SAN ANTONIO — Targeting bone in patients with breast cancer appears to have life-preserving, not just bone-preserving, benefits, according to results from a study on the monoclonal antibody denosumab, presented here at the San Antonio Breast Cancer Symposium (SABCS) 2015.
"Most scientists, including myself, believe that bone-targeted therapies exert their benefit via indirect mechanisms in the bone marrow microenvironment. And now, at SABCS, we show that adjuvant denosumab actually improves disease-free-survival," said lead investigator Michael Gnant, MD, from the Medical University of Vienna.
"It's the first time ever that the antibody demonstrated disease-free-survival benefit," he told Medscape Medical News.
The results come from the phase 3 ABSCG-18 trial, in which postmenopausal women with nonmetastatic breast cancer were randomized to receive denosumab or placebo in addition to aromatase inhibitor therapy. The primary outcomes were related to bone health, and the secondary outcomes included disease-free survival.
In an intention-to-treat analysis, the impact of denosumab on disease-free survival reached borderline significance (hazard ratio [HR], 0.82, 95% confidence interval, 0.66 - 1.00), "but a sensitivity analysis showed that that may be a conservative estimate," Dr Gnant reported.
"In absolute numbers, the benefit is about 1% after 3 years, 2% after 5 years, and 3% at 7 years of follow-up," he said.
Exploratory subgroup analyses suggest that the benefit increases when denosumab is started early, along with aromatase inhibitor therapy, and that the benefit is greater in patients with larger tumors and ductal histology, he added.
Overall, the disease-free survival benefit seen with denosumab is comparable to that reported in a recent meta-analysis of bisphosphonates (Lancet. 2015;386:1353-1361).
"A bone-targeted agent should be part of the standard of care now in postmenopausal women. I think that's where the data are going," said Adam Brufsky, MD, PhD, from the University of Pittsburgh School of Medicine.
But which type of agent to use is an open question, he told Medscape Medical News.
"Clearly, denosumab has some advantages compared with bisphosphonates — mostly about convenience and ease of use — but it is expensive. Bisphosphonates, which are generic, seem to have the same effect. What bone-targeted agent you use is a good question. it's going to come down to insurance issues and tolerability issues," Dr Brufsky explained. Dr Gnant's team is likely trying to point out "that it could be any bone-targeted agent."
Previous results from the ABCSG-18 trial demonstrate the fracture benefit of adjuvant denosumab over placebo in postmenopausal women with hormone-receptor-positive breast cancer who were treated with aromatase inhibitors (Lancet. 2015;386:433-443).
"The issue with this study is there's only disease-free survival and no overall survival yet," said Virginia Kaklamani, MD, from the University of Texas Health Science Center San Antonio, who is a codirector of the meeting.
"Denosumab is an extremely expensive drug, so I would be very surprised if any insurance company would pay for it based on the results of this study, especially because we don't have overall survival data," she explained.
"The results of the ABSCG-18 trial are very encouraging, albeit not surprising," said Alison Stopeck, MD, from the University of Arizona Cancer Center in Tucson.
"These data certainly suggest that osteoclast inhibition may play a role in preventing or delaying disease recurrences in postmenopausal women," she told Medscape Medical News.
"Perhaps, most importantly, this trial provides clinicians with the necessary supportive data to prescribe denosumab every 6 months to patients receiving aromatase inhibitor therapy as a convenient and well-tolerated treatment to prevent bone loss, prevent fractures, and perhaps even improve disease-free survival."
Dr Gnant believes that denosumab should be used for what appears to be a dual benefit.
"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 healthcare environments, it is only used for patients with established osteoporosis," he said.
"Our new data suggest that this treatment should be offered to all patients with hormone-receptor-positive breast cancer who are receiving adjuvant aromatase inhibitor therapy, irrespective of their bone health. In my opinion, the advantage of this treatment is that it is easy (two subcutaneous injections per year), safe, and without notable side-effect differences, compared with placebo."
The ABCSG-18 trial was supported by Amgen. Dr Gnant reports receiving grants unrelated to this study from sanofi-aventis, Novartis, Roche, GlaxoSmithKline, Pfizer, and Smith Medical, and personal fees for consulting work unrelated to this study from Novartis, Roche, GlaxoSmithKline, AstraZeneca, Nanostring Technologies, and Accelsiors.
San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S2-02. Presented December 10, 2015.