Dosing Zoledronic Acid Less Often Doesn't Reduce Efficacy

Gabriel N. Hortobagyi, MD

Phase III trial results presented at the 2014 ASCO Annual Meeting showed that the dosing frequency of zoledronic acid (Zometa) can be reduced by 67% without compromising effectiveness in women with breast cancer and bone metastases, potentially lowering the risk of serious adverse events.

“[Less frequent dosing] means [patients] have more time to spend with their family and friends doing things that they care about rather than visiting the doctor’s office; it means less toxicity…and less cost. So I think that this is really part of the value equation,” moderator Patricia Ganz, MD, director of Cancer Prevention and Control Research at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, said at an ASCO press briefing.

Zoledronic acid, a third-generation bisphosphonate, is used to reduce complications from bone metastases in women with breast cancer. Standard administration is 4 mg every 3 to 4 weeks for the first year following diagnoses of metastases. However, an optimal treatment regimen following the induction period has yet to be established, and there are safety concerns (ONJ, chronic kidney function impairment) with long-term bisphosphonate use.

The double-blind, multicenter, phase III OPTIMIZE-2 trial included 403 women (median age, 59 years) with bone metastases from breast cancer who were previously treated with IV bisphosphonates monthly for 10 to 15 months. Patients had received at least nine doses of either zoledronic acid or pamidronate (Aredia).

At a 1:1 randomization, patients continued bisphosphonate therapy with 4 mg of IV zoledronic acid either monthly (n = 200) or every 3 months (n = 203) for 1 year. To maintain the blind, patients receiving treatment every 12 weeks were given a placebo between doses. Patient characteristics at baseline were similar between the treatment arms. The study initially included a placebo-only arm that was terminated due to poor accrual.

The primary endpoint was the skeletal-related event (SRE) rate, defined as the proportion of patients with ≥1 SRE (eg, pathologic fractures, spinal cord compression, or the need for radiotherapy or surgery to bone). Specifically, the researchers assessed noninferiority (10% predefined margin) for the difference in SRE rates between the treatment arms. Skeletal morbidity rate (SMR), time to first SRE, change in bone turnover markers, bone pain score, and safety were secondary endpoints.

The results established that after a median follow-up of 11.9 months, administering zoledronic every 12 weeks was noninferior to a monthly regimen. There was a 1.2% difference in SRE rates between the arms (95% CI, 7.5%-9.8%; P = .724), at 22% (n = 44) and 23.2% (n = 47) in the monthly and every-3-month arms, respectively. The 9.8% upper limit of the 95% CI was lower than the 10% predefined margin for noninferiority.

Secondary endpoints were comparable between the two treatment arms, as well. Mean SMRs were 0.46 and 0.50 (P = .854) in the higher- and lower-frequency arms, respectively. The times to first SRE (HR = 1.06; 95% CI, 0.70-1.60; P = .792) and changes from baseline in bone turnover markers were also similar.

The toxicity profiles were also comparable between the two dosing schedules, with a similar incidence of adverse events (AEs). Grade 3/4 AEs were reported in 47.5% (n = 94) and 42.6% (n = 86) of patients in the monthly and every-3-month arms, respectively. Pain levels and use of pain medications also did not vary between the two arms.

The reduced-frequency arm did have a lower incidence of some of the more serious side effects associated with zoledronic acid. There were two cases (1%) of ONJ in patients receiving monthly treatment, compared with no cases in patients receiving therapy every 3 months. Increased renal toxicities also occurred with the higher-frequency regimen, at 9.6% (n = 19) versus 7.9% (n = 16).

Commenting on the nonsignificance of the efficacy results, lead author Gabriel N. Hortobagyi, MD, professor of Medicine at the MD Anderson Cancer Center, said, “Due to design limitations and statistical concerns, the noninferiority claim should be interpreted with caution.”

The OPTIMIZE-2 study was funded by Novartis, which manufactures zoledronic acid.

Hortobagyi GN, Lipton A, Chew HK, et al. Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial. J Clin Oncol. 2014;32:5s (suppl; abstr LBA9500).