Optimizing denosumab treatment strategies to balance skeletal-related events for prevention and osteonecrosis of the jaw risk in metastatic breast cancer patients: A Korean nationwide target trial emulation.

1103 Background: Administration of bone-modifying agents (BMAs) is essential for reducing the incidence of skeletal-related events (SREs) in breast cancer bone metastases patients. As denosumab showed superior effect for prevention of SREs compared to zoledronic acid, denosumab is commonly used BMA in this setting; however, the optimal administration interval and treatment duration of denosumab remain unclear. Methods: This study utilized the Health Insurance Review and Assessment Service (HIRA) database and emulated a target trial using the clone–censor–weight approach. Among the overall breast cancer population, 2,023 metastatic breast cancer patients who received regular denosumab administration were identified during Jan 2009 to Aug 2023. We examined the administration patterns and duration of denosumab therapy and evaluated their associations with the incidence of skeletal-related events (SREs) and osteonecrosis of the jaw (ONJ). Results: During follow-up, approximately 23% of patients continued regular denosumab administration at intervals of less than 8 weeks. Patients who received denosumab for ≥25 months exhibited a low risk of skeletal-related events (SREs) (3.42–6.15%, according to treatment compliance); however, the cumulative risk of osteonecrosis of the jaw (ONJ) increased to 19.47% (95% confidence interval [CI], 13.79–26.75) at 4 years of follow-up. Among patients treated with denosumab for 13–24 months, the risk of SREs was comparable to that observed in those treated for ≥25 months (5.15–6.77% vs. 6.15%), while the risk of ONJ remained relatively low (10.02–10.19%, depending on compliance). In contrast, patients who received denosumab for less than 12 months demonstrated a substantially higher risk of SREs, reaching 19.44% (95% CI, 6.47–45.69). Shorter administration intervals were associated with increased ONJ risk but did not significantly affect SRE prevention. Conclusions: This nationwide real-world study is the largest to date to evaluate the optimal duration and administration interval of denosumab in metastatic breast cancer patients with bone metastases. To effectively prevent SREs while minimizing the risk of ONJ, a denosumab treatment duration of 13–24 months appears to offer the most favorable benefit-risk balance and may be considered an optimal treatment strategy in clinical practice.