Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial

Abstract

Importance: Zoledronic acid, a potent bisphosphonate, is commonly administered to patients with bone metastases to reduce the risk of skeletal-related events (SREs). However, there have been concerns regarding its long-term monthly administration.

Objective: To examine whether zoledronic acid every 12 weeks was noninferior to zoledronic acid every 4 weeks in patients with metastatic breast cancer that involved the bone who had previously received a standard dosing regimen of zoledronic acid and/or pamidronate disodium.

Design, setting, and participants: OPTIMIZE-2 was a prospective, randomized, double-blind, multicenter phase 3 trial of intention-to-treat (full analysis set), evaluable (per protocol), and safety populations. Patients were randomized (1:1) to receive 4.0 mg of intravenous zoledronic acid every 4 or every 12 weeks with placebo for interim infusions for 1 year. The study was conducted at 102 clinical trial centers in the United States from March 3, 2006, to July 25, 2013. Data analysis was performed from October 7, 2013, to March 24, 2014. The study randomized 416 women (≥18 years old) with bone metastases from breast cancer who previously received 9 or more doses of zoledronic acid and/or pamidronate during the first 10 to 15 months of therapy.

Main outcomes and measures: The primary end point was the proportion of patients with 1 or more SRE on study (SRE rate). The key secondary end points included time to first SRE and skeletal morbidity rate (SMR).

Results: A total of 416 women were randomized: 200 patients received zoledronic acid every 4 weeks (mean [SD] age, 59.2 [11.1] years; 173 were white [86.5%]), 203 patients received zoledronic acid every 12 weeks (mean [SD] age, 58.6 [11.2] years; 178 were white [87.7%]), and 13 patients received placebo (mean [SD] age, 60.8 [12.2] years; 13 were white [100%]). Baseline characteristics were similar in both zoledronic acid treatment arms. After 1 year of follow-up, SREs occurred in 44 patients (22.0%) in the zoledronic acid every 4 weeks group and 47 patients (23.2%) in the zoledronic acid every 12 weeks group (proportional difference of -1.2%; 1-sided 97.5% CI bound of the difference in SRE rate between arms, -9.8%; noninferiority P = .02). The time to first SRE between treatment groups was not statistically significantly different (hazard ratio [HR], 1.06; 95% CI, 0.70-1.60; P = .79). The mean (SD) SMR was 0.46 (1.06) vs 0.50 (1.50) events per year in the every 4 weeks vs every 12 weeks groups (P = .85). The safety profiles of the every 4 weeks and every 12 weeks groups were comparable, with 189 patients (95.5%) in the every 4 weeks group having at least 1 adverse event compared with 189 (93.5%) in the every 12 weeks group.

Conclusions and relevance: 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 SRE. These results may have a substantial influence on current clinical practice for treatment of patients with bone metastasis from breast cancer.

Trial registration: clinicaltrials.gov Identifier: NCT00320710.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Hortobagyi reported receiving consulting fees from Hoffman-La Roche, Lilly USA, Merck, and Celegene and serving as a member of Scientific Advisory Committee for Bayer and Pfizer. Dr Van Poznak reported receiving grants from Novartis Pharmaceuticals Corporation during the conduct of the study and grants from Amgen and Bayer outside the submitted work. Dr Sauter reported being an employee of Novartis Pharmaceuticals Corporation and holding stock options. Dr Mohanlal reported receiving employment-related salary from Novartis Pharmaceuticals Corporation during the conduct of the study and being employed with Novartis Pharmaceutical Corporation until July 2015, at the time the study was conducted and when the first draft of the manuscript was developed. Dr Zheng reported being an employee of Novartis Pharmaceuticals Corporation and holding stock options. Dr Lipton reported receiving laboratory grants from Novartis Pharmaceuticals Corporation. No other disclosures were reported.

Figures

Figure 1.. Patient Disposition (Full Analysis Set)

Figure 2.. Kaplan-Meier Curve for Time From Randomization to First Skeletal-Related Event (SRE)