Gabriel N. Hortobagyi, MD
In the phase III OPTIMIZE-2 trial reported in JAMA Oncology, Gabriel N. Hortobagyi, MD, of The University of Texas MD Anderson Cancer Center, and colleagues found that an every-12-week schedule of zoledronic acid was noninferior to an every-4-week schedule with regard to skeletal-related event rate in women with bone metastases from breast cancer who were currently receiving intravenous bisphosphonate therapy.1
This double-blind trial enrolled 403 women with metastatic disease from 102 sites in the United States who had previously received at least 9 doses of intravenous zoledronic acid or pamidronate during the first 10 to 15 months of therapy and were still receiving bisphosphonate treatment. Between March 2006 and July 2013, participants were randomly assigned to intravenous zoledronic acid at 4.0 mg every 4 (n = 200) or 12 weeks (n = 203) for 1 year, with placebo given for interim infusions. The trial initially contained a placebo arm (to which 13 patients were randomized), but that arm was dropped after regulatory approval of bisphosphonates in this setting.
Data analysis was performed from October 2013 to March 2014. The primary endpoint was the proportion of patients with at least one skeletal-related event on study. Skeletal-related events were defined as pathologic bone fracture, radiation therapy or surgery to bone, or spinal cord compression.
The trial was initially designed to test zoledronic acid superiority vs placebo; after the placebo arm was dropped, the primary outcome was amended to noninferiority between the every-4-week and every-12-week regimens. Noninferiority was to be established if the upper limit of the two-sided 95% confidence interval (CI)—equivalent to a 1-sided 97.5% CI—for the rate difference did not exceed 10%.
For the every-12-week vs every-4-week groups: mean age was 59 vs 59 years (27% vs 33% ≥ 65 years); 88% vs 87% were white; Eastern Cooperative Oncology Group performance status was 0 or 1 in 96% in both; 52% vs 59% had received > 15 months of intravenous bisphosphonate treatment prior to study entry; mean Brief Pain Inventory score was 2.2 vs 2.0; urinary N-telopeptide to urinary creatinine ratio was < 100 in 99% vs 96%.
Skeletal-Related Event Rate
After 1 year of follow-up, skeletal-related events had occurred in 47 patients (23.2%) in the every-12-week group vs 44 patients (22.0%) in the every-4-week group (proportional difference = −1.2%; 1-sided 97.5% CI bound of the difference between groups = −9.8%; noninferiority P = .02). The most common skeletal-related events were radiation to bone (11.3% vs 14.5%) and nonvertebral pathologic fractures (8.9% vs 7.5%).
There was no significant difference between groups with regard to time to first skeletal-related event (hazard ratio [HR] = 1.06, P = .79). The mean skeletal morbidity rate was 0.50 vs 0.46 events per year (P = .85). No significant changes from baseline in Brief Pain Inventory score or serum bone-specific alkaline phosphatase were observed between groups. A significantly higher change in the urinary N-telopeptide to urinary creatinine ratio was observed in the every-12-week group only at week 36.
The most common adverse events of any grade in both the every-12-week and every-4-week groups were fatigue (33.7% vs 30.3%), arthralgia (27.7% vs 32.8%), and nausea (26.2% vs 29.8%). Grade 3 or 4 adverse events occurred in 42.6% vs 47.5%. Serious adverse events occurred in 25.2% vs 25.3%. Adverse events led to treatment discontinuation in 8.9% vs 11.6%.
The every-12-weeks regimen of zoledronic acid was noninferior to the every-4 weeks regimen for the proportion of patients experiencing 1 or more [skeletal-related event]. These results may have a substantial influence on current clinical practice for treatment of patients with bone metastasis from breast cancer.— Gabriel N. Hortobagyi, MD, and colleagues
Renal adverse events occurred in 7.9% vs 9.6% of patients in the every-12-week and every-4-week groups, with renal failure occurring in 2.5% vs 0.5% and acute renal failure in 1.0% vs 0.5%. A total of 16 vs 15 cardiac events were observed. Two adjudicated cases of osteonecrosis of the jaw were reported in the every-4-week group, with none observed in the every-12-week group. No adjudicated cases of atypical femur fracture were observed in either group. Death occurred in 3.4% of patients in the every-12-week group and 5.0% in the every-4-week group.
The investigators concluded: “The every-12-weeks regimen of zoledronic acid was noninferior to the every-4-weeks regimen for the proportion of patients experiencing 1 or more [skeletal-related event]. These results may have a substantial influence on current clinical practice for treatment of patients with bone metastasis from breast cancer.” ■
Disclosure: The study was funded by Novartis Pharmaceuticals Corporation. Dr. Hortobagyi has received consulting fees from Hoffmann-La Roche, Lilly USA, Merck, and Celgene and has served as a member of scientific advisory committees for Bayer and Pfizer.
1. Hortobagyi GN, Van Poznak C, Harker WG, et al: Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone. JAMA Oncol. January 26, 2017 (early release online).