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Continued Benefit for Everolimus in Updated Results of BOLERO-2

October 2012, Vol 5, No 7

Updated results from the pivotal phase 3 BOLERO-2 trial uphold, and even add to, the previous benefits reported for the addition of everolimus to exemestane in advanced breast cancer, including a positive effect on bone markers.1,2

The 18-month data from BOLERO-2 were reported at the American Society of Clinical Oncology 2012 Breast Cancer Symposium, held in San Francisco, California.

BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing treatment with the aromatase inhibitor exemestane (25 mg once daily) plus the mammalian target of rapamycin (mTOR) inhibitor ever­olimus (10 mg once daily) or placebo in 724 postmenopausal women with advanced estrogen receptor-positive breast cancer who progressed or recurred after treatment with letrozole or anastrozole.

In the previous 12-month analysis, the combination was associated with more than a doubling in disease-free survival, which led to the recent US Food and Drug Administration approval of the regimen after treatment with letrozole or anastrozole. The incorporation of an mTOR inhibitor into an endocrine-based regimen is a novel approach and represents a milestone in treating this disease, said Gabriel Hortobagyi, MD, chair of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, Houston, and the principal investigator of the pivotal trial.

“Everolimus is the first and only treatment that boosts the effectiveness of endocrine therapy,” he said. “This approval redefines the treatment and management of advanced hormone receptor-positive breast cancer."

18-Month Update Shows 55% Reduction in Risk
At the Breast Cancer Symposium, Hope S. Rugo, MD, of the University of California San Francisco, reported, “The progression-free survival [PFS] at the 18-month follow-up confirms the benefits observed at the 6.5-month and 12.5-month follow-ups, and the PFS benefits were consistent in all subgroups.” The study’s lead author was Francis P. Arena, MD.1

By local assessment, PFS was 7.8 months with everolimus/exemestane versus 3.2 months with exemestane alone, for a 55% reduction in risk. By central review, PFS was 11.0 months with the combination and 4.1 months with exemestane, for a 62% reduction in risk. The differences in each analysis were highly significant (P <.0001).

Overall survival differences, however, have yet to emerge, although the difference between the arms is widening, she said. Mortality rates are 25.4% with the combination and 32.2% in the control arm, for an absolute difference of 6.8% favoring the everolimus arm.

A post hoc analysis showed that, in addition to significantly improving PFS, everolimus plus exemestane does not compromise health-related quality of life (Abstract 125).3 Whereas the combination resulted in higher rates of grade 3/4 toxicity, especially stomatitis and fatigue, and more patients discontinued treatment in the experimental arm, the analysis consistently showed that time to deterioration according to the 30-item EORTC QLQ-C30 score was actually longer, not shorter, with the combination, Rugo reported.

Positive Effects on Bone Markers and Progression in Bone
In addition to delaying progression, an exploratory analysis of BOLERO-2 suggested that everolimus reduces bone turnover and reverses the increase in bone resorption associated with endocrine therapy, reported Lowell L. Hart, MD, of Florida Cancer Specialists in Fort Myers.2

Bone turnover markers analyzed at 6 and 12 weeks after treatment initiation included bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal cross-linking telopeptide of type 1 collagen. Progressive disease in bone was defined as worsening of a preexisting bone lesion or a new bone lesion.

In the placebo arm, bone-marker levels increased over baseline by more than 30%, but in the everolimus arm they actually decreased by more than 30%, for an absolute difference of 66%, Hart reported.

At day 60, progressive disease in the bone was observed in 3.03% of the combination arm versus 6.16% of the control arm (P = .0263), and this trend was sustained beyond 6 months. Hart reported that the delay in bone progression was seen in patients with and without bone metastases at baseline, and regardless of the use of bisphosphonates.

Fractures were observed in 2.3% of patients receiving the combination versus 3.8% on single-agent exemestane.

The positive bone effects occurred in addition to the reported increase in PFS, and “data suggest favorable bone health clinical benefits,” Hart said. “The bone-protective effect with everoli­mus suggests the potential for using everolimus in the adjuvant breast cancer setting for this purpose.” This hypothesis, in fact, will be tested in a trial by SWOG (Southwest Oncology Group).

Rugo elaborated on these findings. “Patients who took everolimus not only had less bone loss but actually seemed to improve from baseline. This is an unusual finding,” she said, noting that it is in keeping with preclinical models that suggest that mTOR inhibitors alter the effect of exemestane on bone.

“You are actually getting some buildup of the bone,” she pointed out, “which suggests that there is a site-specific effect with this targeted agent. This is exciting. It is not something we have seen much with other targeted agents.”

Future Trials of Everolimus
BOLERO-4, an open-label, international, single-arm phase 2 study, will evaluate everolimus plus letrozole in 200 patients, who will also receive everolimus plus exemestane upon progression. The phase 2 BOLERO-6 trial will evaluate everolimus, with and without exemestane, versus capecitabine in 300 patients. The phase 2 PrECOG trial will evaluate fulvestrant plus everolimus in 132 patients. SWOG 2107 will move everolimus into the adjuvant setting, evaluating 5 years of endocrine therapy with and without everolimus in high-risk early breast cancer patients.


  1. Arena FP, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. Presented at: American Society of Clinical On­cology 2012 Breast Cancer Symposium; Sept­ember 13-15, 2012; San Francisco, CA. Abstract 99.
  2. Hart LL, Baselga J, Rugo HS, et al. Effects of ever­olimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone meta­stases (mets). Presented at: American Society of Clinical Oncology 2012 Breast Cancer Sym­posium; Sept­ember 13-15, 2012; San Francisco, CA. Ab­stract 102.
  3. Rugo HS, Beck JT, Baselga J, et al. BOLERO-2: Health-related quality-of-life (HRQoL) in metastat­ic breast cancer patients treated with everolimus and exemestane versus exemestane. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 125.



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