By Chris Berrie
BERLIN -- September 24, 2009 -- Denosumab significantly delays or prevents skeletal-related events (SREs) compared with zoledronic acid, while providing similar pain improvement, disease control, and toxicity in patients with advanced breast cancer and confirmed bone metastases.
In addition, denosumab shows no renal toxicity or acute phase reactions, although it is accompanied by increased hypocalcaemia, according to a study presented here September 22 at the joint 15th Congress of the European Cancer Organisation (ECCO) and 34th Congress of the European Society for Medical Oncology (ESMO).
"Up to 80% of patients with advanced breast cancer develop bone metastases during the course of their disease," said presenter Alison Stopeck, MD, Breast Cancer Programme, Haematology and Oncology, Arizona Cancer Centre, University of Arizona, Tucson, Arizona. These can lead to osteoclast-mediated bone destruction, with clinical consequences including SREs, hypercalcaemia, and pain.
The multicentre, randomised, double-blind, active-controlled phase 3 study included patients with advanced breast cancer and confirmed bone metastases without prior or current intravenous bisphosphonate use.
The primary endpoint was time to first on-study SRE, as a noninferiority measure. The secondary endpoints were the same as a superiority measure, plus time to first and subsequent on-study SREs, again for superiority.
Patients were stratified by previous SREs, prior bisphosphonate therapy, current chemotherapy, and geographic location, and randomised to intravenous (IV) zoledronic acid 4 mg with subcutaneous (SC) placebo (n = 1,020), or denosumab 120 mg SC with IV placebo (n = 1,026), every 4 weeks.
For zoledronic acid, the dose was adjusted for baseline creatinine clearance, with dose intervals defined by serum creatinine. Supplementation with calcium (>=500 mg/day) and vitamin D (>=400 IU/day) were included.
At a median on-study time of 16.5 months, time to first on-study SRE saw denosumab treatment with significant benefit over zoledronic acid for both noninferiority (P < .0001) and superiority (P = .01). The same was seen for the multiple event analysis of time to first and subsequent on-study SREs (P = .001), and for time to experiencing moderate or severe pain (P = .009).
In contrast, there were no differences across the treatments for time to experiencing pain improvement, overall survival, and overall disease progression.
Adverse events across the treatment groups were similar, with significant between-group differences specifically for toothache and hypocalcaemia with denosumab, and for pyrexia, bone pain, arthralgia, anaemia, chills, pain, renal failure, lumbar vertebral fracture, oedema, and hypercalcaemia for zoledronic acid.
"This trial supports the use of denosumab as a novel treatment option for patients with breast cancer and bone metastases," said Dr. Stopeck.
Funding for this study was provided by Amgen Inc and Daiichi Sankyo Co. Ltd.
[Presentation title: Denosumab Versus Zoledronic Acid for the Treatment of Breast Cancer Patients With Bone Metastases: Results of a Randomized Phase 3 Study. Abstract 2LBA]
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