Subgroup analysis of a randomized, phase III study of the effect of denosumab in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy
Authors: G. K. Ellis, H. G. Bone, R. T. Chlebowski, D. Paul, S. Spadafora, J. Smith, M. Fan, S. Jun
Journal: Journal of Clinical Oncology (2008)

546 Background: In postmenopausal women with breast cancer, adjuvant AI therapy contributes to accelerated bone loss and risk for fracture. Denosumab, a fully human monoclonal antibody to RANKL, inhibits osteoclast-mediated bone loss. Methods: In this 2-year, double-blind, placebo-controlled study, we evaluated factors that may influence BMD in patients (pts) ≥ 18 years old with hormone receptor-positive breast cancer who were receiving adjuvant AI therapy and had evidence of low bone mass. Pts were stratified by duration of prior AI therapy (≤ 6 vs >6 months) and randomized to receive, together with calcium and vitamin D, placebo (n = 125) or 60 mg denosumab (n = 127) subcutaneously every 6 months for 4 doses. A sample size of 104 pts/group was planned to provide 95% power to detect a 2% difference between groups (α = 0.05). An analysis of covariance model was used for subgroup analyses, adjusting for treatment, stratification factor, baseline BMD value, densitometer type, and baseline BMD value-by-densitometer-type interaction. The primary endpoint was the percentage change from baseline to month 12 in lumbar spine BMD (Ellis G et al, 2007 SABCS Annual Meeting). We present a subgroup analysis (post-hoc) of the percentage change in BMD at the lumbar spine, total hip, femoral neck, and distal 1/3 radius at 12 months. Results: At all anatomic sites, representing both trabecular and cortical bone, denosumab consistently increased BMD compared with placebo at month 12; this increase was consistent regardless of site or subgroup (Table). The incidences of adverse events (AEs) (91% denosumab, 90% placebo) were similar in both groups. Conclusions: Twice-yearly administration of denosumab resulted in consistent increases from baseline compared with placebo in BMD at month 12 across the skeleton, regardless of subgroups, with an overall adverse event profile that was similar to that seen for placebo. Subgroup Analysis of the Effects of Denosumab at 12 Months (Least Squares Mean Percentage Difference) Baseline Characteristic Lumbar Spine Total Hip Femoral Neck Distal 1/3 Radius Baseline Characteristic Lumbar Spine Total Hip Femoral Neck Distal 1/3 Radius Menopause ≤ 5 years 6.9 (5.3, 8.5)* 3.8 (2.8, 4.9)* 3.4 (1.7, .1)+ 4.3 (2.5, 6.1)* Age < 65 5.8 (4.8, 6.7)* 4.0 (3.2, 4.7)* 2.9 (1.8., 3.9)* 3.9 (2.8, 5.0)* Menopause > 5 years 5.1 (4.2, 6.0)* 3.8 (3.0, 4.6) 2.2 (1.2, 3.3)* 3.9 (2.7, 5.1)* Age ≥ 65 5.1 (3.7, 6.4)* 3.0 (1.8, 4.3)* 1.3 (-0.4, 2.9) 3.4 (1.4, 5.4)+ T-score ≤ -1.0 a 5.4 (4.4, 6.4)* 3.8 (2.8, 4.7)* 2.1 (1.1, 3.2)+ 4.0 (2.8, 5.1)* BMI < 25 5.5 (4.2, 6.8)* 3.5 (2.5, 4.5)* 2.6 (1.3, 3.9)+ 3.4 (1.7, 5.0)+ T-score > -1.0 a 5.8 (4.6, 7.0)* 3.8 (2.8, 4.7)* 3.7 (2.3, 5.0)* 3.2 (1.6, 4.8)+ BMI ≥ 25 5.6 (4.6, 6.6)* 3.9 (3.0, 4.8)* 2.4 (1.2, 3.6) 4.2 (3.0, 5.4) Prior tamoxifen 5.3 (4.1, 6.5)* 4.3 (3.5, 5.1)* 2.6 (1.2, 4.0)+ 3.8 (2.4, 5.1)* Non-steroidal AI therapy 5.8 (4.7, 6.4)* 3.8 (3.1, 4.8)* 2.5 (1.5, 3.4)* 4.3 (3.3, 5.3)* No prior tamoxifen 5.8 (4.7, 6.8)* 3.3 (2.4, 4.3)* 2.4 (1.3, 3.6)* 3.9 (2.6, 5.3)* Steroidal AI therapy 5.8 (3.7, 8.0)* 3.0 (1.4, 4.7)+ 2.5 (0.3, 4.7)+ 1.3 (-2.3, 4.8) * = p<0.0001; + = p<0.05; a = Baseline t-score at the lumbar spine, total hip, femoral neck, or distal 1/3 radius Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen, Inc., AstraZeneca, Lilly, Novartis Amgen AstraZeneca, Genentech, Lilly, Novartis Amgen, Inc. Amgen