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Originally published as JCO Early Release 10.1200/JCO.2008.20.7001 on February 23 2009 © 2009 American Society of Clinical Oncology.
A Step in the Journey of Denosumab From Bone-Targeted Therapy to Seed- and Soil-Targeted TherapyService d'Oncologie Médicale, Groupe Hospitalier Pitié Salpêtrière, Paris, France
Oral or intravenous bisphosphonates are largely used in oncology and can be considered as bone-targeted therapies. Denosumab represents a new therapeutic opportunity by targeting the receptor activator of nuclear factor
In this issue, Fizazi et al4 present another aspect of denosumab development through a randomized phase II study of 111 patients with bone metastases or myeloma, evaluating two schedules of denosumab compared with placebo. In this study, tumor types were mainly prostate or breast cancer (45% and 41%, respectively); 8% of patients had myeloma. Denosumab activity has been reported previously in another phase II study of women with bone metastases from breast cancer who were naive to bisphosphonates.5,6 As in this previous publication, the present study evaluates several schedules of administration for denosumab (two schedules were selected: 180 mg subcutaneously every 4 weeks or every 12 weeks) and a biologic end point was chosen. Elevated levels of bone turnover markers such as elevated urinary N-telopeptide (uNTx) represent excessive bone resorption activity and have been linked to skeletal-related events.7,8 Levels of uNTx are therefore considered as a convenient biomarker for the early evaluation of bone-targeted therapies and are commonly used in this setting. The originality of the present phase II study is the focus on patients who present with bone metastases and persistent elevated uNTx levels despite ongoing intravenous bisphosphonates. This situation could represent a major concern, given that one fifth of patients treated with bisphosphonates have been shown to have moderate or high uNTx levels (defined as 50 to 99 and In summary, this study demonstrates activity of denosumab in the setting of biologic failure of intravenous bisphosphonates. Phase III trials are now awaited to define the efficacy of denosumab compared with bisphosphonates using clinical primary end points such as time to skeletal-related event in first-line therapy for patients with bone metastases. Bone-targeted therapy development is nevertheless wider than the meaningful but restricted setting of bone metastases. Both bisphosphonates and denosumab are currently being evaluated in other settings (summarized in Table 1). First, several bisphosphonates are approved for the treatment of osteoporosis, and the most efficacious modes of administration (oral v intravenous) are currently being investigated. Denosumab has also been evaluated for osteoporosis treatment for postmenopausal women in a phase II study. Raloxifene is the third agent proposed in this setting in relation to selective estrogen receptor modulator activity.10–12 The second aspect of bone-targeted therapy development is represented by prevention of bone loss, mainly for women receiving aromatase inhibitors for breast cancer treatment and also for men receiving hormonal therapy for prostate cancer.13,14 Bisphosphonates and denosumab are both currently evaluated in this indication, and we suggest that you read the recent editorial15 in Journal of Clinical Oncology for a clear focus on this subject. Not surprisingly, future evaluation of these agents should certainly be based on efficacy but also on schedule and routes of administration, on toxicity profiles, and on cost.
Another aspect of bone-targeted therapies is the possible direct impact of those treatments on metastatic disease, resulting in a survival benefit. Several reports led to consideration of this activity for bisphosphonates in preclinical models and in some clinical study results,16–19 and it may be time to evaluate those compounds as seed- and soil-targeted therapies rather than bone-targeted therapies. This question is not only semantic, but could be proposed to plan their development as molecular-targeted therapies. Denosumab can indeed be considered in this manner on the basis of a number of observations. 