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

被引:131
作者
Hortobagyi, Gabriel N. [1 ]
Van Poznak, Catherine [2 ]
Harker, W. Graydon [3 ]
Gradishar, William J. [4 ]
Chew, Helen [5 ]
Dakhil, Shaker R. [6 ]
Haley, Barbara B. [7 ]
Sauter, Nicholas [8 ]
Mohanlal, Ramon [9 ,10 ]
Zheng, Ming [8 ]
Lipton, Allan [11 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA
[2] Univ Michigan, Dept Internal Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA
[3] Utah Canc Specialists, Salt Lake City, UT USA
[4] Northwestern Univ, Feinberg Sch Med, Dept Med Hematol Oncol, Chicago, IL 60611 USA
[5] UC Davis Comprehens Canc Ctr, Dept Internal Med Hematol Oncol, Sacramento, CA USA
[6] Canc Ctr Kansas, Dept Hematol Oncol, Wichita, KS USA
[7] Univ Texas Southwestern Med Ctr Dallas, Dept Hematol Oncol, Dallas, TX 75390 USA
[8] Novartis Pharmaceut, One Hlth Plaza, E Hanover, NJ USA
[9] AstraZeneca, London, England
[10] BeyondSpring Pharmaceut, New York, NY USA
[11] Penn State Milton S Hershey Med Ctr, Hershey, PA USA
关键词
QUALITY-OF-LIFE; SURVIVAL; BISPHOSPHONATES; PAMIDRONATE; RESORPTION; DISEASE;
D O I
10.1001/jamaoncol.2016.6316
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 4weeks 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 4.0mg 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.
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页码:906 / 912
页数:7
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