Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.
How much does Medicare spend each year on non-recommended bone therapy?
The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.
Overall, this study found that "the Medicare program pays tens of millions of dollars each year" for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, "which is not effective and may cause side effects," lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.
"These findings suggest reducing bone agent overuse could be a rare healthcare 'win-win'. Lower costs AND improved patient outcomes," tweeted Mitchell. "If I were a payer, I'd be paying attention!"
In Prostate Cancer, Bone-Modifying Drug Indications Vary
Bone-modifying drugs are indicated for some patients with prostate cancer.
The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.
Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.
For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.
In this population, "treatment with bone agents results only in avoidable toxicity and financial cost," Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.
An earlier study from Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.
To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).
The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.
The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.
The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion's share at $43,303,078.
Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.
The study focused on the Medicare-age population, which means the estimates are conservative. "Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total," the authors wrote.
"This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community," said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, Pennsylvania, who wasn't involved in the research. "While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don't need them upfront."
Why Is the Overuse Happening?
One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.
Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.
"Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy," but "I think there is significant undertreatment" in these patients, Laurent told Medscape Medical News.
However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston, Massachusetts.
Meanwhile, "monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons," Saylor said.
When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, "we have no evidence that it is beneficial," he said, adding that "when the prostate cancer itself is well controlled by hormonal therapy, there just aren't very many pathologic fractures or other bone complications."
Alongside possible confusion over the recommendations, many physicians also likely don't know how much denosumab costs.
"In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor," Mitchell said.
Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but "in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses," Mitchell explained.
However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.
In another recent paper, Mitchell said he found about "30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year."
These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.
Mitchell suggested a few ways to help curb inappropriate prescribing.
Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Mitchell said.
More physician education would be another solution. "I think that physician education would be one 'bottom-up' approach that could work," Mitchell added.
Mitchell, Takvorian, and Saylor had no disclosures to report. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will-Pharma.
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