The addition of denosumab to adjuvant aromatase inhibitor therapy offered improved outcomes in women with postmenopausal HR+ early breast cancer.
The addition of denosumab to adjuvant aromatase inhibitor therapy offered an improved disease-free survival (DFS) over placebo in a phase III study of women with postmenopausal hormone receptor–positive early breast cancer. The treatment was well tolerated, with similar rates of adverse effects in the two groups.
“Aromatase inhibitors reduce recurrences of breast cancer, breast cancer deaths, and all-cause mortality, but at the cost of decreased bone mineral density and increased fracture risk,” wrote study authors led by Michael Gnant, MD, of the Medical University of Vienna. “Antiresorptive agents such as bisphosphonates and denosumab have been successfully used in patients with early breast cancer to maintain bone health and counteract bone loss induced by cancer treatment.”
The ABCSG-18 trial already showed that adjuvant denosumab administered subcutaneously twice yearly significantly delayed the time to first clinical fracture and increased bone mineral density in patients with postmenopausal hormone receptor–positive early breast cancer being treated with an aromatase inhibitor. They reported the results for DFS after a median of 73 months of follow-up, published in Lancet Oncology.
The study included 1,711 patients randomized to receive denosumab, and 1,709 patients who received placebo. Nearly all patients in the trial were white, and about three-quarters of the patients were over the age of 60. Most patients had HER2-negative disease (93.2% in both groups). Just over 75% of both groups had not received chemotherapy prior to randomization.
There were a total of 240 DFS events in the denosumab group (14.0%), and 287 such events in the placebo group (16.8%). This yielded a hazard ratio favoring denosumab of 0.82 (95% CI, 0.69–0.98; P = .0260).
At 5 years, the DFS rate was 89.2% with denosumab and 87.3% with placebo. At 8 years, these rates were 80.6% and 77.5%. There were similar rates of locoregional or contralateral recurrences, ductal carcinoma in situ, and verified distant metastases. The difference in DFS was largely driven by non–histologically verified distant metastases and by new primary cancers.
There were similar rates of treatment-emergent adverse events between the two groups, with 1,367 events in the denosumab group (521 serious events) and 1,339 in the placebo group (515 serious events). Serious cases of musculoskeletal and connective tissue disorders occurred in 7.8% of denosumab patients and 7.2% of placebo patients. There were no cases of osteonecrosis of the jaw in the trial.
“Adjuvant denosumab constitutes an effective and safe treatment option for postmenopausal patients with hormone receptor–positive breast cancer who receive aromatase inhibitor therapy,” the authors concluded.
In an accompanying editorial, Marc Lippman, MD, of Georgetown University in Washington, DC, called these “practice-changing results,” and that the study establishes denosumab as a reasonable alternative to bisphosphonates. “However, many crucial questions remain unanswered,” he wrote. “Foremost is the continued lack of understanding of how denosumab or bisphosphonates favorably affect disease-free survival, and particularly recurrences at sites other than bone.”
Other questions include why a delay in initiation of denosumab-similar to that seen in other studies of bisphosphonates-is associated with diminished DFS benefit, and why the success of this approach appears limited to hormone receptor–positive breast cancer.