Oral Ibandronic Acid Is Not Noninferior to IV Zoledronic Acid in Preventing Skeletal-Related Events in Patients With Breast Cancer
In a phase III noninferiority trial (ZICE) reported in The Lancet Oncology, Barrett-Lee et al compared oral ibandronic acid vs intravenous zoledronic acid in treatment of bone metastases from breast cancer. The study showed that ibandronic acid was not noninferior to zoledronic acid in preventing skeletal-related events.
Study Details
In this open-label trial, conducted in 99 UK hospitals, 1,404 patients with ≥ 1 radiologically confirmed bone metastasis from histologically confirmed breast cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and clinical decision to treat with bisphosphonates within 3 months of randomization were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3 to 4 weeks (n = 705) or oral ibandronic acid at 50 mg daily (n = 699). The primary noninferiority endpoint was skeletal-related events over 96 weeks analyzed in the per-protocol population. The trial is now in long-term follow-up.
The per-protocol population consisted of 93% (n = 654) of patients in the ibandronic acid group and 96% (n = 672) in the zoledronic acid group and who started treatment, with a median treatment duration of 75 weeks in both groups. The per-protocol ibandronic acid and zoledronic acid groups were balanced for sex (98% and 99% women, 69% and 68% postmenopausal), age (median, 61 years in both), ECOG performance status (0 or 1 in 87% in both), ≥ 2 metastatic bone lesions (59% and 60%), previous skeletal-related event (42% in both), previous therapy (adjuvant chemotherapy in 46% and 49%, recent chemotherapy in 26% and 25%, recent hormone therapy in 82% and 81%, adjuvant trastuzumab in 6% in both), receptor status (82% and 84% estrogen receptor–positive, 39% in both progesterone receptor positive, 14% and 16% HER2 positive), visceral metastases (29% and 30%), and baseline cancer medication (current chemotherapy in 16% in both, current hormone therapy in 71% and 68%, and current trastuzumab in 5% in both).
Risk of Skeletal-Related Events
Rates of skeletal-related events were 0.499 per person-year in the ibandronic acid group vs 0.435 per person-year in the zoledronic acid group, with a rate ratio of 1.148 (95% confidence interval [CI] = 0.967–1.362, P = .11); since the upper bound of the confidence interval was greater than the margin of noninferiority of 1.08, noninferiority of ibandronic acid could not be concluded. Skeletal-related events consisted of fracture in 14% vs 13% of patients, radiotherapy to bone in 30% vs 27%, hypercalcemia in 11% vs 9%, orthopedic surgery in 6% vs 4%, and spinal cord compression in 3% vs 3%. Median time to first skeletal-related event was 97 weeks in the ibandronic acid group vs 99 weeks in the zoledronic acid group (hazard ratio = 1.034, P = .70).
Toxicities
Fewer patients in the ibandronic acid group had renal toxicity (24% vs 32%). The most common grade 3 or 4 adverse events were fatigue (14% vs 14%), increased bone pain (12% vs 13%), joint pain (5% vs 6%), infection (3% vs 5%), and nausea or vomiting (6% vs 5%). Osteonecrosis of the jaw occurred in five ibandronic acid recipients (< 1%) and nine zoledronic acid recipients (1%).
Serious adverse events occurred in 29% vs 26% of patients. Treatment intolerance resulted in withdrawal in 10% of ibandronic acid patients and 8% of zoledronic acid patients. Three deaths in the ibandronic acid group and four in the zoledronic acid group were considered treatment-related.
The investigators concluded, “Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions.”
Angela Casbard, MSc, of Cardiff University, is the corresponding author for the Lancet Oncology article.
The study was supported by Roche Products Ltd and the National Institute for Health Research Cancer Network. The study authors reported no potential conflicts of interest.
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