Effects of everolimus (EVE) on disease progression in bone and bone markers (BM) in patients (pts) with bone metastases (mets).

Abstract

512 Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor–positive breast cancer (BC) refractory to non-steroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J, et al. NEJM. 2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. Methods: Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation, and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a pre-existing bone lesion or a new bone lesion. Results: Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (P < .0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO, but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively) and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade1/2 and occurred with similar frequency in EVE- (2.9%) and PBO- (3.8%) treated patients. Conclusions: Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.