Effects Of Arzoxifene On Breast Cancer Incidence In Postmenopausal Women With Osteoporosis Or With Low Bone Mass

Abstract Precinical and early clinical data indicate that arzoxifene, a third generation SERM, is more potent and bioavailable than raloxifene. Here we report the results of the phase 3, multicenter, placebo-controlled, double-blind GENERATIONS trial of 9354 postmenopausal women with osteoporosis (N=5252) or low bone mineral density (BMD) (N=4102), randomly assigned to arzoxifene 20mg/d (N=4676) or placebo (N=4678). The primary endpoints were the incidences of radiographic vertebral fracture in the osteoporotic population (at 36 months) and invasive breast cancer in all study participants (after all participants had completed 48 months of treatment). Breast cancers were detected by annual mammograms and/or clinical breast examination and adjudicated centrally by an independent committee. The primary analysis compared the incidence of adjudicated invasive breast cancer between treatment groups using a log-rank test. Both treatment groups were evenly balanced for risk of breast cancer including age, previous benign breast biopsies, family history of breast cancer, estimated Gail risk and BMD. The trial met both primary endpoints with a 41% reduction in the incidence of vertebral fractures (p<0.001) and 56% percent reduction in incidence of invasive breast cancer (p=0.002). Table 1 summarizes the breast cancer findings after the 48 month follow-up. The incidence of invasive breast cancer in the placebo group was higher in the women who had a Gail score > 1.66 compared to ≤ 1.66 (1.5% vs. 0.6%) and in those with low bone mass versus osteoporosis (1.2% vs. 0.7%), but the risk reduction with arzoxifene was similar between Gail risk groups (HR 0.32 vs 0.57. p-value for interaction=0.31) and between low bone mass and osteoporosis groups (HR 0.34 vs 0.57. p-value for interaction=0.35). Other findings included no significant reduction in non-vertebral fractures or cardiovascular events. Generally, arzoxifene was well tolerated, although there was a significant increase in venous thromboembolism, gall bladder disease, pulmonary obstructive/infective disorders, hot flushes, muscle cramps and gynecological-related events in the arzoxifene group. We conclude that arzoxifene reduces the incidence of invasive breast cancer as well as vertebral fracture. The results of the GENERATIONS trial provide further support for a significant risk reduction of invasive breast cancer by SERMs in post menopausal women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 51.