Bone metastases Tx: 12-week dosing interval appears feasible

Results of a 2-year clinical trial support switching to a less frequent administration schedule when using zoledronic acid (Zometa) to prevent skeletal-related events in men with prostate cancer.

Results of a recently reported prospective, randomized 2-year clinical trial support switching to a less frequent administration schedule when using zoledronic acid (Zometa) to prevent skeletal-related events in men with prostate cancer.

Published in JAMA (2017; 317:48-58), the study featured a noninferiority design and randomized 1,822 patients 1:1 to treatment with the bisphosphonate every 4 weeks or every 12 weeks. The population included 689 men with prostate cancer (37.8%) along with 855 patients with breast cancer (46.9%), and 278 patients with multiple myeloma (15.3%). A total of 795 patients completed the trial.

The primary outcome was the proportion of patients in each group having at least one skeletal-related event (clinical fracture, spinal cord compression, radiation to bone, surgery involving bone) within 2 years of randomization, and the trial met its criteria for noninferiority with 29.5% of patients in the every 4-week dosing group and 28.6% of patients treated every 12 weeks experiencing at least one skeletal-related event.

A secondary endpoint analysis found there were no significant differences between the two zoledronic acid dosing groups in the probability of experiencing at least one skeletal-related event among the subgroups of patients with breast cancer, prostate cancer, or multiple myeloma. In addition, there were no statistically significant differences between zoledronic acid treatment groups in any other prespecified secondary endpoints, which included pain assessed with the Brief Pain Inventory, ECOG performance status, and incidences of osteonecrosis of the jaw and kidney function. The less frequent dosing schedule was, however, associated with better treatment adherence.

Next: “Based on these results, we feel that patients with prostate cancer, breast cancer, or multiple myeloma who are candidates for zoledronic acid now have the option of being treated every 12 weeks."

“Based on these results, we feel that patients with prostate cancer, breast cancer, or multiple myeloma who are candidates for zoledronic acid now have the option of being treated every 12 weeks. This dosing schedule would mean fewer visits to the doctor’s office, fewer intravenous treatments, and lower cost without loss of effectiveness, at least over 2 years,” said lead author and principal investigator Andrew L. Himelstein, MD, of Helen F. Graham Cancer Center & Research Institute, Newark, DE.

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Dr. Himelstein and colleagues were interested in conducting the study recognizing that while monthly administration of zoledronic acid is standard practice, the regimen was established empirically.

“There were no studies comparing different dosing schedules or any pharmacokinetics or pharmacodynamics data to support administration every 4 weeks, whereas we know that the effect of zoledronic acid persists in the body for quite a long time,” he said.

“We also know that the incidence of osteonecrosis of the jaw, which can be a devastating side effect of zoledronic acid, increases as cumulative drug exposure increases.”

Although there were no significant differences between the two groups in the incidence of osteonecrosis of the jaw or kidney dysfunction, there was a trend for the incidence to be higher in patients treated every 4 weeks versus every 12 weeks (2.0% vs. 1.0%; p=.08).

“Serious side effects were uncommon in both groups in our study, and failure of the difference between groups in the incidence of osteonecrosis to achieve statistical significance may be explained by low power,” Dr. Himelstein said.

Discussing limitations of the study, Dr. Himelstein noted no conclusions can be drawn about the relative efficacy of dosing zoledronic acid every 12 weeks versus every 4 weeks for treatment durations beyond 2 years. In addition, the study did not investigate survival in the two groups.

“However, the standard of care in the community has been to use zoledronic acid for just 2 years, and with the exception of multiple myeloma, there is not much evidence that zoledronic acid has any impact on survival,” he told Urology Times.

Only two previous studies investigated extending the zoledronic acid dosing interval to every 12 weeks. Both, however, included only patients with breast cancer only and had a wash-in period of 9 to 16 months during which patients were treated every 4 weeks before being switched to the less frequent schedule.