Session

Oral presentation clinical solid tumor oncology

Nov. 20, 2024, 1:45 p.m. - 3:15 p.m., Kairo 1-2

Abstract

Osteonecrosis of the jaw (ONJ) in patients with bone metastases treated with denosumab every 4 vs. 12 weeks (randomized phase 3 trial; SAKK 96/12)

R. von Moos¹, A. Müller², S. Hayoz³, M. Mark⁴, S. Fischer⁵, R. Popescu⁶, S. I. Rothschild⁷, M. K. Fehr⁸, C. Egger⁹, S. Anchisi¹⁰, F. A. Schmid¹¹, K. Zaman¹², C. J. Ackermann¹³, A. Schreiber⁶, P. Bützberger⁷, C. Uhlmann Nussbaum¹⁴, M. Küng¹⁵, C. Schär³, S. Gillessen¹⁶, A. J. Templeton¹⁷, Presenter: R. von Moos¹ (¹Chur, ²Winterthur, ³Bern, ⁴Lugano, ⁵St. Gallen, ⁶Aarau, ⁷Baden, ⁸Frauenfeld, ⁹Schlieren, ¹⁰Sion, ¹¹Zurich, ¹²Lausanne, ¹³Thun, ¹⁴Olten, ¹⁵Fribourg, ¹⁶Bellinzona, ¹⁷Basel)

Objective

While reducing skeletal-related events in patients with bone metastases, bone-modifying agents such as bisphosphonates and denosumab have adverse events. One major adverse event of these agents is osteonecrosis of the jaw (ONJ), which often significantly impacts quality of life. The risk of ONJ increases with treatment duration and can reach cumulative rates of up to 10%. Here we report ONJ rates in a randomized phase III non-inferiority trial investigating the optimal dose schedule of denosumab (DN).

Methods

Patients with metastatic breast cancer (mBC) or metastatic castration resistant prostate cancer (mCRPC) were randomized 1:1 to receive DN q4w (Arm A) versus q12w (Arm B) after a 3-month induction phase with application q4w for both arms. Incidence of ONJ is a secondary endpoint of the study. 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 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. Since the differentiation between ONJ and tooth abscess (the term according to CTCAE v5.0 is tooth infection) can be difficult, we report these two outcomes separately as well as combined.

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. For tooth infections (tooth abscess) the numbers during the induction phase were 0.8%, then after induction 7.5% for arm A and 5.0% for arm B. 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).

Conclusion

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.