Denosumab Demonstrates Survival Benefit in Postmenopausal Women

Michael Gnant, MD

A follow-up analysis of the benefits of adding denosumab to aromatase inhibitor (AI) therapy has found that the agent not only helps to prevent fractures, it reduces the risk of recurrence and death in postmenopausal women with HR-positive breast cancer.

In this phase III trial, a 19% relative survival improvement was seen among women who had denosumab added to their AI therapy, suggesting that the agent should be recommended in this setting, regardless of the patient’s bone health status.

“We now finally have evidence that bone-targeted treatment is not only successful in treating bony metastases and preventing treatment-induced bone loss. It also reduces recurrence and improves survival, at least in postmenopausal breast cancer patients,” said Michael Gnant, MD, presenting findings from the ABCSG-18 trial during a press conference at the 2015 San Antonio Breast Cancer Symposium.

This prospective, double-blind trial enrolled 3425 postmenopausal women at a median age of 64 years, who were receiving adjuvant AI therapy for their early, HR-positive breast cancer at 58 centers in Austria and Sweden between 2006 and 2013. Patients were randomized evenly to receive 60-mg denosumab subcutaneously every 6 months or placebo.

Gnant, a professor of surgery at the Medical University of Vienna, previously presented data from the ABCSG-18 trial at the 2015 ASCO Annual Meeting showing that twice-yearly, low-dose denosumab reduced the number of clinical fractures by half, with 176 fractures reported in patients receiving placebo, but only 92 fractures observed in the denosumab arm (HR, 0.50, P <.0001).²

“That’s quite a dramatic difference, and there was no measurable difference in toxicity between denosumab and placebo,” noted Gnant. He said that in view of these positive results, an independent data monitoring committee recommended that all trial participants be given the option to cross over to the denosumab arm after discussion with their treating physician.

Because investigators also wanted to see if denosumab would impact survival, they performed a time-driven analysis of disease-free survival (DFS) in September, before the study is unblinded next year, Gnant explained. For their analysis, the researchers defined a DFS event as “time to any evidence of local or distant metastases, contralateral breast cancer, secondary cancer, or death from any cause.”

More events occurred in the placebo arm than in the denosumab arm, 203 versus 167, respectively (HR, 0.816), Gnant reported, noting that while this finding was of “borderline statistical significance” due to a low number of events, sensitivity analyses of the data indicate that the DFS difference estimate is a conservative one.

“In absolute figures, the benefit is about 1% after 3 years, 2% after 5 years, and 3% after 7 years of follow up,” Gnant reported.

In an exploratory analysis to uncover any signals of which subgroups might benefit more from adjuvant denosumab, Gnant said there is some indication that the benefits may be greater for those who start their treatment earlier (HR, 0.61), patients with larger tumors (HR, 0.66), those with ductal invasive histology (HR, 0.79), and patients whose tumors are HR-positive (HR, 0.75).

Specifically, in the group of patients whose tumors were >2 cm (n = 950), Gnant noted, “the absolute difference goes to about 4% after 3 years, 7% at 5 years, and more than 10% at 7 years—that’s quite a relevant difference.”

Gnant drew a comparison of denosumab’s efficacy versus bisphosphonate therapy, using data from a meta-analysis conducted by the Early Breast Cancer Trialists Cooperative Group (EBCTCG).³ He noted that the observed DFS benefit of adjuvant denosumab in ABCSG-18 for postmenopausal women is similar to that seen with bisphosphonates as reported by the EBCTCG. In that trial, a 14% overall relative difference in recurrence was observed in 11,767 postmenopausal women who received bisphosphonates ([relative risk] RR, 0.86), and he added that a 3% recurrence benefit held up after 10 years.

While Gnant cautioned that the comparison is an indirect one, “I believe it is fair to say that adjuvant denosumab does at least as much as adjuvant bisphosphonates do.”

He reiterated that the agent has a proven track record of safety, with ABCSG-18 showing no difference with denosumab in the occurrence of any-grade adverse events compared with placebo, and no confirmed cases of osteonecrosis of the jaw or atypical fractures.

Denosumab is also being evaluated in the ongoing D-CARE study examining the therapy as adjuvant treatment for women with high-risk early breast cancer receiving neoadjuvant or adjuvant therapy (NCT01077154).

Although the FDA has approved adjuvant denosumab as a treatment to increase bone mass in patients on AI therapy who are at high risk for fracture, it’s typically used only for those with established osteoporosis. With these new data, Gnant said, denosumab should be offered to all postmenopausal women with HR-positive breast cancer on AIs, regardless of their bone health status:

“When I see a new patient next week, I will start her on the two subcutaneous injections every 6 months for 3 years.”

References:

1. Gnant M, Pfeiler G, Dubsky PC, et al. The impact of adjuvant denosumab on disease-free survival: results from 3425 postmenopausal patients of the ABCSG-18 trial. Presented at: 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S2-02.
2. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicenter, randomized, double-blind placebo-controlled trial. Lancet. 2015;386(9992):433-443.
3. Early Breast Cancer Trialists Cooperative Group. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomized trials. Lancet. 2015;386(10001):1353-1361.

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