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Pharmaceutical economics & health policy Original research| Volume 34, ISSUE 6, P1334-1349, June 2012

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Cost-Effectiveness of Denosumab Versus Zoledronic Acid in the Management of Skeletal Metastases Secondary to Breast Cancer

      Abstract

      Background

      Denosumab has been approved in the United States for the prevention of skeletal-related events (SREs) in metastatic breast cancer. In a Phase III trial in patients with bone-metastatic breast cancer (N = 2033), denosumab was associated with a significantly delayed time to first SRE (by 18%; P < 0.001 noninferiority; P = 0.01 superiority) and time to first and subsequent SREs (by 23%; P = 0.001). Overall survival (HR = 0.95; 95% CI, 0.81–1.11; P = 0.49) and disease progression (HR = 1.00; 95% CI, 0.89–1.11; P = 0.93) did not differ significantly between groups. Denosumab was associated with a nonsignificant reduction in serious adverse events (44.4% vs 46.5%).

      Objectives

      Given the current ambiguity regarding the cost-effectiveness of these agents in light of these trial outcomes, the present analysis assessed, from a US payer perspective, the cost-effectiveness of denosumab versus zoledronic acid in patients with bone metastases secondary to breast cancer.

      Methods

      A literature-based Markov model was developed to estimate the survival, quality-adjusted life-years (QALYs) gained, number and costs of SREs, and drug and administration costs in patients receiving denosumab or zoledronic acid over 27 and 60 months. Clinical inputs reproduced the trial outcomes. SRE-related costs and utilities were literature based. Costs and QALYs were discounted 3% annually.

      Results

      In the 27-month base-case analysis, denosumab was associated with fewer SREs (−0.298), more QALYs (+0.0102), and lower SRE-related costs (−$2016), but higher drug-related (+$9123) and total costs (+$7107) versus zoledronic acid. The cost per QALY gained (ie, incremental cost-effectiveness ratio [ICER]) was $697,499. In sensitivity analyses, the ICER ranged from $192,472 to $1,340,901/QALY, depending on assumptions regarding treatment benefits, drug costs, and analytical horizon. In the probabilistic sensitivity analysis, denosumab was cost-effective in 2 of 5000 modeled replicates (0.04%).

      Conclusions

      Despite the limitations of restricted availability of clinical data and uncertainty regarding the price of generic zoledronic acid, the findings from the present analysis suggest that the use of denosumab is associated with a high ICER compared with zoledronic acid. This finding may raise important questions regarding the economic value of denosumab in bone-metastatic breast cancer.

      Key words

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      References

        • Howlander N.
        • Noone A.
        • Krapcho M.
        • et al.
        Surveillance, Epidemiology and End Results Cancer Statistics Review, 1975–2008.
        National Cancer Institute, Bethesda, Md2011
        • Biswas S.
        • Nyman J.S.
        • Alvarez J.
        • et al.
        Anti-transforming growth factor ss antibody treatment rescues bone loss and prevents breast cancer metastasis to bone.
        PLoS One. 2011; 6: e27090
        • Yong M.
        • Jensen A.O.
        • Jacobsen J.B.
        • et al.
        Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999–2007).
        Breast Cancer Res Treat. 2011; 129: 495-503
        • Major P.P.
        • Cook R.J.
        • Lipton A.
        • et al.
        Natural history of malignant bone disease in breast cancer and the use of cumulative mean functions to measure skeletal morbidity.
        BMC Cancer. 2009; 9: 272
        • Ford J.
        • Cummins E.
        • Sharma P.
        • et al.
        Systematic review of the clinical effectiveness and cost effectiveness and economic evaluation of denosumab for the treatment of bone metastases from solid tumors.
        Aberdeen Health Technology Assessment Group, Institute of Applied Sciences, University of Aberdeen, Aberdeen, UK2011
        • Coleman R.
        Management of bone metastases.
        Cancer Treat Rev. 1997; 23: S69-S75
        • Delea T.
        • Langer C.
        • McKiernan J.
        • et al.
        The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer.
        Oncology. 2004; 67: 390-396
        • Hillner B.E.
        • McDonald M.K.
        • Desch C.E.
        • et al.
        Costs of care associated with nonsmall-cell lung cancer in a commercially insured cohort.
        J Clin Oncol. 1998; 16: 1420-1424
        • Schulman K.L.
        • Kohles J.
        Economic burden of metastatic bone disease in the U.S.
        Cancer. 2007; 109: 2334-2342
        • Coleman R.E.
        Metastatic bone disease: clinical features, pathophysiology and treatment strategies.
        Cancer Treat Rev. 2001; 27: 165-176
        • Coleman R.E.
        The role of bisphosphonates in breast cancer.
        Breast. 2004; 13: S19-S28
      1. US Food and Drug Administration. CfDEaR. Xgeva BLA 125320/7 Approval Letter. 2010.

