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Originally published as JCO Early Release 10.1200/JCO.2008.16.3832 on August 25 2008 © 2008 American Society of Clinical Oncology. Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer
From the Seattle Cancer Care Alliance, Seattle, WA; Michigan Bone and Mineral Clinic, Detroit, MI; University of California at Los Angeles Medical Center, Torrance; Amgen Inc, Thousand Oaks, CA; US Oncology, Houston, TX; Rocky Mountain Cancer Centers, Denver, CO; and Algoma Regional Cancer Program, Sault Ste Marie, Ontario, Canada Corresponding author: Georgiana K. Ellis, MD, Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mail Stop G3-200, Seattle, WA 98109-1023; e-mail: gellis{at}u.washington.edu
Purpose Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor–positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-  B ligand, to protect against aromatase inhibitor–induced bone loss.
Patients and Methods Eligible women with hormone receptor–positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy ( Results At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. Conclusion In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.
For decades, tamoxifen has been the standard for adjuvant hormone therapy in postmenopausal women with hormone receptor–positive, early-stage breast cancer because it significantly reduces tumor recurrence risk and improves patient survival.1,2 Tamoxifen has also been reported to have a weak mitigating effect on loss of bone mass resulting from estrogen deficiency in postmenopausal women with breast cancer.3 However, use of tamoxifen is associated with several uncommon, but potentially life-threatening side effects, including thromboembolic events and endometrial cancer.4,5 More recently, aromatase inhibitors have been shown to improve progression-free survival and to have fewer life-threatening adverse effects (AEs) as compared with tamoxifen in women with receptor-positive, early-stage breast cancer.4,6-12 Consequently, the American Society of Clinical Oncology (ASCO) has recommended that optimal adjuvant hormonal therapy of such patients should include an aromatase inhibitor.13
Aromatase inhibitor use is associated with bone loss and increased fracture risk.3,8,10,11,14,15 Bone loss is mediated by osteoclasts, whose formation, function, and survival depend on the receptor activator of nuclear factor-
Patients Full inclusion and exclusion criteria are described in the Appendix (online only). Eligible patients were women  18 years of age who had early-stage histologically or cytologically confirmed breast cancer that was hormone receptor–positive and who were undergoing adjuvant aromatase inhibitor therapy and had completed treatment with surgery and/or radiation and chemotherapy 4 weeks before study entry. At enrollment, all patients were required to have evidence of low bone mass (lumbar spine, total hip [total proximal femur], or femoral neck BMD corresponding to a T-score of –1.0 to –2.5). Patients were also required to have serum 25-hydroxyvitamin D levels 12 ng/mL. Key exclusion criteria included patients with osteoporosis (T-score < –2.5), prior vertebral fracture, current use of bisphosphonates, and use of any antineoplastic therapy apart from aromatase inhibitors.
Study Design
Assessment of Outcomes Bone turnover markers serum C-telopeptide I (sCTx) and procollagen type I N-terminal peptide (P1NP) were collected at baseline and at months 1, 6, 12, and 24. sCTx was assayed at Amgen using Serum CrossLaps kit (Nordic Bioscience Diagnostics A/S, Herlev, Denmark); P1NP was assayed at Covance Laboratories using the P1NP RIA kit (Orion Diagnostica Oy, Espoo, Finland). All patients who completed the study or who terminated early were observed for safety every 6 months for up to an additional 24 months. Safety end points included all AEs and serum chemistry and hematology values. Antidenosumab antibody assessments were conducted using screening methods described previously.20
End Points
Statistical Analysis The primary and secondary efficacy end points were analyzed for all randomly assigned patients who had observations for the relevant end point at baseline and at least once at or before the relevant time point (last observation carried forward as the primary imputation method). Analyses of primary and secondary BMD end points were conducted hierarchically using an analysis of covariance model,21 adjusting for treatment, stratification variable, baseline BMD value, densitometer type, and baseline value-by-densitometer type interaction. Primary conclusions on the efficacy of denosumab were made using the difference of the point estimates for the least-squares mean and the two-sided 95% CI for the treatment difference at month 12. The significance level of the primary end point was .05. Statistical inferences on secondary end points were carried out because the primary end point was statistically significant. Hochberg multiplicity adjustment22 was used for the secondary end points. Differences in percentage changes from baseline in bone turnover markers between groups were analyzed using the van Elteren stratified rank test (adjusting for duration of aromatase inhibitor therapy at study entry). Safety analysis included all patients who received one or more dose of investigational product; patients were analyzed according to the actual treatment received regardless of the randomized treatment assignment (ie, a patient who received denosumab, regardless of randomized treatment assignment, was included in the denosumab group). All AEs were coded using the Medical Dictionary for Regulatory Activities, version 9, and characterized by evaluating incidence and severity of events. Investigators classified AEs as being related to study drug if they considered such a relationship possible or probable with blinding maintained. Laboratory toxicities were graded using the Common Toxicity Criteria, version 3.0, from the National Cancer Institute. No formal statistical testing was done for safety analyses.
