COST EFFECTIVENESS OF ZOLEDRONIC ACID

At a time when rising healthcare costs in the United States are coming under intense scrutiny, one of the first independent analyses to compare a proprietary drug with its generic counterpart shows that zoledronic acid given every 3 months is more cost-effective than monthly denosumab (Prolia, Xgeva, Amgen) in women with breast cancer and skeletal metastases, say researchers.

Analysis of data from the Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology trial 70604 shows that compared with the cost of zoledronic acid every 3 months, the mean cost of administering monthly denosumab to prevent skeletal-related events (SREs) was nine times higher over a 2-year period, according to Charles L. Shapiro, MD, professor of medicine, Icahn School of Medicine at Mt Sinai, New York City, and colleagues.

The study also compared monthly denosumab to monthly zoledronic acid.

The mean incremental costs per mean SRE avoided ranged from $162,918 to $347,655 for denosumab, the study authors say in a report published online October 12 in the Journal of Clinical Oncology. When compared with the cost of zoledronic acid given monthly, the mean incremental costs of denosumab per mean SRE avoided ranged from $137,905 to $283,109 over 24 months.

Importantly, the analysis was sponsored by the National Cancer Institute and not by Novartis, the manufacturer of zoledronic acid, or by Amgen, which makes denosumab, the investigators note. In the past, most analyses comparing cost-effectiveness between zoledronic acid and denosumab have been sponsored by the companies, they say.

"As we move toward a value-based health care model, every 3-month ZA [zoledronic acid] may be a viable alternative to monthly denosumab when costs are considered," write Dr Shapiro and colleagues.

Up to 75% of women with metastatic breast cancer develop bone metastases, a cause of significant morbidity, including pain, pathologic fracture, spinal cord compression, and hypercalcemia requiring surgery and/or radiation therapy.

Earlier this year, the CALGB/Alliance trial showed that zoledronic acid every 4 months was noninferior to monthly zoledronic acid in terms of 2-year cumulative incidence of SRE and selected toxicities in patients with breast cancer, prostate cancer, and multiple myeloma. Dr Shapiro and colleagues used these data to construct a hypothetical cohort of 10,000 women with breast cancer and bone metastases to analyze the value of monthly zoledronic acid and  zoledronic acid every 3 months and compare them to monthly denosumab.

We've got to start doing more trials like this. Dr Charles L. Shapiro

"We've got to start doing more trials like this," Dr Shapiro said in an interview with Medscape Medical News."It's about value — how much do you get for what it costs? In this age, we're moving towards a value assessment of costs and yet it's part of our culture that no matter how expensive a drug is, we keep going back to it. Is $100K to $200K a year for a 2-month survival advantage worth it?"

Even though denosumab is more efficacious in terms of delaying time to first SRE and time to subsequent events, "there is no survival difference," Dr Shapiro emphasized. "This is not strong enough [evidence] to make it a preference."

There is no survival difference. Dr Charles L. Shapiro 

A 2010 randomized, double-blind trial showed that monthly denosumab was 23% better than zoledronic acid in delaying time to first SRE and the time to first and subsequent SREs, the investigators point out. That study also showed that overall survival, disease progression, and rates of adverse and serious adverse events were similar between the treatment groups.

On October 16, the American Society of Clinical Oncology (ASCO), in collaboration with Cancer Care Ontario (CCO), published an online update on the role of bone-modifying agents in metastatic breast cancer.

After conducting a targeted literature review, the joint ASCO-CCO update committee concluded there was insufficient evidence to support the use of one bone-modifying agent over another in the treatment of patients with breast cancer with bone metastases. Their recommended treatment options include denosumab, 120 mg subcutaneously, every 4 weeks; pamidronate (Aredia, Novartis), 90 mg intravenously, every 3 to 4 weeks; or zoledronic acid, 4 mg intravenously every 12 weeks or every 3 to 4 weeks.

Given that the new ASCO guidelines don't endorse any single bone-modifying agent, Dr Shapiro said he found the price differential between zoledronic acid and the new denosumab somewhat surprising. "I think that's the point," he told Medscape Medical News. "This study is a way to alert the oncology community to the fact that if you use every-3-month zoledronic acid, you can save a whole bunch of costs. It's a lot cheaper."

Sensitivity analyses were performed from a US payer perspective. The average cost of a treatment strategy was calculated by using the average of the drug cost, the cost of drug administration, and the cost associated with having SREs.

The researchers used the assumption that the probability of SREs in patients treated with denosumab would be 50%, 75%, and 90% lower than the probability of SREs with zoledronic acid. Factors taken from data in the CALGB/Alliance trial as well as the 2012 study by Xie et al were used to determine SRE probabilities.

Other Considerations Come Into Play

When asked to comment, Hatem Soliman, MD, associate member of the breast, tumor biology, and immunology departments at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, pointed out that it would be "difficult to demonstrate cost-effectiveness between a branded drug given monthly and a generic drug given once every 3 months unless the difference in the primary outcome was very large."

Depending on which cost-effectiveness model is used, "less expensive pamidronate may be even more cost-effective than zoledronic acid," said Dr Soliman, who is associate professor in the Division of Oncologic Sciences at the University of South Florida.

Definitions of cost-effectiveness can vary, he said, depending on what healthcare policy experts consider "acceptable" in any particular healthcare setting. However, monthly pamidronate is about 20% less effective than zoledronic acid in patients with breast cancer, he noted. "The ultimate question becomes, is the difference in efficacy observed worth the extra cost to us? The answer to this question can vary depending on who you ask."

The costs associated with SRE-related events, such as the costs of monitoring and treating renal events with bisphosphonates, providing additional rehabilitation care, and lost productivity, aren't included in the study, noted Dr Soliman. He acknowledged that estimating and incorporating these costs would be difficult to model.

The take-home message is that every-3-month zoledronic acid is likely to be a cost-effective method to reduce SREs in an increasingly resource-challenged medical care environment," he told Medscape Medical News. "However," he emphasized, "patient-specific characteristics should be taken into consideration to make sure the optimal treatment for their particular circumstance is selected, and costs/benefits should be discussed with patients as well."

The "trade-offs" for using less expensive zoledronic acid include a less convenient dosing route, Dr Soliman pointed out. Some patients may require port placement for intravenous administration, and others with poor peripheral circulation will need maintenance and a longer infusion time for each appointment.

There are also a higher risk for acute phase reactions with zoledronic acid compared with denosumab (27% vs 10%) and a greater likelihood of kidney dysfunction with zoledronic acid. In addition, "acceptance of a higher rate of skeletal events affecting patient functioning to achieve the desired cost savings" would be needed, he said.

Currently, two open-label phase 3 noninferiority trials are actively recruiting patients with metastatic breast or prostate cancer to receive different dosing schedules of bone-modifying agents. The SAKK 96/12: REDUSE trial is randomly assigning patients to monthly or every-3-months courses of denosumab, and the REaCT-BTA trial is randomly assigning patients to 4-week or 12-week denosumab, pamidronate, or zoledronic acid.

"The benchmark is that every-3-month denosumab is not going to be noninferior to zoledronic acid, but it's not a slam-dunk for me," said Dr Shapiro. "We will have to wait and see."

This study was supported by the National Cancer Institute of the National Institutes of Health. Dr Shapiro has disclosed no relevant financial relationships. Dr Soliman reports relationships with Amgen, Novartis, Celgene, Eli Lilly, and AstraZeneca.

J Clin Oncol.  Published online October 12, 2017. Abstract