August 16, 2012
2 min read

Denosumab superior to zoledronic acid in reducing bone metastases

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Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained health-related quality of life, according to results of a phase 3 study.

For patients with breast cancer and bone metastases, the occurrence of skeletal-related events — including pathologic fracture, spinal cord compression and radiation to bone or surgery to bone — has been linked to poorer physical, functional and emotional status, and poorer overall quality of life. Skeletal-related events also increase patients’ risk of hospitalization and the duration of hospital stays.

“In recent studies, women with metastatic breast cancer had an estimated median survival ranging from 27 to 39 months, underscoring the importance of managing patients’ overall health and well-being, including bone health and [health-related quality of life],” researcher Miguel Martin, MD, PhD, head of the Medical Oncology Service at Hospital General Universitario Gregorio Marañón in Madrid, Spain, and colleagues wrote. “A 2009 international study of patients with metastatic cancer found that patients rated chronic pain as the most important [health-related quality of life] issue related to their disease, followed by difficulty in carrying out  their usual tasks and worries about loss of independence and mobility.”

Although IV bisphosphonates, such as zoledronic acid (Zometa, Novartis Pharmaceuticals), are able to reduce or delay the occurrence of skeletal-related events and have been a component of standard care for patients with breast cancer and bone metastases, up to 47% of treated patients continue to experience skeletal-related events. Additionally, the use of zoledronic acid requires IV access and may cause renal toxicity and acute-phase reactions.

Based on prior studies that indicated denosumab (Xgeva, Amgen) could provide a more effective and more tolerable therapy, the researchers enrolled 2,046 patients in an international, randomized, double blind study comparing denosumab with zoledronic acid for the prevention of skeletal-related events in patients with advanced breast cancer.

Patients were randomly assigned to receive either 120 mg subcutaneous denosumab (n=1,026) along with an IV placebo, or 4 mg IV zoledronic acid (n =1,020) with subcutaneous placebo every 4 weeks.

According to data results, only 31% of patients who received denosumab experienced a skeletal-related event vs. 36% of those assigned to zoledronic acid (P=.006). Among patients who experienced a skeletal-related event, few of those assigned to denosumab experienced a second event while enrolled in the study.

“Our data indicate that denosumab should be the treatment of choice for the prevention of skeletal-related events and hypercalcemia in patients with breast cancer that has metastasized to the bone,” Martin said in a press release.

Additionally, patients assigned to denosumab had fewer acute phase reactions associated with a flu-like syndrome and fewer adverse events related to kidney dysfunction compared with those assigned to zoledronic acid.

The incidence of first radiation to bone was 12% (n=123) with denosumab vs. 16% (n=162) with zoledronic acid. Treatment with denosumab prolonged the time to first radiation to bone by 26% vs. zoledronic acid (HR=0.74; 95% CI, 0.59-0.94) and exhibited an 18% lower risk for developing a skeletal-related event or hypercalcemia of malignancy (HR=0.82; 95% CI, 0.70-0.95).

“A key difference between denosumab and zoledronic acid results from their distinct pharmacokinetic and pharmacodynamic profiles,” the researchers wrote. “Zoledronic acid is excreted intact primarily through the kidneys and has been associated with clinically significant deterioration in renal function — potentially including acute tubular necrosis and collapsing focal glomerulosclerosis — and renal failure in some patients. Denosumab elimination does not rely on renal function, as the antibody is metabolized through nonspecific catabolism in the reticuloendothelial system. The extent of renal impairment, therefore, has no effect on the pharmacokinetics or pharmacodynamics of denosumab.”

Disclosures: The researchers report, honoraria, research grants, consulting positions, advisory positions, and employment relationships with Amgen, Novartis. Chugai Pharmaceutical, Janssen Pharmaceutical, Nippon Boehringer Ingelheim Co Ltd, Takeda Bio Development Center Limited, GlaxoSmithKline, Roche Diagnostics, Nicomed, Sanofi-Aventis, Geron and Genentech.