November 19, 2010 — The novel biologic agent denosumab (XGEVA, Amgen) has received US Food and Drug Administration (FDA) approval to prevent skeletal-related events in cancer patients with solid tumors and bone metastases.
The same drug is marketed under the trade name Prolia for postmenopausal osteoporosis, an indication the FDA approved in June.
It is used at 2 different doses for these 2 indications. In cancer patients with bone metastases, the drug is administered by subcutaneous injection at a dose of 120 mg every 4 weeks for the prevention of skeletal-related events; for postmenopausal osteoporosis, it is administered at a dose of 60 mg every 6 months.
The new biologic is a fully human monoclonal antibody that binds to RANK ligand, a protein found on osteoclasts and involved in bone breakdown. It is a first-in-class therapeutic — which in pharmaceutical drug development commands a price premium — but it is entering therapeutic domains that have been, to date, dominated by bisphosphonates.
Denosumab has shown superiority over the bisphosphonate zoledronic acid in 2 of 3 trials that tested the agents head to head in cancer patients with bone metastases. The biologic was significantly better at reducing skeletal-related events in a large trial of breast cancer patients (published online November 8 in the Journal of Clinical Oncology and reported by Medscape Medical News), and in a large trial of prostate cancer patients (to date only presented at meetings). In the third trial, conducted in patients with advancer cancer, excluding breast and prostate cancer, the difference did not reach statistical significance, but there was a trend toward superiority.
"The magnitude of the benefit was similar in all of the trials," said Matthew Smith, MD, who headed the prostate cancer trial. "There was a consistency across all of the tumor types," he told Medscape Medical News.
"The aim of these therapies is to reduce skeletal-related events, and here we have level 1 evidence," Dr. Smith reported. "I would certainly want to use the most effective treatment."
Denosumab also has 2 other advantages, Dr. Smith noted. It is administered subcutaneously, which is more convenient than the intravenous administration required for zoledronic acid, he said. This allows it to be used in patients who otherwise might not receive treatment; for example, prostate cancer patients with bone metastases often do not receive bone-targeted therapy because urologists are often not set up to administer intravenous agents.
The adverse-effect profile is also different. "There are no concerns about renal safety with denosumab, so there are no requirements for renal monitoring, which is a key requirement for bisphosphonate treatment," Dr. Smith said. Also, there are fewer acute-phase reactions with denosumab. The risk for osteonecrosis of the jaw is similar with both drugs, and although the incidence rate of adverse effects is low with both drugs, it is something that needs to be looked out for, he added.
Extent of Clinical Impact?
When these data on reducing skeletal-related events in cancer patients with bone metastases were reported last year, an expert not involved in any of the trials said that she was "not overwhelmed by the new data."
Joanne Mortimer, MD, from the City of Hope in Duarte, California, also said that the bisphosphonates have already had a huge impact on the natural history of this complication. "Twenty-five years ago, we were seeing hips that needed replacement and spinal compression, but we don't see these serious complications when we use bisphosphonates," she said. In the United States, intravenous pamidronate (Aredia) is used as well as zoledronic acid; in Europe, oral ibandronate (Boniva) is used.
However, Dr. Smith disagreed to some extent. Bisphosphonates are well established as treatment for patients with bone metastases who have breast cancer and multiple myeloma, he said, but their use in other tumor types is less well established, and many patients go untreated. This is particularly true for prostate cancer patients, he added.
Up to "70% of patients with prostate cancer that has metastasized to the bone are not currently receiving therapy to prevent complications from these bone metastases," said Neal Shore, MD, FACS, medical director at the Carolina Urologic Researcher Center, Myrtle Beach, South Carolina. This might be because urologists are not comfortable in administering, or lack the facilities in which to administer, intravenous agents, he said in a statement issued by Amgen.
"As many as 3 out of 4 patients with advanced prostate, lung, and breast cancer will experience spread to their bones. Despite the availability of current treatments, a significant proportion of these patients still experience bone complications or are not candidates for existing treatment," David Henry, MD, clinical professor of medicine at Pennsylvania Hospital in Philadelphia, said in the same statement.
"Based on the compelling science and robust clinical evidence seen with denosumab, I expect this new option to quickly become a mainstay of cancer care and to play an important role in reducing the incidence of debilitating bone complications in patients with advanced cancer," he said. Dr. Henry was involved in the trial of denosumab conducted in tumor types other than breast and prostate cancer.
High Price Tag
Denosumab has been launched with a high price tag. XGEVA will cost $1650 monthly (based on wholesale acquisition costs), the manufacturer noted.
Perhaps anticipating that its high price will be an issue, Amgen has launched a program to help patients meet deductible, coinsurance, and/or copayment requirements. Under its XGEVA FIRST STEP Coupon Program, eligible patients will incur no out-of-pocket costs for their initial denosumab dose, and will then pay a maximum of $25 for subsequent injections.
All 3 trials of denosumab in cancer patients with bone metastases were funded by Amgen.
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Cite this: Denosumab Approved for Cancer Patients With Bone Metastases - Medscape - Nov 19, 2010.