Denosumab improves disease-free survival for postmenopausal patients w HR+ breast cancer

Previous results from ABCSG-18 showed denosumab also reduces clinical fractures.

Adding denosumab to adjuvant aromatase inhibitor therapy improved disease-free survival for postmenopausal patients with early-stage, hormone receptor (HR)-positive breast cancer, according to results from the phase III ABCSG-18 clinical trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.

Nearly all postmenopausal women with early-stage, HR-positive breast cancer are treated with an aromatase inhibitor, either alone or in sequence with tamoxifen, for five to 10 years after completing their initial post-diagnosis treatment, explained Michael Gnant, MD, professor of surgery at the Medical University of Vienna in Austria. "This is referred to as adjuvant endocrine therapy, and it compromises bone health," he said.

"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," Gnant continued. "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."

Among the 3,425 postmenopausal patients with early-stage, HR-positive breast cancer enrolled in ABCSG-18, 1,711 were randomly assigned to 60 milligrams of subcutaneously administered denosumab once every six months and 1,709 were randomly assigned placebo.

The researchers found that after a median follow-up of four years, patients assigned denosumab had an 18 percent reduced risk of disease recurring compared with those assigned placebo. In light of previously published results, which showed that adjuvant denosumab reduced fractures caused by adjuvant aromatase inhibitor therapy by 50 percent, the new finding reported here amplifies the benefit of adjuvant denosumab, Gnant said.

Gnant noted that this analysis was performed as a result of a recommendation from the Independent Data Monitoring Committee (IDMC) and was based on only 370 disease-free survival events. "Therefore, it does not provide perfectly undisputable statistical power, and will have to be confirmed by future analyses with longer follow-up," he said. "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.

"It is also important to mention that the IDMC recommended 'patients choice' unblinding of this placebo-controlled trial because of the dramatic benefit in terms of fractures," Gnant added. "This will occur in 2016, offering eligible trial patients the option of unblinding and subsequent treatment with denosumab if it turns out that they were in the placebo group."

Abstract: S2-02

Title: The Impact of Adjuvant Denosumab on Disease-Free Survival: Results from 3,425 Postmenopausal Patients of the ABCSG-18 Trial

Authors: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF, on behalf of the Austrian Breast and Colorectal Cancer Study Group

Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve disease-free and overall survival outcomes in postmenopausal (natural or induced) BC patients (EBCTCG meta-analysis, Lancet 2015). The aim of ABCSG-18 was to investigate the effects of adjuvant anti-RANK-ligand Denosumab on bone health and disease outcomes in postmenopausal patients with early hormone receptor+ (HR+) BC receiving AI treatment.

Patients and Methods: 3,425 postmenopausal patients with HR+ BC receiving AI were recruited in 58 trial sites into this prospective, randomized, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to either Denosumab 60mg or placebo q6mo s.c. Bone end point results showed that adjuvant denosumab significantly reduced clinical fractures (primary endpoint, HR=0.5, p<0.0001), improved bone mineral density, and reduced vertebral fractures without relevant toxicity (Gnant et al., Lancet 2015). Disease-free survival (DFS) is a secondary endpoint. Following an IDMC 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 the year 2016. Additional disease outcome related end points (BMFS, OS) will be analysed during further study follow up.

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

Summary and conclusion: Adjuvant Denosumab 60mg q6mo s.c. improves disease-free survival of HR+ breast cancer patients receiving aromatase inhibitors. Numerically, this benefit of adjuvant Denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. Bases on these results and the previously reported dramatic reduction of fractures, adjuvant Denosumab should be offered to all postmenopausal HR+ breast cancer patients on AI.