Denosumab favourably affects bone health, HR+ breast cancer outcomes
Postmenopausal women with hormone receptor (HR)-positive breast cancer fare well with the addition of denosumab to aromatase inhibitors, with data from the phase III ABCSG-18 trial showing that the antiresorptive drug cuts the risk of fractures and confers a modest but significant improvement in disease-free survival (DFS) with a favourable tolerability profile.
ABCSG-18 randomized 3,425 women (median age, 64 years) with early stage HR+ breast cancer to receive subcutaneous denosumab 60 mg (n=1,711) or placebo (n=1,709) every 6 months during aromatase inhibitor therapy. In the open-label phase, 14.7 percent of patients in the placebo arm crossed over to receive denosumab.
Results for the primary endpoint of time to first clinical fracture after randomization were reported previously. Compared with placebo, twice-yearly denosumab doubled the time to first fracture (hazard ratio [HR], 0.5; 95 percent CI, 0.39–0.65; p<0.0001) and increased bone mineral density at the total lumbar spine, total hip and femoral neck. Moreover, the study drug could be administered without added toxicity. [Lancet 2015;386:433-443]
In the current analysis, data for the secondary endpoint of DFS also favoured denosumab. DFS events occurred less frequently than in the placebo arm after a median follow-up of 73 months (14.0 percent vs 16.8 percent). Denosumab produced about a 20-percent improvement in DFS (HR, 0.82; 0.69-0.98; p=0.0260). [Lancet Oncol 2019;20:339-351]
DFS rates were significantly higher with the antiresorptive drug vs placebo both at 5 years (89.2 percent vs 87.3 percent) and 8 years (80.6 percent vs 77.5 percent).
“Adjuvant denosumab therapy at the dose used in the ABCSG-18 trial had very few measurable side-effects, as previously reported. The updated serious adverse event [AE] data, including those of patients treated with open-label phase denosumab, shows that this adjuvant therapy is safe and highly tolerable,” noted lead study investigator Prof Michael Gnant from the Medical University of Vienna in Austria.
None of the patients developed osteonecrosis of the jaw or atypical femoral fractures. Furthermore, the total number of AEs was similar in the denosumab and placebo arms (n=1,367 [521 serious] and n=1,339 [515 serious], respectively). Commonly reported serious AEs were osteoarthritis, meniscus injury and cataract. One treatment-related death (due to pneumonia, septic kidney failure and cardiac decompensation) occurred in the denosumab arm.
Denosumab an attractive alternative to bisphosphonates
“Use of aromatase inhibitors for a total of 5 years has been established as the preferred choice for early HR+ breast cancer in postmenopausal women, either in the upfront or in the sequential or extended adjuvant therapy setting, and such patients often have a very good prognosis. The disadvantage of this treatment is bone loss and bone degradation, leading to a higher risk of fracture,” according to Gnant.
Cancer treatment-induced bone loss can be countered by bisphosphonates and denosumab, but only the latter significantly reduces clinical and vertebral fractures in postmenopausal breast cancer patients treated with an aromatase inhibitor. [Ann Oncol 2019;doi:10.1093/annonc/mdy537; Lancet 2015;386:1353-1361]
“Given the negligible side-effect profile of denosumab, and the previously reported reduction in clinical fractures, adjuvant subcutaneous denosumab at 60 mg every 6 months should be offered to postmenopausal women with HR+ breast cancer,” Gnant said.
In a linked commentary, Dr Marc Lippman from Georgetown University’s Department of Oncology in Washington DC, US, concurred that the data from the ABCSG-18 trial are practice-changing and establish denosumab as an acceptable alternative to bisphosphonates. [Lancet Oncol 2019;20:312-313]
“The results also strongly support the inclusion of some form of bone agent in addition to standard-of-care adjuvant therapy for HR+ breast cancer in postmenopausal patients,” Lippman wrote.