Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials

Luca Mastrantoni; Giovanna Garufi; Elena Di Monte; Noemi Maliziola; Mariangela Pasqualoni; Letizia Pontolillo; Sergio Pannunzio; Maria Chiara Cannizzaro; Armando Di Bello; Alessandra Fabi; Antonella Palazzo; Giampaolo Tortora; Emilio Bria; Armando Orlandi

doi:10.1177/17588359231173180

Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials

Ther Adv Med Oncol. 2023 May 29:15:17588359231173180. doi: 10.1177/17588359231173180. eCollection 2023.

Authors

Luca Mastrantoni¹, Giovanna Garufi^{2

3}, Elena Di Monte², Noemi Maliziola², Mariangela Pasqualoni², Letizia Pontolillo², Sergio Pannunzio², Maria Chiara Cannizzaro², Armando Di Bello², Alessandra Fabi⁴, Antonella Palazzo^{2

3}, Giampaolo Tortora^{2

3}, Emilio Bria^{2

3}, Armando Orlandi^{2

3}

Affiliations

¹ Department of Medical Oncology, Università Cattolica del Sacro Cuore, via della Pineta Sacchetti, 217, Rome 00168, Italy.
² Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.
³ Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
⁴ Precision Medicine Breast Unit, Scientific Directorate, Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Abstract

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.

Keywords: adjuvant therapy; bone-health; denosumab; early breast cancer; meta-analysis.