Osteonecrosis of the jaw (ONJ) in patients with metastatic castration resistant prostate cancer (mCRPC) treated with denosumab in a randomized phase III trial comparing 4 vs. 12 weekly administration (REDUSE, SAKK 96/12).

163 Background: While reducing skeletal-related events in patients (pts) with bone metastases (BM), bone protecting agents such as DN have adverse events. One major adverse event is osteonecrosis of the jaw (ONJ), which can significantly impact quality of life. The risk of ONJ increases with treatment duration and reaches cumulative rates of up to 9%. We report ONJ rates in a randomized phase III non-inferiority trial investigating the optimal dose schedule of denosumab (DN). Methods: Pts with BM from mCRPC were randomized 1:1 to receive DN every 4 weeks (q4w; arm A, standard arm) versus every 12 weeks (q12w; arm B, experimental arm) after a 16-week induction phase with q4w therapy for both arms. The primary endpoint of the study is time to first symptomatic skeletal event (SSE) while the incidence of ONJ is an important secondary endpoint. Since the differentiation between ONJ and tooth abscess (the term according to CTCAE v5.0 is tooth infection [TI]) can be difficult, we report these two outcomes separately as well as combined (in case both events were reported for one patient, the timepoint of earlier event was counted). 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 prior to treatment start was recommended. Data from patients who received at least one 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. As this is an interim analysis, only descriptive analyses were performed without formal statistical comparison between the arms. Results: 546 pts from 39 centers with a median follow-up time of 2.4 years were evaluated for ONJ. The median number of administered DN-doses was 16 doses in arm A and 8 doses in arm B, the treatment duration was 64 weeks in arm A versus 72 weeks in arm B. Rates of ONJ, tooth infection, and the combined rates are given in the table. Time to first ONJ and time to first ONJ or TI was in favor of arm B with HRs 0.63 (95% CI 0.33 - 1.21) and 0.71 (95% CI 0.43 – 1.16), respectively. Conclusions: Administration of DN q12w reduces the risk of ONJ. This risk reduction of ONJ or TI is clinically relevant with an overall absolute difference of 1.6% for all grades and 1.9% for ≥3 after a median follow-up of 2.4 years. Efficacy data for time to first SSE (the primary endpoint of this trial) is not yet mature and will be reported later. Clinical trial information: NCT02051218 . Term Induction phase Arm A (q4w) Arm B (q12w) ONJ, all grades (G) 1/546 (0.2%) 21/242 (8.7%) 15/233 (6.4%) TI, all G 7/546 (1.3%) 13/242 (5.4%) 13/233 (5.6%) ONJ or TI, all G 8/546 (1.5%) 31/242 (12.8%) 26/233 (11.2%) ONJ ≥ G3 0/546 (0%) 12/242 (5.0%) 8/233 (3.4%) TI ≥ G3 1/546 (0.2%) 4/242 (1.7%) 1/233 (0.4%) ONJ or TI, ≥ G3 1/546 (0.2%) 14/242 (5.8%) 9/233 (3.9%)