Abstract P2-02-06: Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials
Authors: Mastrantoni Luca , Garufi Giovanna , Monte Elena Di , Maliziola Noemi , Pasqualoni Mariangela , Pontolillo Letizia , Pannunzio Sergio , Cannizzaro Maria Chiara , Bello Armando Di , Fabi Alessandra , Palazzo Antonella , Bria Emilio , Tortora Giampaolo , Orlandi Armando 
Published: March 2023

Abstract
Background. Adjuvant denosumab treatment improved bone-health related outcomes in early breast cancer (BC) patients with discordant survival results. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods. PubMed, CENTRAL, Scopus, Embase, clinicaltrials.gov and key oncological meetings websites were screened to identify potentially eligible RCTs based on the PICOs model: P) Participant: pre and postmenopausal early BC patients; I) Intervention: adjuvant denosumab; C) Comparator: placebo; O) Outcomes: Disease-free survival (DFS), Bone Metastasis-free survival (BMFS), Overall Survival (OS), fracture incidence and time to first fracture were adopted as survival endpoints, and Adverse Events, Serious Adverse Events, Osteonecrosis of the Jaw (ONJ) and Atypical Femur Fractures (AFF) as safety endpoints; S) Study design: phase III RCTs. Risk of bias was assessed with Cochrane Collaboration Risk of Bias Tool. Pooled hazard ratios (HR), risk ratios (RR), risk differences (RD) and respective confidence intervals (CI) were computed using both a fixed and a random effect model. Subgroup analyses based on menopausal status, hormone receptor and HER2 status and immunophenotype were performed. Results. Two phase III RCTs were included (ABCSG-18, D-CARE), for an overall population of 7929 early BC patients receiving denosumab or placebo. Denosumab addition to standard of care anticancer treatment showed no difference in DFS (HR 0.93; 95% CI 0.75-1.16, p=0.53), BMFS (HR 0.90; 95% CI 0.75-1.07, p=0.23) and OS (HR 0.92; 95% CI 0.72-1.17, p=0.49). In hormone receptor-positive/HER2 negative patients, denosumab significantly prolonged both DFS (HR 0.88; 95% CI 0.78-0.99, p=0.04) and BMFS (HR 0.83; 95% CI 0.71-0.97, p=0.02). No interaction was found between denosumab addition and menopausal status. Fracture incidence (RR 0.79; 95% CI 0.70-0.89, p&lt; 0.01) and time to first fracture (HR 0.76; 95% CI 0.66-0.87, p&lt; 0.01) were also improved with denosumab. No association between denosumab addition and overall toxicity was seen and no difference was observed in terms of ONJ and AFF between the 60mg every 6 months schedule and placebo (RD 0.001, 95% CI from -0.001 to 0.002, p=0.48) Conclusions. Findings from this meta-analysis validate the role of denosumab as a highly effective anti-resorptive agent. We provide robust evidence that its addition to standard anticancer treatment significantly improves survival outcomes in hormone receptor-positive/HER2 negative early BC patients, suggesting that the implementation of denosumab use in combination with endocrine therapy in this patient population should be reconsidered. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022332787.
Citation Format: 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, Emilio Bria, Giampaolo Tortora, Armando Orlandi. Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-06.