        • Stopeck A.T.
        • Lipton A.
        • Body J.J.
        • et al.
        Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
        J Clin Oncol. 2010; 28: 5132-5139
      2. Amgen.
        Amgen Inc, Thousand Oaks, Calif2010
      3. Drug Topics Red Book.
        Montvale, NJ, Montvale, NJ2010
        • Aapro M.S.
        Denosumab for bone metastases from breast cancer: a new therapy option?.
        J Clin Oncol. 2011; 29: e419-e420
        • Fornier M.N.
        Denosumab: second chapter in controlling bone metastases or a new book?.
        J Clin Oncol. 2010; 28: 5127-5131
        • West H.
        Denosumab for prevention of skeletal-related events in patients with bone metastases from solid tumors: incremental benefit, debatable value.
        J Clin Oncol. 2011; 29: 1095-1098
        • Fojo T.
        • Grady C.
        How much is life worth: cetuximab, nonsmall cell lung cancer, and the $440 billion question.
        J Natl Cancer Inst. 2009; 101: 1044-1048
        • Greenberg D.
        • Earle C.
        • Fang C.H.
        • et al.
        When is cancer care cost-effective?.
        J Natl Cancer Inst. 2010; 102: 82-88
        • Smith T.J.
        • Hillner B.E.
        Bending the cost curve in cancer care.
        N Engl J Med. 2011; 364: 2060-2065
        • Hillner B.E.
        • Weeks J.C.
        • Desch C.E.
        • Smith T.J.
        Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis.
        J Clin Oncol. 2000; 18: 72-79
        • Reed S.D.
        • Radeva J.I.
        • Glendenning G.A.
        • et al.
        Economic evaluation of zoledronic acid versus pamidronate for the prevention of skeletal-related events in metastatic breast cancer and multiple myeloma.
        Am J Clin Oncol. 2005; 28: 8-16
        • Dranitsaris G.
        • Hsu T.
        Cost utility analysis of prophylactic pamidronate for the prevention of skeletal related events in patients with advanced breast cancer.
        Support Care Cancer. 1999; 7: 271-279
        • Beck J.R.
        • Kassirer J.P.
        • Pauker S.G.
        A convenient approximation of life expectancy (the “DEALE”).
        Am J Med. 1982; 73: 883-888
        • Wahed A.S.
        • Luong T.M.
        • Jeong J.H.
        A new generalization of Weibull distribution with application to a breast cancer data set.
        Stat Med. 2009; 28: 2077-2094
        • Cykert S.
        • Phifer N.
        • Hansen C.
        Tamoxifen for breast cancer prevention: a framework for clinical decisions.
        Obstet Gynecol. 2004; 104: 433-442
        • Delea T.E.
        • Taneja C.
        • Sofrygin O.
        • et al.
        Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer.
        Clin Breast Cancer. 2010; 10: 267-274
        • El O.K.
        • Karnon J.
        • Delea T.
        • et al.
        Cost-effectiveness of letrozole in the extended adjuvant treatment of women with early breast cancer.
        Breast Cancer Res Treat. 2007; 101: 37-49
        • Lidgren M.
        • Wilking N.
        • Jonsson B.
        • Rehnberg C.
        Health related quality of life in different states of breast cancer.
        Qual Life Res. 2007; 16: 1073-1081
        • Meadows E.S.
        • Klein R.
        • Rousculp M.D.
        • et al.
        Cost-effectiveness of preventative therapies for postmenopausal women with osteopenia.
        BMC Womens Health. 2007; 7: 6
        • Moeremans K.
        • Annemans L.
        Cost-effectiveness of anastrozole compared to tamoxifen in hormone receptor-positive early breast cancer.
        Int J Gynecol Cancer. 2006; 16: 576-578
        • Plevritis S.K.
        • Kurian A.W.
        • Sigal B.M.
        • et al.
        Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging.
        JAMA. 2006; 295: 2374-2384
        • Sorensen P.D.
        • Jakobsen E.H.
        • Langkjer S.T.
        • et al.
        Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting.
        Clin Chem Lab Med. 2009; 47: 1117-1123
        • Taneja C.
        • Edelsberg J.
        • Weycker D.
        • et al.
        Cost effectiveness of breast cancer screening with contrast-enhanced MRI in high-risk women.
        J Am Coll Radiol. 2009; 6: 171-179
        • Hillner B.E.
        Benefit and projected cost-effectiveness of anastrozole versus tamoxifen as initial adjuvant therapy for patients with early-stage estrogen receptor-positive breast cancer.
        Cancer. 2004; 101: 1311-1322
        • Locker G.Y.
        • Mansel R.
        • Cella D.
        • et al.
        Cost-effectiveness analysis of anastrozole versus tamoxifen as primary adjuvant therapy for postmenopausal women with early breast cancer: a US healthcare system perspective.
        Breast Cancer Res Treat. 2007; 106: 229-238
        • Logman J.F.
        • Heeg B.M.
