Combining an every-6-month dose of the osteoporosis medication denosumab (Prolia, Xgeva) with standard adjuvant aromatase-inhibitor treatment significantly delayed disease recurrence in postmenopausal women with hormone receptor-positive breast cancer, according to updated results of the ABCSG-18 trial.
At 8 years of follow-up, women randomly assigned to denosumab had about a three percentage-point difference in absolute disease-free survival compared with those who received placebo (80.6% vs 77.5%), Michael Gnant, MD, of Medical University of Austria in Vienna, and colleagues reported.
These results combined with the previously reported reduction in fracture risk (primary endpoint) seen with denosumab indicate that “adjuvant denosumab constitutes an effective and safe treatment option for postmenopausal patients with hormone receptor-positive breast cancer who receive aromatase inhibitor therapy,” they wrote in Lancet Oncology.
The ABCSG-18 trial included 3,425 postmenopausal women with early, hormone-receptor positive, non-metastatic breast cancer who had finished initial treatment and were receiving adjuvant aromatase inhibitors. Patients were randomly assigned to receive subcutaneous denosumab at 60 mg (1,711 patients) or placebo (1,709 patients) every 6 months during adjuvant therapy.
With a median follow-up of 73 months, patients assigned to denosumab had an 18% reduction in the risk for disease progression compared with those in the placebo group (HR 0.82, 95% CI 0.69-0.98, P=0.0260).
By 5 years, 89.2% of patients assigned to denosumab and 87.3% of patients assigned to placebo were disease free; these numbers decreased by 8 years, with denosumab still having an advantage. Locoregional and contralateral recurrences occurred in a similar percentage of patients in both arms of the study.
“Although the disease-free survival analysis presented in this article was based on the intention-to-treat principle (to remain highly conservative towards potential crossover bias), various sensitivity analyses were done to account for potential bias resulting from the partial crossover of some patients after unmasking,” the researchers wrote. “All analytical methods used showed results similar to those of the intention-to-treat analysis, substantiating a statistically significant increase in disease-free survival in the denosumab group.”
Although not statistically significant, subgroup analyses suggested a disease-free survival benefit with denosumab in patients younger than age 60, those who received no aromatase inhibitor treatment prior to the study, those with ductal invasive tumors, those with ER and PR double-positive status, and those with HER2-negative disease, Gnant and co-authors added.
Data on the primary endpoint was originally reported at the 2015 American Society of Clinical Oncology annual meeting and simultaneously published in The Lancet. Women assigned to denosumab had a 50% reduction in the risk for fracture compared with women assigned to placebo (HR 0.50, 95% CI 0.39-0.65, P<0.0001).
Although there were initial concerns about the possibility of development of osteonecrosis of the jaw, no cases had occurred with median of about 6 years follow-up. The overall incidence of adverse events were similar between the two study arms, with similar rates of the most common adverse events — osteoarthritis, meniscus injury, and cataract. One treatment-related death occurred in the denosumab arm.
In an accompanying editorial, Marc Lippman, MD, of Georgetown University in Washington, D.C., called the results of ABCSG-18 “practice changing,” establishing denosumab as an alternative to bisphosphonates for these patients, and supporting the use of either bone agent in addition to standard adjuvant therapy.
However, he added, many questions remain unanswered — specifically:
- How do denosumab and bisphosphonates affect disease-free survival?
- Why does a delay in initiation diminish a disease-free survival benefit?
- Why is this benefit limited to hormone receptor-positive disease?
“This study of denosumab, in addition to many randomized controlled trials of bisphosphonates, indicates that adjuvant dosing with these therapies is generally safe, leads to a substantial reduction in skeletal events and an improvement in disease-free survival, and should be part of almost all adjuvant regimens for postmenopausal hormone receptor-positive breast cancer,” Lippman concluded.
Among other indications, denosumab is currently approved by the FDA to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer and in men with prostate cancer taking androgen deprivation therapy.
Funding for the study came from Amgen.
Gnant reported a financial relationship with Amgen and various other industry entities.
Lippman reported having no conflict of interests