Armando Orlandi

Background: In early breast cancer (BC) the impact of denosumab on survival outcomes is still unclear. We undertook a systematic review and meta-analysis to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods: PubMed, CENTRAL, Scopus, Embase, and oncological meetings websites were screened to identify potentially eligible randomized controlled trials (RCTs). Survival outcomes were disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). Fracture incidence and time to first fracture were bone-health outcomes. Osteonecrosis of the jaw (ONJ), atypical femur fractures (AFF), and other adverse events were also evaluated. Pooled hazard ratios (HRs) and risk ratios (RR) with respective 95% confidence interval (95% CI) were computed using a random-effects model. Exploratory subgroup analyses were performed. Results: Two phase III RCTs were included, the Austrian Breast & Colorectal Cancer Study Group-18 (ABCSG-18) and the D-CARE trials, for a total of 7929 patients. In the ABCSG-18 trial, denosumab was administered every 6 months during endocrine therapy (for a median of seven cycles) while the D-CARE trial used an intensive schedule for a total treatment duration of 5 years. Adjuvant denosumab showed no difference in DFS (HR: 0.932; 95% CI: 0.748–1.162), BMFS (HR: 0.9896; 95% CI: 0.751–1.070), and OS (HR: 0.917; 95% CI: 0.718–1.171) compared to placebo in the overall population. In hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative BC patients, a DFS (HR: 0.883; 95% CI: 0.782–0.996) and BMFS (HR: 0.832; 95% CI: 0.714–0.970) benefit was observed and BMFS was prolonged in all hormone receptor positive patients (HR: 0.850; 95% CI: 0.735–0.983). Fracture incidence (RR: 0.787; 95% CI: 0.696–0.890) and time to first fracture (HR: 0.760; 95% CI: 0.665–0.869) were also improved. No increase in overall toxicity was seen with denosumab and no differences were observed for ONJ and AFF between the 60-mg every 6-month schedule and placebo. Conclusion: Denosumab addition to anticancer treatment does not improve DFS, BMFS, or OS in the overall population, although a DFS improvement was observed in hormone receptor positive/HER2 negative BC patients and a BMFS improvement in all hormone receptor positive patients. Bone-health outcomes were improved with no added toxicity with the 60-mg schedule. Registration: PROSPERO identifier: CRD42022332787.