ABCSG-18 trial – Amplified benefit of adding denosumab for the treatment of postmenopausal patients with early stage hormone receptor (HR)-positive breast cancer receiving aromatase inhibitors

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Last December at the 2015 San Antonio Breast Cancer Symposium (Texas, USA), Professor Michael Gnant presented updated findings of the ABCSG-18 phase III adjuvant trial. The study, whose primary results demonstrating a 50 percent reduction in bone fractures and osteoporosis were published in The Lancet in June 2015, demonstrated that after a median follow-up of four years, postmenopausal patients with early stage HR-positive breast cancer receiving adjuvant aromatase inhibitor therapy and denosumab (for bone health) also benefited from improved disease-free survival.

Adding a monoclonal antibody (denosumab) to the standard adjuvant therapy with aromatase inhibitors given to postmenopausal, hormone-receptor-positive (HR+) breast cancer patients with early stage disease reduces the rate of disease recurrence by 18 percent, according to the disease-free analysis results from the ABSCG-18 trial presented on 9 December in San Antonio by Prof. Michael Gnant, Principal investigator of the study, Professor of Surgery at the Medical University of Vienna, Austria, and President of the Austrian Breast & Colorectal Study Group (ABCSG).

Between 2006 and 2013 the trial enrolled 3,425 postmenopausal patients from 58 trial centres in Austria and Sweden with early-stage, hormone receptor (HR)-positive breast cancer, who were receiving an adjuvant endocrine therapy with aromatase inhibitors. These patients very often face bone health issues (fractures, osteoporosis), a common side-effect of aromatase inhibitors.

The primary aim of ABCSG-18 was to demonstrate the benefit on bone health when administrating denosumab together with the adjuvant endocrine therapy with aromatase inhibitors. The first results of the study, which were published last June 2015 in The Lancet, showed that the addition of denosumab to the standard treatment reduced bone fractures and osteoporosis events caused by the aromatase inhibitors treatment by 50 percent. Moreover, the drug could be administered without any additional toxicity in this double-blind placebo-controlled trial. For patients, this means that the addition of denosumab can significantly reduce a main side-effect of their adjuvant treatment.

At San Antonio, Prof. Gnant presented the results of a further analysis from the ABCSG-18 trial data: the impact of denosumab on disease-free survival. After a follow up of four years, researchers found that the patients who were receiving denosumab in addition to their therapy had an 18 percent reduced risk of disease relapse compared to the patients who were receiving a placebo. In addition, exploratory subgroup analyses suggest that some patients in particular (those with tumours >2cm and high receptor density) may benefit from the drug.

These new findings, together with the ones published last June in The Lancet, could well lead to a change in clinical practice in the near future. ‘While the regulatory and reimbursement issues around adjuvant denosumab need to be clarified in coming months, scientifically we now have a treatment addition that cuts fractures in half and improves disease-free survival similarly to what bisphosphonates do in postmenopausal women. Importantly, there is no measurable toxicity at this low dose, and patient burden can be considered minimal since this is only two subcutaneous injections per year’, explains Dr Michael Gnant.

Overall, the ABCSG-18 trial has marked an important milestone for ABCSG, breast cancer research and for patients.

 ‘Next, we will implement a “patient’s choice” unblinding phase, as per recommendation of the IDMC (independent data monitoring committee), based on the dramatic difference we observed. This means that eligible patients of this double-blind placebo-controlled trial will be offered the option of un-blinding – they can decide together with their physician whether they want to be informed about their blinded trial therapy, and in case it turns out that they had received placebo, they will be offered active therapy for three years. I believe that this innovative approach to trial management provides a new level of trial ethics and patient empowerment. After a few more years of trial follow-up, there will be additional outcome analysis, including overall survival’, adds Dr Gnant.

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