Denosumab Superior for Bone Metastases, But of 'Debatable Value'

Zosia Chustecka

March 02, 2011

March 2, 2011 — More clinical trial data — from 2 pivotal studies — have been published showing that the novel bone-modifying drug denosumab (Xgeva, Amgen) is superior to zoledronic acid in preventing skeletal-related events (SREs) in cancer patients with bone metastases.

These new data come from 2 of 3 trials funded by the manufacturer that led to the approval of denosumab for this indication late last year. The third trial has already been published (J Clin Oncol. 2010;28:5132-5139).

Data from these 3 studies were widely publicized when they were reported at meetings last year, and the principal investigators of these trials have spoken enthusiastically about denosumab replacing zoledronic acid in this setting.

However, an editorial commentary published online February 22 in the Journal of Clinical Oncology, which accompanies the publication of one of these trials, adds a qualifier to such proposals.

It falls short of a mandate for a new standard of care.

Howard West, MD, from the Swedish Cancer institute in Seattle, Washington, sees denosumabas "a strong option to displace" zoledronic acid in this setting, but adds that the need to balance cost and benefits means that "it falls short of a mandate for a new standard of care."

Dr. West says denosumab offers "incremental benefit" but "debatable value."

It costs nearly twice as much as zoledronic acid, he points out, and generic versions of zoledronic acid are due out in early 2013. These will offer "a far less expensive but still comparative alternative," he writes.

Superiority Not Recognized in Update

Bone metastases

In addition, the superiority emphasized by the clinical trialists was not recognized in the just-published updated guideline from the American Society of Clinical Oncology on the use of bone-modifying drugs in metastatic breast cancer patients.

This update adds denosumab to the drugs that are recommended for use in this setting, alongside zoledronic acid and pamidronate, but it states 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 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 end points 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, patients preference, and cost.

New Clinical Trial Data

The newly published clinical data come from 2 pivotal head-to-head comparator trials.

One of the new trials, published online February 25 in the Lancet, was conducted in 1904 patients with advanced castration-resistant prostate cancer, and showed that denosumab significantly reduced the median time to the first on-study SRE, compared with zoledronic acid (20.7 vs 17.1 months; P = .008 for superiority).

Denosumab is a "welcome addition to the options available for the treatment of metastatic prostate cancer," Jeanny Aragon-Ching, MD, from the George Washington University Medical Center in Washington, DC, writes in an accompanying editorial. 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 wonders whether the superior efficacy — in this prostate cancer trial, delaying the time to first on-study SRE by a median time of 3.6 months — is clinically significant enough to justify the choice of denosumab over zoledronic acid, in light of the potential increased cost and, especially, in the absence of survival or progression benefit.

The other trial, published online February 22 in the Journal of Clinical Oncology, was conducted in 1776 patients with advanced cancer (excluding prostate and breast cancer) and bone metastases or with myeloma. This study showed that denosumab was noninferior to zoledronic acid in delaying time to first on-study SRE, but in this study it was not statistically superior.

The third pivotal head-to-head study was published last year. That trial involved 2046 patients with advanced breast cancer, and like the prostate cancer study, it showed that denosumab was significantly superior to zoledronic acid in reducing the time to first on-study SRE.

When that breast cancer study was published, an accompanying editorial in the Journal of Clinical Oncology (2010;28:5127-5131), authored by Monica Fornier, MD, from the Memorial Sloan-Kettering Cancer Center at Weill Cornell Medical College in New York City, suggested that "denosumab might indeed provide a new clinical standard."

However, the editorial by Dr. West is more circumspect.

Provides "Incremental Gains"

"Bisphosphonate therapy, most commonly zoledronic acid, has been the cornerstone stone of secondary prevention of SREs in patients with solid tumors during approximately the last decade," Dr. West writes.

However, these drugs have several downsides: they are administered by intravenous infusion, so there is a potential for acute-phase reactions; there is a risk for renal toxicity, so there is a need to monitor creatinine function with each administration of the drug; and there is a "small but worrisome risk of osteonecrosis of the jaw, hypocalcemia, and other adverse effects," Dr. West writes.

In addition, enthusiasm "may remain muted by the recognition that the efficacy of these agents is still relatively modest."

Denosumab provides "incremental gains," Dr. West suggests. It delays the time to SRE, but this is a secondary clinical end point, he points out. The trial data so far have shown no effect on progression-free survival or overall survival, although there was a hint of improved overall survival with denosumab in a subset of patients with nonsmall-cell lung cancer in a post hoc analysis.

"This is not to say that a decrease in SREs is not a laudable goal and a clinically significant end point," he notes, but it is "no longer tenable" to compare efficacy and toxicity without also considering cost differentials.

Denosumab offers a clear advantage over zoledronic acid, in that there is no need for renal monitoring, and it offers the convenience to patients of subcutaneous administration, with a lower risk for acute-phase reactions than is seen with intravenous administration. However, denosumab presents its own toxicity concerns, Dr. West points out, including an increased risk for hypocalcemia. It is also associated with osteonecrosis of the jaw (to the same extent as zoledronic acid), when data from all of the 3 comparator trials are considered, Dr. Van Poznak told Medscape Medical News.

Cost is the real sticking point. Denosumab, with its novel mechanism of action, is a first-in-class therapeutic and commands a premium price ($1650 monthly).

It costs nearly twice as much as zoledronic acid, and Dr. West believes that it is appropriate to question "whether the modest incremental gains provided by the newest therapy justify a disproportionate increase in cost."

"It is only fair that oncologists step back and ask whether the heady cost of the newest agents that offer relatively subtle care advantages in bone health, pain control, reduction of nausea/vomiting, or need for blood product support provide such a clear advantage over far less expensive options," he writes.

"The economic reality is that American oncologists simply cannot reflexively recommend the latest and almost invariably most expensive new option for managing clinical end points that are, at best, secondary to the primary goals of cancer treatment if the costs escalate at a rate disproportionate with the benefits that these agents confer," Dr. West concludes.

All 3 clinical trials comparing denosumab with zoledronic acid were funded by Amgen, and some of the coauthors of these papers are Amgen employees. Dr. West, who writes the Blowing Smoke blog on Medscape Medical News, has disclosed no relevant financial relationships. Dr. Aragon-Ching reports receiving speaker fees from Sanofi-Aventis and acting as an advisor to Centocor Ortho Biotech.

J Clin Oncol. Published online February 22, 2011. Abstract, Abstract

Lancet. Published online February 25, 2011. Abstract, Abstract

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