ECCLU 2011 - N. Clarke - Bone targeted agents
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1. The document discusses bone metabolism and prostate cancer, describing how factors like RANK ligand and osteoprotegerin regulate the balance between bone formation and resorption. 2. It summarizes a clinical trial comparing denosumab, a RANK ligand inhibitor, to zoledronic acid for treating bone metastases in prostate cancer patients. Denosumab delayed time to first skeletal-related event compared to zoledronic acid and reduced risk of multiple events. 3. Rates of adverse events were generally similar between the treatments, though denosumab resulted in fewer acute phase reactions and more cases of osteonecrosis of the jaw compared to zoledronic acid.
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ECCLU 2011 - N. Clarke - Bone targeted agents
- 1. Bone Targeted Agents in Prostate Cancer NW Clarke Professor of Urological Oncology Manchester UK
- 2. Normal Physiology: The Balance Between Bone Resorption and Formation Activation Adapted from Baron, R. General Principles of Bone Biology. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. 2003;1-8. Osteoblasts Formation Osteoid Tissue Resting Osteoblasts Mesencymal cells and Preosteoblasts Resorption Osteoclasts Reversal Apoptotic Osteoclasts Preosteoblasts
- 3. Normal Bone
- 4. Bone Metabolism and Prostate Cancer Osteoblast Activated Osteoclast Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast Adapted from: Boyle WJ, et al. Nature . 2003;423:337-342. Clines et al. Mol Endocrinol. 2007 February; 21(2):486-498 Hofbauer LC, et al. JAMA . 2004;292:490-495. RANKL RANK
- 6. Metastatic Bone Clarke et al Brit J Urol 1991
- 7. Bone Formation and Destruction in Prostate Cancer Clarke NW et al BJU 1991 / 1992 Eur Urol 1992
- 8. Bone Metabolism and Prostate Cancer Osteoblast Activated Osteoclast Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast Adapted from: Boyle WJ, et al. Nature . 2003;423:337-342. Clines et al. Mol Endocrinol. 2007 February; 21(2):486-498 Hofbauer LC, et al. JAMA . 2004;292:490-495. RANKL RANK
- 9. Bone Metabolism and Prostate Cancer Osteoblast Activated Osteoclast TNF- PTH IL-1 PTHrP Glucocorticoids Vitamin D PGE 2 IL-11 IL-6 Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast CFU-M = colony-forming unit-macrophage; PTH = parathyroid hormone; PGE 2 = prostaglandin E 2 ; IL = interleukin; PTHrP = PTH-related peptide; RANKL = receptor activator of nuclear factor kappa B ligand. ET-1 = endothelin ET-1 RANKL RANK
- 10. Bone Metabolism and Prostate Cancer Adapted from Roodman D. N Engl J Med . 2004;350:1655. PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Osteoblasts Activated Osteoclast PDGF, BMPs TGF-β, IGFs FGFs Tumor Cell CA +2 RANKL RANK OPG
- 12. Bone Markers in Osteolytic and Osteoblastic Metastatic Bone Disease Coleman RE, et al. JCO. 2005;23(22):1-11. U/L (median) Baseline BAP n = 744 n = 611 n = 263 n = 247 n = 318 nmol/mmol Creatinine (median) Baseline NTx n = 762 n = 626 n = 366 n = 379 n = 319 202 155 162 134 268 0 50 100 150 200 250 300 BC PC NSCLC Other ST MM 76 68 68 57 89 0 20 40 60 80 100 BC PC NSCLC Other ST MM
- 13. Increased Bone Resorption in Metastatic Bone Disease NTx excretion (nmol/mmol creatinine) % Coleman et al. J Clin Oncol 2005;23:4925-4935 . Normal Markedly elevated Modestly elevated