A total of 252 patients enrolled onto the study. Most patients (88%) completed 12 months of study, with consent withdrawal (5%) being the most common reason for discontinuation. Overall, 81% of patients completed the 24-month study. Consent withdrawal (3%) was also the most common reason for study discontinuation between 12 and 24 months (Fig 1).
Baseline characteristics were generally well balanced between treatment arms (Table 1). Ninety-three percent of patients were white; the mean age was 59.5 years. More patients (63%) had received prior aromatase inhibitor therapy for more than 6 months; 50% were postmenopausal with more than 10 years since their last menstrual period and 23% were postmenopausal with 5 to 10 years since their last menstrual period; 47% had prior hormonal therapy (excluding aromatase inhibitors).
BMD At 12 months, lumbar spine BMD increased by 5.5% in the denosumab group versus the placebo group (4.8% v –0.7%; P < .0001; Fig 2A). Increases in lumbar spine BMD at 12 months were not influenced by duration of prior aromatase inhibitor therapy (5.4% increase for patients with  6 months and 5.7% increase for patients with more than 6 months of prior aromatase inhibitor therapy) compared with placebo (Figs 2B and 2C). Similar increases in lumbar spine BMD compared with placebo at 12 months were seen in patients treated with nonsteroidal (anastrozole or letrozole) and steroidal (exemestane) aromatase inhibitor therapy (5.6% and 5.8%, respectively; P < .0001 v placebo for both subgroups). Patients who had prior treatment with tamoxifen also had similar increases in lumbar spine BMD compared with placebo at 12 months as those with no prior experience with tamoxifen (5.3% and 5.8%, respectively; P < .0001 v placebo for both subgroups). When covariates, including age, race, baseline weight, body mass index, prior chemotherapy, prior selective estrogen receptor modulator use, and time from last menstrual period, were added to the primary efficacy model, the treatment effect of denosumab on lumbar spine BMD at 12 months was still significantly different from placebo (P < .0001). Increases in lumbar spine BMD in the denosumab group were significantly different from placebo as early as 1 month and were sustained at 24 months (7.6% difference between denosumab and placebo; P < .0001).
A post hoc analysis assessed treatment effects on the preservation of BMD at 24 months (Fig 3). Eighty percent of patients in the denosumab group had more than 3% increase in lumbar spine BMD compared with 13% of patients in the placebo group. Fifty percent of patients in the denosumab group had more than 6% increases in lumbar spine BMD compared with 3% in the placebo group.
Significant increases in BMD were observed in the denosumab group at all other measured sites, including the predominantly cortical one-third radius (Fig 4).
Markers of Bone Remodeling Markers of bone remodeling were rapidly reduced by denosumab. sCTx levels reached a nadir at the earliest evaluation at 1 month, with a median percentage reduction from baseline of 91% compared with 9% in the placebo group (P < .0001). Denosumab administration led to suppression of sCTx levels throughout the study, with median percentage reductions ranging from 63% to 80% over 6 to 24 months. A median percentage reduction in P1NP of 29% was observed with denosumab at 1 month, compared with 2% for placebo (P < .0001). P1NP decreased further with denosumab treatment and then stabilized, with reductions of 71% to 73% between 6 months and 24 months.
Fractures
Safety
The proportion of patients who, because of AEs, withdrew from either investigational product (2% for denosumab, 4% for placebo) or from the study (1% for denosumab, 4% for placebo) was similar between treatment groups. Most events were related to progression of underlying cancer, and none were considered by the investigators to be treatment related. Serious AEs were reported in 19 patients (15%) in the denosumab group and 11 patients (9%) in the placebo group; none were considered by the investigators to be treatment related. No specific category or type of AE accounted for this numerical difference. Serious AEs involving infections, defined as infections treated in hospitals, were reported in three patients (2%) in the denosumab group and one patient (1%) in the placebo group. No trends in serum chemistry or hematology parameters were noted other than expected decreases in serum calcium, phosphorus, and total alkaline phosphatase. The incidence of hypocalcemia (laboratory value changes only) was low and balanced across treatment groups (two patients [2%] in each group had grade 1 hypocalcemia), with no clinical sequelae resulting from decreases in calcium being observed. No neutralizing antidenosumab antibodies were reported. Two deaths (one in each group) were reported, both attributed to breast cancer progression. Neither death was considered by the investigator to be treatment related. Because of the small number of deaths, an analysis of overall survival was not conducted.
