown to dramatically improve progression-free survival. The study, known as BOLERO-2, was presented by professor Hortobagyi (University of Texas MD Anderson Cancer Center, Houston, TX, USA) during the 2011 CRTC-AACR San Antonio Breast Cancer Symposium. 

BOLERO-2 researchers enrolled 724 postmenopausal patients with hormone receptor positive (HR+) metastatic breast cancer and evidence of progressive disease while receiving anastrozole or letrozole. Patients were randomised between treatment with exemestane plus everolimus (N= 485), or exemestane plus placebo (N=239). “This study is based on the concept that we know more about resistance mechanisms to endocrine therapy. As such, the experimental arm of the study uses a dual attack on treatment refractory HR+ breast cancer: it simultaneously inhibits ER signaling with exemestane and the PI3-kinase/AKT/mTOR pathway with the use of everolimus,” Hortobagyi said. Preliminary results of BOLERO-2 were presented earlier this year at the European Multidisciplinary Cancer Congress (EMCC) and showed a significant progression-free survival benefit for patients treated with the combination therapy. The updated results presented by professor Hortobagyi represented six additional months of follow-up.

The presented results revealed a median progression-free interval of 3.2 months for patients in the exemestane plus placebo arm compared to 7.4 months in patients treated with the combination of exemestane and everolimus (HR[95%CI]: 0.44[0.36-0.53]; p1x10-16), a finding Hortobagyi describes as “highly significant.” Furthermore, the clinical benefit rate, defined as complete and partial responses and disease stabilisation exceeding six months, was 50.5% in patients in the combination arm, compred to only 25.5% in patients treated with hormonal therapy and placebo.

The incidence of adverse events, such as shortness of breath, hyperglycemia, mouth sores and fatigue were all higher in the combination arm, but were easily manageable and did not disturb the patient’s quality of life. Furthermore, researchers reported that bone resorption and formation markers increased in the exemestane arm and decreased in the combination arm. Due to the limited follow-up, researchers were not yet able to measure overall survival in BOLERO-2.

Hortobagyi believes that these findings are truly practice changing for women who meet the criteria for BOLERO-2. “Over the years, our treatment approach for women with metastatic breast cancer has been the sequential use of as many hormone therapies as possible, keeping metastatic disease under control for as long as possible. These new findings may allow us to change our approach in this group of heavily pre-treated patients, all of whom progressed on prior endocrine therapy, the addition of this mTOR inhibitor resulted in significant prolongation of progression-free survival and an improved response rate, with only a modest addition of toxicity.” Said Hortobagyi. Additional studies are currently planned to assess the combination of everolimus with an aromatase inhibitor in the adjuvant setting, as well as in the metastatic setting.

Speaker Gabriel N. Hortobagyi


Gabriel N. Hortobagyi, MD, FACP
University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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