- 14. Influence of Accelerated Bone Resorption on Outcome in CRPC Relative Risk* P value 95% C.I. Brown J et al JNCI 2005 NTX > 100 v < 100 nmol/mmol creatinine Placebo treated patients n = 200 All SREs 2.36 1.30 - 4.29 .021 First SRE 2.56 1.44 - 4.55 .001 Prog Disease 2.17 1.17 - 4.05 .014 Death 5.09 2.90 - 8.91 <.001
- 15. Can Bone Directed Therapies Help? Osteoblast Activated Osteoclast TNF- PTH IL-1 PTHrP Glucocorticoids Vitamin D PGE 2 IL-11 IL-6 Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast CFU-M = colony-forming unit-macrophage; PTH = parathyroid hormone; PGE 2 = prostaglandin E 2 ; IL = interleukin; PTHrP = PTH-related peptide; RANKL = receptor activator of nuclear factor kappa B ligand. ET-1 = endothelin ET-1 RANKL RANK
- 16. Can Bone Directed Therapies Help? Osteoblast Activated Osteoclast Pre-fusion Osteoclast CFU-M Multinucleated Osteoclast Endothelin-1 Blockade Bisphosphonates RANK Ligand Blockade
- 19. Skeletal Related Events Saad et al. JNCI 2004; 96:879
- 22. Bone Resorption is Dependent on RANK Ligand An Essential Mediator of Osteoclast Activity Bone Osteoblast Lineage Inactive Osteoclast CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast CFU-M = colony forming unit macrophage Growth Factors Hormones Cytokines RANK RANKL RANK Ligand is Essential for Osteoclast Formation, Function, and Survival Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
- 23. Osteoprotegerin (OPG) Neutralises the Effects of RANK Ligand Bone Osteoblast Lineage Inactive Osteoclast CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast CFU-M = colony forming unit macrophage Growth Factors Hormones Cytokines RANK RANKL Osteoclast Formation, Function, and Survival Inhibited by OPG OPG Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
- 24. Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function and Survival Adapted from Roodman D. N Engl J Med . 2004;350:1655. PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Osteoblasts Inactivate Osteoclast PDGF, BMPs TGF-β, IGFs FGFs Tumor Cell CA +2 Bone Resorption Inhibited RANKL RANK Denosumab
- 25. RANK Ligand Inhibition with Denusomab in Cancer Patients with Bone Metastases Adapted from Suarez T, et al. J Clin Oncol. 2006;24(18S):6S. Abstract 8562 and poster. Median Percent Change in uNTx -120 -100 -80 -60 -40 -20 0 20 40 60 Visit Week 0 1 2 5 9 13 17 21 25 33 IV Bisphosphonate 180 mg Q4W 180 mg Q12W Total Denosumab
- 37. Inhibiting the Endothelin Axis ET A Antagonists and Prostate Cancer ET A R ET B R ET-1 ET-1 Metastasis Disease progression Angiogenesis Osteoblast stimulation Vasodilatation Apoptosis ZD4054 specifically blocks ET A R, with no detectable activity at ET B R Morris CD et al. Br J Cancer 2005;92:2148–2152 Atrasentan ZD4054
- 38. ZD4054 VS Placebo: Overall Survival ZD4054 15 mg versus placebo: HR 0.62; 80%CI 0.38, 0.99; P = 0.19 ZD4054 10 mg versus placebo: HR 0.38; 80%CI 0.22, 0.64; P = 0.019 Proportion of patients alive Time to death (days) 0 0.2 0.4 0.6 0.8 1.0 0 50 100 150 200 250 300 350 500 450 400 James ND et al Eur Urol Epub 2008 ZD4054 15 mg Placebo ZD4054 10 mg
- 39. ZD4054 Phase III Programme ENTHUSE M0 (15) ZD4054 vs placebo Metastatic (M1) No symptoms No Metastases (M0) No Symptoms Metastatic (M1) Symptomatic ENTHUSE M1 (14) ZD4054 vs placebo ENTHUSE M1C (33) docetaxel +/- ZD4054