Bone loss contributing to increased fracture risk is a predictable consequence of aromatase inhibitor therapy23-25 and worsens with duration of exposure.8,10,11,26 In recent years, aromatase inhibitor treatment has become the mainstay of adjuvant hormone therapy in postmenopausal women with early-stage breast cancer because of its demonstrated effects in improving progression-free survival.4,6-12 Because of the increasing use of aromatase inhibitors, accelerated bone loss represents a challenge in the management of these patients. Organizations such as the National Osteoporosis Foundation and the American Association of Clinical Endocrinologists recommend treatment of women with low BMD to prevent further bone loss,27,28 particularly when additional risk factors are present. According to the ASCO 2004 status report, aromatase inhibitor–associated bone loss represents a preventable and treatable condition.13 ASCO guidelines support strategies for early detection and prevention of osteoporosis in women with breast cancer who have low bone mass.29 Although no treatment is currently approved specifically for the prevention of aromatase inhibitor–induced bone loss, bisphosphonates are often used to treat osteoporosis and limit further bone loss.
Denosumab is a fully human monoclonal antibody with a novel mechanism of action. It binds to RANKL with high affinity and high specificity, but it does not bind to other tumor necrosis factor (TNF) ligands, such as TNF In this study of breast cancer patients who were at risk for aromatase inhibitor–induced bone loss, denosumab treatment resulted in rapid, marked, and sustained increases in lumbar spine BMD over 24 months. Consistent increases in BMD were also observed at all measured skeletal sites. In the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial of postmenopausal women with breast cancer, 5 years of anastrozole treatment was associated with a cumulative 6.1% decrease in lumbar spine BMD.26 After 2 years in the current study, denosumab therapy resulted in a 6.2% gain in lumbar spine BMD. Significant gains in lumbar spine BMD were seen regardless of the duration of prior aromatase inhibitor therapy or whether patients were previously treated with tamoxifen. Thus denosumab therapy increased BMD in patients who have switched from tamoxifen to aromatase inhibitor therapy and in patients receiving aromatase inhibitor therapy as their initial treatment. Increases in BMD at the spine and hip seen with denosumab in this study compare favorably with those previously reported for bisphosphonates.23,30 The effect of denosumab on the one-third radius BMD suggests a positive effect on predominantly cortical bone sites. In contrast, a decline of radial BMD over time has been seen after bisphosphonate treatment.30 The cortical effect of denosumab, coupled with the effect on trabecular bone, may translate into improved bone quality and strength. Data from the Arimidex, Tamoxifen, Alone or in Combination trial suggested that an 8% difference in lumbar spine BMD between anastrozole and tamoxifen translated to an increased fracture risk of 43% after 5 years of treatment. The positive effects of denosumab on BMD may have benefit for patients undergoing aromatase inhibitor therapy over time. This study was neither designed nor powered to draw any conclusions regarding fracture rates. The absence of clinical vertebral fractures in either treatment arm and the balanced rate of nonvertebral fractures reflect what could be expected in a relatively small study of a group of relatively young women who did not have osteoporosis, who were all taking vitamin D and calcium supplements, and who were observed for a limited duration. AEs in this study are consistent with those associated with aromatase inhibitor therapy (ie, arthralgias) and/or underlying conditions (ie, extremity and back pain). Denosumab treatment was generally well tolerated in this study population, with overall rates of AEs similar to those of placebo. No allergic or local skin reactions or renal or gastrointestinal toxicities were reported after denosumab treatment, and no neutralizing antidenosumab antibodies were detected. Hypocalcemia was also not observed in these patients who were receiving calcium and vitamin D supplementation. Although patients in the denosumab group reported a slightly greater number of serious AEs than patients in the placebo group, no specific pattern of AEs was identified in either group. In conclusion, in women with nonmetastatic breast cancer who were receiving adjuvant aromatase inhibitor therapy and who were at risk of developing osteoporosis and fracture, twice-yearly treatment with denosumab was generally well tolerated, with an AE profile similar to that of placebo, and significantly increased BMD and reduced bone turnover. Denosumab is currently being investigated in clinical trials for the prevention and treatment of bone loss associated with cancer therapies (eg, 20040138 study in men with nonmetastatic prostate cancer receiving androgen-deprivation therapy) and with bone metastases from various cancer types.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Judy Smith, Amgen (C); Michelle Fan, Amgen (C); Susie Jun, Amgen (C) Consultant or Advisory Role: Georgiana K. Ellis, Amgen (C); Henry G. Bone, Amgen (C); Rowan Chlebowski, Astra-Zeneca (C), Novartis (C), Lilly (C) Stock Ownership: Judy Smith, Amgen; Michelle Fan, Amgen; Susie Jun, Amgen Honoraria: Georgiana K. Ellis, Novartis; Rowan Chlebowski, Astra-Zeneca, Novartis Research Funding: Georgiana K. Ellis, Amgen; Henry G. Bone, Amgen; Rowan Chlebowski, Lilly, Amgen Expert Testimony: None Other Remuneration: Silvana Spadafora, Amgen
