Denosumab Flops in Breast Cancer Study

A randomized trial found no benefit of adjuvant denosumab in early breast cancer.

“Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer,” the researchers wrote in their introduction.

D-CARE was an international, double-blind, randomized, placebo-controlled, phase 3 study including patients from 389 institutions spanning 39 countries. Women aged 18 years or older with confirmed stage II or III breast cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients were randomized 1:1 to receive either denosumab 120 mg or placebo every three to four weeks, beginning with neoadjuvant or adjuvant chemotherapy, for six months, followed by every 12 weeks for five years in total. The main outcome measure was bone metastasis-free survival.

Randomization of 4,509 patients took place from June 2, 2010 through Aug. 24, 2012; 2,256 women were placed in the denosumab group and 2,253 in the placebo group. Bone metastasis-free survival did not largely differ between the groups (median not reached in either group; hazard ratio=0.97; 95% CI, 0.82-1.14; P=0.70). Treatment-emergent adverse events grade 3 or worse were reported in 2,241 denosumab patients and 2,218 placebo patients, the most common of which were neutropenia (340 [15%] vs. 328 [15%]), febrile neutropenia (112 [5%] vs. 142 [6%]), and leucopenia (62 [3%] vs. 61 [3%]). Denosumab patients were more likely to develop positively adjudicated osteonecrosis of the jaw (n = 122 [5%]) compared to placebo patients (n = 4 [<1%]), as well as treatment-emergent hypocalcemia (n = 152 [7%] vs. n = 82 [4%]). Two placebo patients died, due to acute myeloid leukemia and depressed level of consciousness.

The results of the study were published in The Lancet Oncology.

The study authors concluded, “Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer.”