Prevention of Symptomatic Skeletal Events with Denosumab Administered Every 4 Weeks Versus Every 12 Weeks–A Non-Inferiority Phase III Trial: Sakk 96/12 - Reduse

Abstract

ABSTRACT Background: Denosumab is a monoclonal antibody against RANK-Ligand with a higher activity in preventing skeletal related events (SREs) than zoledronic acid but without impact on disease progression or death. SREs are pathologic bone fractures, surgery or radiation to the bone or spinal cord compression. The relative effects on SREs in patients with bone metastases from castration resistant prostate cancer and breast cancer are similar (hazard ratio 0.82). Denosumab is usually well tolerated but a dose-dependent increase in risk of osteonecrosis of the jaw in up to 8% of patients and cases of fatal hypocalcaemia have been observed. The approved dose of denosumab is 120mg sc every 4 weeks (q4w); the basis for this dose and schedule, however, is not quite clear. E.g. in a study of 255 women with bone metastases from breast cancer who were randomized to receive denosumab 30mg q4w, 120 mg q4w, 180 mg q4w, 60mg q12w, 180mg q12w or an iv bisphosphonate, a similar degree of creatinine-corrected urinary N-telopeptide (uNTx/Cr) suppression was observed at weeks 13 and 25 in all cohorts. Given that the optimal dose and schedule of denosumab is unknown and this drug is associated with considerable costs and adds toxicity a study of de-escalation is warranted. Trial design: The aim of this trial is to test the hypothesis that the benefit of denosumab is maintained if administered 120mg q12w as compared to 120mg q4w. The primary endpoint of this randomized phase III non-inferiority trial is time to first on-trial symptomatic skeletal event (SSE) defined as clinically significant pathological fracture, surgery to bone, radiation therapy to bone, or spinal cord compression. With a non-inferiority margin of 1.2 for the hazard ratio, a power 80% and a type I error 5%, the total sample size is 1380. Secondary endpoints include safety, time to first and subsequent on-trial SSE, health economic outcomes, quality of life, and change in bone turnover markers. Patients with adequate organ function and bone metastases from breast cancer of from castration resistant prostate cancer are eligible. This trial is open for international collaboration. ClinicalTrials.gov identifier: NCT02051218. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting. All rights reserved. Disclosure: S. Gillessen: Advisory board Novartis; B. Thurlimann: Stock owndership Novartis: R. von Moos: Research funding, honoraria, and consultant Amgen. Honoraria and advisory board Novartis. All other authors have declared no conflicts of interest.