Conception and design: Henry G. Bone, Susie Jun Financial support: Susie Jun Administrative support: Susie Jun Provision of study materials or patients: Georgiana K. Ellis, Rowan Chlebowski, Devchand Paul, Silvana Spadafora, Judy Smith, Susie Jun Collection and assembly of data: Judy Smith, Susie Jun Data analysis and interpretation: Georgiana K. Ellis, Henry G. Bone, Rowan Chlebowski, Michelle Fan, Susie Jun Manuscript writing: Georgiana K. Ellis, Henry G. Bone, Rowan Chlebowski, Devchand Paul, Silvana Spadafora, Judy Smith, Michelle Fan, Susie Jun Final approval of manuscript: Georgiana K. Ellis, Henry G. Bone, Rowan Chlebowski, Devchand Paul, Silvana Spadafora, Judy Smith, Michelle Fan, Susie Jun
Study Inclusion And Exclusion Criteria Eligible patients were women 18 years of age with early-stage histologically or cytologically confirmed breast cancer who had hormone receptor–positive cancer (ie, estrogen receptor–positive or progesterone receptor–positive), who were undergoing adjuvant aromatase inhibitor therapy, and who had completed their treatment pathway (surgery, chemotherapy, radiation, and/or hormone therapy) 4 weeks before study entry. Patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, serum 25-hydroxyvitamin D of 12 ng/mL, and evidence of low bone mass (lumbar spine, proximal femur [total hip], or femoral neck bone mineral density (BMD) corresponding to a T-score classification of –1.0 to –2.5). BMD measurements were performed by dual-energy x-ray absorptiometry using Hologic or Lunar densitometers. Densitometers were calibrated across various clinical sites. Patients were excluded if they had osteoporosis or if their T-score was less than –2.5 at the lumbar spine, total hip, or femoral neck. Patients were also excluded from the study if they had evidence of distant metastases, were taking any antineoplastic therapies besides aromatase inhibitors, had a history of nontraumatic or vertebral fractures after the age of 25 years, and had height, weight, or girth that precluded accurate dual-energy x-ray absorptiometry measurements or fewer than two assessable lumbar vertebrae. Patients also were excluded if they had any of the following: a diagnosis of any other nonbreast malignancy within 5 years of study entry, with the exception of previously treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix; Paget's disease, Cushing's disease, or chronic liver disease; unstable systemic disease (eg, rheumatoid arthritis, heart disease) within 6 months of study entry; HIV, hepatitis C, or chronic hepatitis B infection; major surgery or traumatic injury within 4 weeks of study entry; hyperprolactinemia, hyper- or hypothyroidism, any serum chemistry or hematology abnormality or inadequate organ function as determined by standard laboratory assessments; pregnancy; or a known sensitivity to mammalian cell-derived biotechnology products.
Current use of oral bisphosphonates was not allowed nor was
Denosumab Hormone Ablation Bone Loss Trial Breast Cancer Study Group
We thank Ting Chang, PhD, of Amgen Inc, and Linda Melvin for writing assistance.
published online ahead of print at www.jco.org on August 25, 2008 Supported by Amgen Inc, Thousand Oaks, CA. This study is registered with ClinicalTrials.gov with the identifier NCT00089661 [ClinicalTrials.gov] . Presented in part at the San Antonio Breast Cancer Symposium, December 13-16, 2007, San Antonio, TX. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information can be found for the following: NCT00089661 [ClinicalTrials.gov] .
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Land SR, Wickerham DL, Costantino JP, et al: Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2742-2751, 2006 6. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: Double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16:453-461, 1998[Abstract] 7. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:2596-2606, 2001 8. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline] 9. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 23:5138-5147, 2005 10. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 11. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003 12. 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New York, NY, Oxford University Press, 1993 22. Hochberg Y: A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75:800-802, 1988 23. Brufsky A, Harker WG, Beck JT, et al: Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25:829-836, 2007 24. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 25. Coleman RE, Banks LM, Girgis SI, et al: Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): A randomised controlled study. Lancet Oncol 8:119-127, 2007[CrossRef][Medline] 26. Coleman RE: Effect of anastrozole on bone mineral density: 5-year results from the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial. J Clin Oncol 24:5s, 2006 (suppl; abstr 511) 27. National Osteoporosis Foundation: Clinician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC, National Osteoporosis Foundation, 2008 28. Hodgson SF, Watts NB, Bilezikian JP, et al: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 9:544-564, 2003[Medline] 29. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 30. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= 0.05). Allowing for a loss of 20% of follow-up DXA assessments per year, 104 patients per arm were predicted to be necessary to detect such a treatment effect. 
