July 19, 2011 — The novel bone agent denosumab (Xgeva, Amgen) has been approved in all 27 member states of the European Union for use in adult patients with solid tumors and bone metastases. The indication is for preventing skeletal-related events (SREs) including pathological fracture, radiation to bone, spinal cord compression, or surgery to bone.

The same indication was approved in the United States in November 2010, after a 6-month priority review.

The European Commission also granted the product "an additional year of data and market exclusivity in the European Union since the indication was considered new for denosumab and based on the significant clinical benefit of denosumab in comparison with existing therapies," the manufacturer noted.

"Skeletal-related events associated with bone metastases are truly devastating for patients living with cancer," commented Ingo Diel, MD, from the Institute for Gynecological Oncology, SPGO, Mannheim, Germany. Denosumab represents a "real advance," he said in a statement. In clinical trials, this drug demonstrated "sustained protection from SREs and also delayed the progression of pain. These factors will make a genuine difference in the lives of patients living with advanced cancer," he said.

The approval is based on 3 pivotal clinical trials, all of which have now been published, in which denosumab was compared with the bisphosphonate zoledronic acid (Zometa, Novartis).

In the trial conducted in breast cancer (J Clin Oncol. 2010:28:5132-5139) and the trial in patients with prostate cancer with bone metastases (Lancet. 2011; 377:813-822), densumab was superior to zoledronic acid in reducing the risk for SREs, and in a third trial in patients with other solid tumors or multiple myeloma and bone metastases (J Clin Oncol. 2011;29:1125-1132), denosumab was noninferior to zoledronic acid.

An integrated analysis of all 3 trials shows that denosumab was superior to zoledronic acid in delaying time to the first on-study SRE by 17%, or by 8.2 months (median time to first SRE, 27.6 months for denosumab vs 19.4 months for zoledronic acid; P < .0001), notes the manufacturer. In this analysis, denosumab was also superior in delaying time to the first and subsequent on-study SRE by 18% (P < .0001). In addition, in patients with mild or no pain at the start of the trial, the time to worsening pain was delayed by denosumab compared with zoledronic acid (198 vs 143 days; P = .0002).

Clinicians involved in these trials have emphasized the superior efficacy of denosumab and highlighted other potential advantages over zoledronic acid, including subcutaneous administration (vs infusion) and no need for renal monitoring, concluding that denosumab offers the "better" option.

However, other experts reviewing the data have not been quite as convinced, and several have highlighted the much higher cost of the new drug.

Denosumab offers "a strong option to displace" zoledronic acid in this setting, comments Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, in an editorial published in the Journal of Clinical Oncology (2011;29:1095-1098) that accompanied one of the published studies.

Denosumab offers "incremental benefit," but "debatable value," Dr. West writes. In addition, the need to balance cost and benefits means that, "It falls short of a new standard of care."

When it was launched in the United States, denosumab was priced at $1650 monthly, which is nearly twice as much as zoledronic acid, Dr. West points out, noting that generic versions of this drug are expected in early 2013. These generics would offer "a far less expensive but still comparable alternative," he comments.

Denosumab is a "welcome addition," comments Jeanny Aragon-Ching, MD, from the George Washington University Medical Center in Washington, DC, in an editorial in The Lancet (2011;377:785-786) that accompanied the publication of another of these trials. Denosumab is easier to administer (subcutaneously vs intravenously for zoledronic acid), which allows "for shorter visit times and applicability in various physician's office settings by removing the need for an infusion clinic," she notes. In addition, it reduces the need to manage acute-phase reactions, renal monitoring, and dose adjustments.

However, Dr. Aragon-Ching wondered whether the superior efficacy seen with denosumab was clinically significant enough to justify its choice over zoledronic acid, in light of the potential increased cost, and especially, in the absence of survival or progression benefit.

In addition, recently updated guidelines from the American Society of Clinical Oncology on the use of bone-modifying agents in patients with metastatic breast cancer did not acknowledge superior efficacy for denosumab. Denosumab was listed alongside zoledronic acid and pamidronate as an option, but the guideline stated that "there is insufficient evidence relating to efficacy to support one bone-modifying agent over another."

When asked about this in an interview with Medscape Medical News, lead author of these guidelines, Catherine Van Poznak, MD, breast medical oncologist at the University of Michigan, Ann Arbor, said that the panel of experts who wrote the update chose these words very carefully. She acknowledged that there have been head-to-head clinical trials comparing denosumab and zoledronic acid that have shown some superior outcomes at some endpoints for denosumab, but when all of the available data were taken into consideration, the panel felt that the evidence was insufficient to recommend any one agent over another, she explained.

For each individual patient, there are a number of factors that should be taken into consideration in addition to efficacy, she emphasized; these include mode of administration, toxicity profile, patient preference, and cost.

Medscape Medical News © 2011  WebMD, LLC

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Cite this: Denosumab Approved in EU for Cancer With Bone Metastases - Medscape - Jul 19, 2011.

Zosia Chustecka is the News Editor for Medscape Oncology. A pharmacology graduate based in London, UK, she has edited and written extensively for publications aimed at clinician audiences. Her work has been recognized by the British Medical Journalists Association, and most recently she was the recipient of the 2010 National Press Foundation Cancer Issues Fellowship. She can be reached at zchustecka@medscape.net.

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