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BOLERO-2: Practice-Changing Results With Exemestane Plus Everolimus in Advanced Breast Cancer

TOP - February 2012, Vol 5, No 1 published on February 28, 2012 in Breast Cancer

Updated results of the phase 3 BOLERO-2 trial demonstrated that adding everolimus to hormonal therapy extends progression-free survival (PFS) in hormone receptor–positive (HR+) metastatic breast cancer that progressed on hormonal therapy with anastrozole or letrozole. The positive outcomes observed in this study suggest that everolimus plus exemestane will be a new option for postmenopausal metastatic HR+ breast cancer.

First results of this study, called BOLERO-2, were presented in September 2011 at ECCO/ESMO/ESTRO. Updated results with additional follow-up, presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, confirm the PFS benefit of adding everolimus to exemestane in this group of women. Overall survival (OS) data are not yet mature.

“We believe these results underline that everolimus is the first agent to significantly enhance the efficacy of hormonal therapy in patients with HR+ breast cancer. The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient population,” 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, Texas

“Endocrine therapy is the treatment of choice for the majority of breast cancers that express the estrogen receptor, which represents about 75% of patients over age 50. The standard is to use multiple endocrine regimens in sequence to get multiple mileage. But the sad truth is that after a few months of suppression of tumor cells on one agent, tumor cells become smarter and resistant and we need to change agents,” Hortobagyi explained.

Everolimus is an mTOR inhibitor. This pathway is activated in hormone-resistant advanced breast cancer. Phase 2 clinical trials of everolimus monotherapy and in combination with endocrine therapy were encouraging in advanced HR+ breast cancer, Hortobagyi explained. Positive results of phase 2 trials with everolimus added to hormonal therapy led to the strategy tested in BOLERO-2, he said.

BOLERO-2 was a prospective, double-blind, placebo-controlled, phase 3 trial. The study population included 724 postmenopausal women with HR+ metastatic breast cancer with disease progression on previous hormonal therapy (ie, resistance). Patients were randomized 2:1 to exemestane plus everolimus (n=485) versus exemestane plus placebo (n=279).

Baseline demographics and disease characteristics were similar between the arms. 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%). Sixty percent had excellent performance status. The study population reflects a variety of ethnic groups, he said.

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 percentage of patients who experienced clinical benefit (complete response, partial response, stable disease, amount of pain, and overall benefit of the drug) was almost double in the combination arm: 50.5% for the combination versus 25.5% for exemestane plus placebo.

The combination of exemestane plus everolimus was well tolerated, Hortobagyi told listeners. The most common grade 3 or higher adverse events for the combination versus exemestane plus placebo, respectively, were stomatitis (8% vs 1%), anemia (7% vs 1%), hyperglycemia (5% vs <1%), dyspnea (4% vs 1%), and fatigue (4% vs 1%). Adverse events were manageable with dose delays or dose reductions. 

Quality of life was almost identical in both arms of the study.

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Last modified: July 22, 2021