Effects of denosumab on bone resorption in patients with solid tumors and bone metastases: Comparison of serum-C telopeptide levels from two randomized, active-controlled, phase II trials

Abstract

9574 Background: Patients with bone metastases have a high risk of skeletal morbidity and high rates of bone remodeling, both mediated by RANKL-stimulated osteoclasts. Denosumab, a fully human monoclonal antibody that is being investigated for the treatment of bone metastases, suppresses bone resorption by inhibiting RANKL. Methods: In 2 recently completed phase II studies, patients with solid tumors and bone metastases were randomly assigned to receive intravenous bisphosphonates (IV BP) or subcutaneous denosumab. Patients were either IV BP-naïve or had evidence of increased levels of bone resorption despite treatment with IV BPs. We evaluated the effects of the 2 treatments by comparing changes in serum-C telopeptide (sCTx), a biochemical marker of bone resorption, from baseline to week 25. Our objective was to determine whether denosumab-induced suppression of bone turnover was affected by previous exposure to IV BPs. Results: In both studies, denosumab was associated with similar rates of suppression of bone resorption, indicated by reductions in sCTx (Table), whether or not patients had previously received IV BPs. The incidence of serious adverse events was similar across treatment groups in both studies (Table). Conclusions: In cancer patients with bone metastases, regardless of IV BP exposure, denosumab suppressed bone resorption and had an adverse event profile similar to that for patients treated with IV BPs. Phase III trials are in progress. Reduction in Bone Turnover with Denosumab and IV BPs Parameter Bisphosphonate-Naive Previously Treated With IV BPs IV BPa N = 43 Denosumabb N = 212 IV BPc N = 35 Denosumabd N = 69 Age, years - mean (SD) 52 (11) 58 (11) 62 (12) 62 (12) Median (Q1, Q3) reduction −80% −85% −45% −80% in sCTx at week 25 (−66%, −88%) (−75%, −90%) (−28%, −71%) (−69%, −90%) Serious adverse events - n (%) 15 (35) 75 (36) 18 (51) 36 (49) Serious treatment-related adverse events - n (%) 0 (0) 0 (0) 0 (0) 1 (1)e a > 80% zoledronic acid b Denosumab every 4 weeks (Q4W; 30, 120, 180 mg) or every 12 weeks (Q12W; 60 or 180 mg) c > 90% zoledronic acid <d Denosumab 180 mg Q4W or Q12W e One patient experienced hypophosphatemia, deemed treatment-related by the investigator. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Inc. Amgen, AstraZeneca, Bristol-Myers Squibb, Ipsen-Beaufour, Merck, Novartis, Pfizer, Pharmion, sanofi-aventis Amgen Inc. Amgen, AstraZeneca, Ipsen-Beaufour, Novartis, Pfizer, sanofi-aventis, Takeda Amgen, Novartis, Oncogene Sciences/Bayer, Pfizer Novartis