By ecancer reporter Jo Armstrong

A recently completed integrated analysis of three identically designed phase III trials found that denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid in preventing or delaying time to first skeletal-related events (SRE) across a variety of tumour types.

The integrated analysis showed that denosumab was superior to zoledronic acid in delaying time to 1st on-study SRE by 17%, with a median time to 1st SRE of 27.7 months for denosumab and 19.5 months for zoledronic acid.[i] Denosumab was also superior to zoledronic acid in delaying time to 1st and subsequent on-study SRE by 18%. Overall disease progression and survival were similar for both groups. Similar percentages of patients in each group reported adverse events (AEs; 96.2% denosumab, 96.8% zoledronic acid) and serious AEs (56.3% denosumab, 57.1% zoledronic acid). Osteonecrosis of the jaw occurred in 1.8% of denosumab and 1.3% of zoledronic acid patients (p = 0.13). Hypocalcaemia was reported by 9.6% of denosumab and 5.0% of zoledronic acid patients. Incidence of AEs potentially associated with renal toxicity was 2.6% higher, serum creatinine (Cr) elevations 3.9% higher, and decline in CrCl < 60 mL/min 3.1% higher in the zoledronic acid vs denosumab group. AEs associated with acute phase reactions within 3 days were reported by 8.7% of denosumab and 20.2% of zoledronic acid patients. Across a broad cancer population with bone metastases, denosumab was superior to zoledronic acid in delaying or preventing SRE.

Patient-reported pain outcomes from this analysis were also presented.[ii] Eligible patients with breast, prostate or other cancer or myeloma received either subcutaneous denosumab 120 mg or IV zoledronic acid 4 mg every 4 weeks in a double-blind double-dummy design (N=5,723). Median time to clinically significant pain worsening was delayed with denosumab versus zoledronic acid (181 days vs 169 days, p=0.026). In patients with no/mild pain at baseline, denosumab showed a prolonged time to moderate/severe pain versus zoledronic acid (198 days vs 143 days, p=0.0002). The proportion of patients with no/mild pain at baseline who reported moderate/severe pain while in the study was consistently lower for denosumab than zoledronic acid. Time to pain improvement was similar between groups. This study concluded that denosumab prevented clinically relevant increase in pain compared with zoledronic acid across the tumour types and was similar to zoledronic acid in relieving pain.

[i] Lipton A et al. Poster 1249P: Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: An integrated analysis of 3 pivotal trials.

[ii] Cleeland CS et al. Poster 1248P: Effects of denosumab vs zoledronic acid (ZA) on pain in patients (patients) with advanced cancer and bone metastases: An integrated analysis of 3 pivotal trials.