The Impact of Adjuvant Denosumab on Disease-free Survival in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer

Results from the Austrian Breast & Colorectal Cancer Study Group trial presented at San Antonio Breast Cancer Symposium 2015

Adjuvant denosumab improves disease-free survival (DFS) of hormone receptor (HR)-positive postmenopausal patients with breast cancer who receive aromatase inhibitors. Numerically, the benefit of adjuvant denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. The results of the Austrian Breast & Colorectal Cancer Study Group (ABCSG)-18 trial are presented in the oral session at San Antonio Breast Cancer Symposium (8–12 December 2015, San Antonio, Texas, USA).

Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer patients. Nearly all postmenopausal women with early-stage, HR-positive breast cancer are treated with an adjuvant aromatase inhibitor, either alone or in sequence with tamoxifen, for 5 to 10 years, explained Dr Michael Gnant, who is a professor of surgery at the Medical University of Vienna in Vienna, Austria.

Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve DFS and overall survival (OS) outcomes in postmenopausal (natural or induced menopause) breast cancer patients according to meta-analysis published in the Lancet earlier this year.

The aim of the ABCSG-18 study was to investigate the effects of adjuvant anti-RANK-ligand denosumab on bone health and disease outcomes in postmenopausal patients with early HR-positive breast cancer treated with aromatase inhibitors.

In total 3,425 postmenopausal patients with HR-positive breast cancer receiving aromatase inhibitors were recruited in this prospective, randomised, double-blind, placebo-controlled, phase-III trial. Patients were randomised 1:1 to either denosumab 60mg or placebo every 6 months subcutaneously.

Bone endpoint results showed that adjuvant denosumab significantly reduced clinical fractures which was the primary endpoint of this study (hazard ratio 0.5, p<0.0001), improved bone mineral density, and reduced vertebral fractures without relevant toxicity (Gnant M, et al., Lancet 2015).

The DFS is a secondary endpoint in this study. Following an Independent Data Monitoring Committee recommendation based on the results of a protocol-specified interim analysis, a DFS analysis took place in September 2015, before a patients' choice unblinding option will be provided to trial patients in 2016. Additional disease outcome related endpoints, including OS will be analysed during further study follow-up.

With a median follow-up of 4 years, 370 DFS events were recorded with 203 DFS events in the placebo group and 167 in the denosumab group (hazard ratio 0.816, p=0.051). Subgroup analyses indicate that the denosumab benefit (overall absolute 2.1% at 5 years) may be particularly driven by tumours larger than 2 cm (hazard ratio 0.66, p=0.016), ductal breast cancer histology type (hazard ratio 0.79, p=0.048), and tumours that are both ER and PR positive (hazard ratio 0.75, p=0.013).

Dr Gnant said in accompanied press release that the current analysis “… does not provide perfectly undisputable statistical power, and will have to be confirmed by future analyses with longer follow-up. I do not, however, have any doubt about the validity of the results, given the fact that the outcome benefits show clearly so early in the follow-up and are numerically bigger than we have seen in the past with bisphosphonates.”

Dr Gnant commented: “Although the FDA has approved adjuvant denosumab as a treatment to increase bone mass in breast cancer patients receiving adjuvant aromatase inhibitor therapy who are at high risk for fracture, in most health care environments, adjuvant denosumab is only used for those patients with established osteoporosis”. He concluded: “Our new data suggest that this treatment should be offered to all patients with HR-positive breast cancer who are receiving adjuvant aromatase inhibitor therapy, irrespective of their bone health status.”

The study was supported by Amgen.

Gnant M, Pfeiler G, Dubsky PC, Hubalek M, et al.The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. Presented at San Antonio Breast Cancer Symposium; San Antonio, Texas, USA: 8–12 December 2015.