Nick Mulcahy

May 30, 2014

CHICAGO — Women with breast cancer and bone metastasis can scale back the use of a bone-building drug over time and apparently still get the same benefit, according to new research presented here at the 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO).

Dr. Gabriel Hortobagyi

It has been demonstrated in previous trials that the drug, zoledronic acid (Zometa, Novartis), reduces the risk for complications from bone metastases, such as bone fractures and spinal cord compression, said lead study author Gabriel N. Hortobagyi, MD, professor of medicine at the University of Texas M.D. Anderson Cancer Center in Houston.

As a result, clinicians give zoledronic acid 4 mg as an intravenous (IV) infusion every 3 to 4 weeks for the first year after the diagnosis of bone metastases. This is standard dosing, approved by the US Food and Drug Administration, he said.

However, in the randomized trial known as OPTIMIZE-2, a less-intense schedule of zoledronic acid — administered every 12 weeks — was found to be comparable in efficacy to once-a-month schedule after 1 year of the standard schedule.

Specifically, the researchers randomized 403 women with breast cancer and bone metastases, and found similar skeletal-related event rates in the monthly and 12-week groups (22.0% vs 23.2%; = .724), indicating that the less-frequent treatment is not inferior.

The median follow-up of the trial, which had a noninferiority design, was 11.9 months.

All patients had received at least 9 doses of an IV bisphosphonate (either zoledronic acid or pamidronate) before trial enrollment.

Women with advanced breast cancer can benefit in a number of ways from these results, said Patricia Ganz, MD, from the Jonsson Comprehensive Cancer Center and University of California, Los Angeles. She moderated the ASCO press conference during which Dr. Hortobagyi discussed the study.

"It's not necessary for them to come in every 4 weeks," said Dr. Ganz about the dosing schedule after 1 year. The reduction in visits and dosing means less toxicity, cost, and inconvenience, she noted.

Other efficacy measures, such as time to first skeletal-related event and bone turnover markers, were also similar in the 2 groups.

These data are important because there are no evidence-based guidelines for the optimal treatment schedule after 1 year, according to ASCO press materials.

Notably, safety profiles were also similar in the 2 groups.

The investigators had hypothesized that lower-frequency dosing might decrease the risk for the rare serious adverse effects associated with zoledronic acid.

Like all bisphosphonates, "zoledronic acid has some safety concerns," said Dr. Hortobagyi. Osteonecrosis of the jaw, long-bone fractures, and chronic kidney function impairment are 3 adverse events of "special interest."

Less-frequent dosing of zoledronic acid, compared with the standard monthly dosing, was associated with fewer cases of osteonecrosis of the jaw (2 vs 0) and lower rates of chronic kidney function impairment (7.9% vs 9.6%). There were no cases of long-bone fractures (i.e., atypical femoral fractures). However, these findings were not statistically significant.

The trial's noninferiority claim should also be "interpreted with caution," said Dr. Hortobagyi, because of design limitations and statistical concerns. The trial was of a "relatively modest size," he said.

The study was funded by Novartis Pharmaceuticals. Dr. Hortobagyi and a number of coauthors report financial ties to Novartis. Coauthors include company employees. Dr. Ganz has disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO). Abstract LBA9500. To be presented June 2, 2014.

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