1) The target: the RANKL/RANK system is crucial for osteoclast activity. RANKL is a tumor necrosis factor family member and its receptor, RANK, is expressed on the surface of osteoclasts as well as several other cell types in the body. The effects of RANKL are prevented by osteoprotegerin (OPG), a tumor necrosis factor receptor family member that binds RANKL and thereby prevents activation of RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG.20,21 Cancer cells induced increased RANKL expression and decreased OPG expression, which implicate increased bone resorption and potential tumor proliferation through release of growth factors.22,23 2) The targeted therapy: denosumab is a fully human antibody directed against RANKL, which has been designed to inhibit this important pathway, suggesting that it be studied in a monoclonal antibody strategy. Studies in animal models initially show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength.24 Clinical impact is now under investigation as detailed above.25 Interestingly, some preclinical data indicate that inhibition of the RANKL/RANK system could influence survival.26 3) Rational development is now essential for new agents. Biomarkers are needed and definition of predictive factors of response is a critical issue. The present study,4 which included biologic inclusion criteria and end points, perfectly fits this pattern of development. Although these biologic end points have to be correlated with clinical results, they represent one important step in a long journey. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Stéphane Vignot, David Khayat Data analysis and interpretation: Stéphane Vignot, David Khayat Manuscript writing: Stéphane Vignot, David Khayat Final approval of manuscript: Stéphane Vignot, David Khayat REFERENCES
1. Hsu H, Lacey DL, Dunstan CR, et al: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 96:3540–3545, 1999. 2. Fouque-Aubert A, Chapurlat R: Influence of RANKL inhibition on immune system in the treatment of bone diseases. Joint Bone Spine 75:5–10, 2008.[CrossRef][Medline] 3. Ellis GK, Bone HG, Chlebowski R, et al: Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 26:4875–4882, 2008. 4. Fizazi K, Lipton A, Mariette X, et al: Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571, 2009. 5. Lipton A, Steger GG, Figueroa J, et al: Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 25:4431–4437, 2007. 6. Lipton A, Steger GG, Figueroa J, et al: Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14:6690–6696, 2008. 7. Brown JE, Cook RJ, Major P, et al: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69, 2005. 8. Coleman R, Brown J, Terpos E, et al: Bone markers and their prognostic value in metastatic bone disease: Clinical evidence and future directions. Cancer Treat Rev 34:629–639, 2008.[CrossRef][Medline] 9. Coleman RE, Major P, Lipton A, et al: Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23:4925–4935, 2005. 10. McClung MR, Lewiecki EM, Cohen SB, et al: Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821–831, 2006. 11. Black DM, Boonen S, Delmas P, et al: Review of comparative effectiveness of treatments to prevent fractures. Ann Intern Med 148:885–886, 2008 author reply 887. 12. Vondracek SF, Minne P, McDermott MT: Clinical challenges in the management of osteoporosis. Clin Interv Aging 3:315–329, 2008.[Medline] 13. Coleman RE, Body JJ, Gralow JR, et al: Bone loss in patients with breast cancer receiving aromatase inhibitors and associated treatment strategies. Cancer Treat Rev 34:S31–S42, 2008 (suppl 1.[CrossRef][Medline] 14. Greenspan SL, Nelson JB, Trump DL, et al: Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy. J Clin Oncol 26:4426–4434, 2008. 15. Lønning PE: Endocrine therapy and bone loss in breast cancer: Time to close in the RANK(L)? J Clin Oncol 26:4859–4861, 2008. 16. Clezardin P: Anti-tumour activity of zoledronic acid. Cancer Treat Rev 31:1–8, 2005 (suppl 3.[Medline] 17. Gnant M, Mlineritsch B, Schippinger W, et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691, 2009. 18. Powles T, Paterson A, McCloskey E, et al: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8:R13; 2006.[CrossRef][Medline] 19. Diel IJ, Jaschke A, Solomayer EF, et al: Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow–a long-term follow-up. Ann Oncol 19:2007–2011, 2008. 20. Blair JM, Zhou H, Seibel MJ, et al: Mechanisms of disease: Roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat Clin Pract Oncol 3:41–49, 2006.[CrossRef][Medline] 21. Kearns AE, Khosla S, Kostenuik PJ: Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29:155–192, 2008. 22. Roodman GD: Biology of osteoclast activation in cancer. J Clin Oncol 19:3562–3571, 2001. 23. Bussard KM, Gay CV, Mastro AM: The bone microenvironment in metastasis; what is special about bone? Cancer Metastasis Rev 27:41–55, 2008.[CrossRef][Medline] 24. Ominsky MS, Li X, Asuncion FJ, et al: RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res 23:672–682, 2008.[CrossRef][Medline] 25. Lipton A, Jun S: RANKL inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care 2:197–203, 2008.[CrossRef][Medline] 26. Canon JR, Roudier M, Bryant R, et al: Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 25:119–129, 2008.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B ligand (RANKL) system, which has been has been linked to osteoclast formation, activity, and survival.
100 nmol/L/mM creatinine, respectively) during treatment. Recent retrospective analyses with bisphosphonates, particularly with zoledronic acid, have shown significant correlations between persistent elevated bone resorption markers levels such as uNTx and clinical outcomes.
