September 22, 2009—During the joint ECCO 15–34th ESMO Multidisciplinary Congress in Berlin, results were presented by Alison Stopeck, MD (University of Arizona), from a trial of denosumab versus zoledronic acid in patients with breast cancer metastatic to bone.

Eighty percent of patients with advanced breast cancer develop bone metastases. Skeletal complications of bone metastases in patients with breast cancer are serious events that have a major adverse impact on quality of life. Intravenous bisphosphonates, most commonly zoledronic acid, are currently included in guidelines for the treatment of skeletal complications in patients with bone metastases.

Local bone destruction caused by increased osteoclast activity is mediated by RANK Ligand (RANKL), a key regulator of bone homeostasis. Denosumab, a fully human monoclonal antibody against RANKL, has been previously shown to decrease bone resorption in patients with breast cancer metastatic to bone (Gralow J, et al. Cancer Res.2009;69(Suppl 2): Abstract #1155).

An international phase III, randomized, double-blind study was conducted to compare denosumab with zoledronic acid in the treatment of patients with bone metastases from breast cancer. The primary endpoint of this study was evaluation of time to first on-study skeletal-related event (SRE), which was predefined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. Secondary endpoints were established to evaluate time to first and subsequent on-study SREs, as well as to assess the safety and tolerability of denosumab compared with zoledronic acid.

A total of 2046 eligible patients with radiographic evidence of bone metastases were randomized to receive either 120 mg of subcutaneous denosumab and intravenous placebo every 4 weeks, or 4 mg of intravenous zoledronic acid and subcutaneous placebo adjusted for creatinine clearance every 4 weeks. Patients receiving prior bisphosphonate therapy for bone metastases were excluded, while previous treatment with an oral bisphosphonate for osteoporosis was permitted with the condition that therapy be terminated prior to study initiation.

The following results were obtained from the trial:

• Denosumab significantly delayed the time to first on-study SRE compared to zoledronic acid [P = .01 (superiority); P < .0001 (non-inferiority)] in this 34-month study.

• The median time to first on-study SRE was not reached for denosumab; the median time to first on-study SRE was 806 days for zoledronic acid.

• Denosumab significantly delayed the time to first and subsequent on-study SRE compared to zoledronic acid (P = .001).

• Overall survival and time to cancer progression were similar in both treatment arms.

The incidence of adverse events was consistent with previous studies involving these agents, and was comparable between the two treatment arms. It should be noted that osteonecrosis of the jaw (ONJ) was an infrequent occurrence in patients treated with either denosumab or zoledronic acid, and there was no statistically significant difference in the rate of ONJ between the two groups.

In summary, denosumab demonstrated superiority to zoledronic acid in regard to delaying or preventing SREs in patients with breast cancer metastatic to bone with a comparable safety profile. These data highlight the role of the RANKL pathway in bone disease.

Eur J Cancer Suppl. 2009;7(3): Abstract 2LBA.