Incidence of osteonecrosis of the jaw (ONJ) in the randomized non-inferiority phase III trial SAKK 96/12 REDUSE comparing denosumab (DN) administered every 4 weeks (q4w) versus every 12 weeks (q12w).

12067 Background: ONJ is a well-known adverse event of bone-modifying agents that can significantly impact quality of life. It is recognized that the risk of ONJ increases with the duration of treatment and can reach rates of up to 10%. Here, we report ONJ rates in a randomized non-inferiority phase 3 study investigating the optimal dose of DN. Methods: Patients with metastatic breast cancer (mBC) or metastatic castration resistant prostate cancer (mCRPC) (planned N=1380) were randomized 1:1 to receive DN q4w (Arm A) versus q12w (Arm B) after a 3-month induction phase with application q4w. Incidence of ONJ is a key secondary outcome of the study (NCT02051218). An oral inspection at baseline as well as before each application of DN was mandatory. In patients with risk factors for ONJ a prophylactic dentist visit was recommended. Data from patients who received at least 1 dose of DN and who were randomized at least one year before data cut-off (December 11, 2023) were included in this interim safety analysis. Since the differentiation between ONJ and tooth infection can be difficult, we also report this outcome. Results: 1271 patients with a median follow-up time of 3 years were analyzed. During the 3-month induction phase 2/1271 patients experienced an ONJ. In Arm A 48/575 (8.3%), in Arm B 32/561 (5.7%) patients experienced an ONJ. Time to first ONJ and/or tooth infection differs remarkably with a clear advantage for the 3-months arm (HR 0.67; 95% CI 0.48-0.93). Details are shown in the table. Conclusions: The observed ONJ rate of 8.3% is in line with the literature for patients who received denosumab q4w for over two years (mBC: 6.0%, mCRPC: 8.2%). Administration of DN q12w reduces the risk of ONJ and/or tooth infections substantially. The numerical difference of events to the standard arm as well as the time to first ONJ and/or tooth infection is clinically relevant with a risk reduction by 33%. Efficacy data for the primary endpoint time to first symptomatic skeletal event is eagerly awaited. Clinical trial information: NCT02051218 . [Table: see text]