        • Botteman M.F.
        • et al.
        Economic evaluation of zoledronic acid for the prevention of osteoporotic fractures in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the UK.
        Ann Oncol. 2010; 21: 1529-1536
        • Mansel R.
        • Locker G.
        • Fallowfield L.
        • et al.
        Cost-effectiveness analysis of anastrozole vs tamoxifen in adjuvant therapy for early stage breast cancer in the United Kingdom: the 5-year completed treatment analysis of the ATAC (‘Arimidex’, Tamoxifen alone or in combination) trial.
        Br J Cancer. 2007; 97: 152-161
        • Peasgood T.
        • Ward S.E.
        • Brazier J.
        Health-state utility values in breast cancer.
        Expert Rev Pharmacoecon Outcomes Res. 2010; 10: 553-566
        • Lage M.J.
        • Barber B.L.
        • Harrison D.J.
        • Jun S.
        The cost of treating skeletal-related events in patients with prostate cancer.
        Am J Manag Care. 2008; 14: 317-322
        • Zhou Z.
        • Redaelli A.
        • Johnell O.
        • et al.
        A retrospective analysis of health care costs for bone fractures in women with early-stage breast carcinoma.
        Cancer. 2004; 100: 507-517
        • US Dept of Labor, US Bureau of Labor Statistics
        Consumer Price Index.
        US Govt Printing Office, Washington, DC2011
        • Gold D.T.
        • Safi W.
        • Trinh H.
        Patient preference and adherence: comparative US studies between two bisphosphonates, weekly risedronate and monthly ibandronate.
        Curr Med Res Opin. 2006; 22: 2383-2391
      4. Denosumab [package insert].
        Amgen Inc, Thousand Oaks, Calif2010
        • Body J.J.
        • Lipton A.
        • Gralow J.
        • et al.
        Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure.
        J Bone Miner Res. 2010; 25: 440-446
        • Hortobagyi G.N.
        • Theriault R.L.
        • Lipton A.
        • et al.
        Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate.
        J Clin Oncol. 1998; 16: 2038-2044
        • Kristensen B.
        • Ejlertsen B.
        • Groenvold M.
        • et al.
        Oral clodronate in breast cancer patients with bone metastases: a randomized study.
        J Intern Med. 1999; 246: 67-74
        • Rosen L.S.
        • Gordon D.
        • Kaminski M.
        • et al.
        Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a Phase III, double-blind, comparative trial.
        Cancer J. 2001; 7: 377-387
        • Theriault R.L.
        • Lipton A.
        • Hortobagyi G.N.
        • et al.
        Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial.
        J Clin Oncol. 1999; 17: 846-854
      5. National Fee Analyzer.
        Ingenix Inc, Minn2011
      6. Zometa (zoledronic acid) [product information].
        (Accessed April 18, 2012)
        • Neumann P.J.
        • Fang C.H.
        • Cohen J.T.
        30 years of pharmaceutical cost-utility analyses: growth, diversity and methodological improvement.
        Pharmacoeconomics. 2009; 27: 861-872
        • Reed S.D.
        • Radeva J.I.
        • Glendenning G.A.
        • et al.
        Cost-effectiveness of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer.
        J Urol. 2004; 171: 1537-1542
        • Nadler E.
        • Eckert B.
        • Neumann P.J.
        Do oncologists believe new cancer drugs offer good value?.
        Oncologist. 2006; 11: 90-95
        • Ubel P.A.
        • Hirth R.A.
        • Chernew M.E.
        • Fendrick A.M.
        What is the price of life and why doesn't it increase at the rate of inflation?.
        Arch Intern Med. 2003; 163: 1637-1641
        • Trinkaus M.
        • Simmons C.
        • Myers J.
        • et al.
        Skeletal-related events (SREs) in breast cancer patients with bone metastases treated in the nontrial setting.
        Support Care Cancer. 2010; 18: 197-203
        • Rader M.
        • Goessl C.
        • Cong Z.
        Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.
        J Manag Care Pharm. 2012; 18: 74-75
        • Hatoum H.T.
        • Lin S.J.
        • Smith M.R.
        • et al.
        Zoledronic acid and skeletal complications in patients with solid tumors and bone metastases: analysis of a national medical claims database.
        Cancer. 2008; 113: 1438-1445
        • Barlev A.
        • Song X.
        • Ivanov B.
        • et al.
        Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer.
        J Manag Care Pharm. 2010; 16: 693-702
        • Lothgren M.
        • Bracco A.
        • Lucius B.
        • et al.
        Cost-effectiveness of denosumab vs zoledronic acid (ZA) for the prevention of skeletal-related events (SRE) in patients with bone metastases from solid tumors in the Netherlands.
        Value Health. 2011; 14: A455