- 40. 4054 In Metastatic CRCP: Window Study Overview Hughes S, Clarke NW Unpublished Scan Urine Plasma & serum Baseline #1 Baseline #2 Scan Urine Whole blood Plasma & serum BM Begin daily ZD4054 Scan Urine Plasma & serum + 1 week < 2 weeks < 4 weeks Scan Urine Whole blood Plasma & serum + 6 weeks + 6 weeks Scan Urine Plasma & serum BM
- 41. Menu of assays www.aushon.com
- 42. Plasma : mean % change from mean baseline -30 -20 -10 0 10 20 30 Mean baseline + 1 week +6 weeks +12 weeks Mean % change from mean baseline Ang2 E Selectin FGFb HGF PDGFbb PlGF VCAM1 VEGFA VEGFC VEGFR1 VEGFR2 Hughes S, Clarke NW Unpublished
- 43. Patient 12 plasma: Good responder -50 -40 -30 -20 -10 0 10 20 30 % change over mean baseline Ang2 FGFb HGF VCAM1 PDGF-bb VEGFA VEGFC PlGF VEGFR1 VEGFR2 E-selectin Mean baseline + 1 week +6 weeks +12 weeks Hughes S, Clarke NW Unpublished
- 44. Patient 14 plasma : Poor responder Hughes S, Clarke NW Unpublished Mean baseline +1 week +6 weeks +12 weeks -40 -20 0 20 40 60 80 100 120 140 % change over mean baseline Ang2 FGFb HGF VCAM1 PDGF-bb VEGFA VEGFC PlGF VEGFR1 VEGFR2 E-selectin
- 45. ZD4054 Circulating Tumour Cells Non-responders Responders/stable Hughes S, Clarke NW Unpublished
- 46. ZD4054 Circulating Tumour Cells Non-responders Responders/stable Hughes S, Clarke NW Unpublished
- 47. Radiotherapy
- 52. Radium-223 vs Placebo in CRPC Time to first SRE Overall survival Nilsson et al Lancet Oncol 2007: 8: 587-94
- 53. Induction chemotherapy Clinical response R A N D O M I Z E Consolidation therapy + Sr-89 Consolidation therapy Tu S-M Lancet 2001 Chemotherapy + Radio-Pharmaceuticals Randomised phase II Studies
- 54. Combination Therapies Ketoconazole + Chemotherapy + 89 Sr Shi-Ming Tu et al The Lancet 2001
- 55. Combination Bone Targeted Therapies: The NCRI Trapeze Study docetaxel + prednisolone zoledronic acid + Sr-89 + D RANDOMISE docetaxel + prednisolone A docetaxel + prednisolone zoledronic acid + B docetaxel + prednisolone strontium - 89 + C docetaxel + prednisolone (cycles 7-10) docetaxel + prednisolone (cycles 7-10) docetaxel + prednisolone (cycles 7-10) docetaxel + prednisolone (cycles 7-10) + 28 Days * + 28 Days *
- 56. Surgery and Metastatic Spinal Cord Compression BD White et al BMJ 2008: 337 Metastatic spinal cord compression
- 59. White, B D et al. BMJ 2008;337:a2538 Management of patients with suspected metastatic spinal cord compression
- 60. Bone Targeted Agents in Prostate Cancer
Notes de l'éditeur
- Bone remodeling is the process by which old bone is replaced by new bone and consists of phases: resting, resorption, reversal, and formation. 1-4 Activation : Resting bone surface is converted to a remodeling surface during activation of the bone remodeling process. 1-4 Recruitment of osteoclast precursors to the bone and their differentiation into mature, active osteoclasts occurs. 1-4 Resorption phase : Osteoclasts remove both mineral and organic components of bone matrix by generating an acidic microenvironment between the cell and bone surface. 1-4 The resorbing surface has a scalloped, eroded appearance known as Howship’s or resorption lacuna. 2 Reversal phase : Reversal begins once the osteoclasts have resorbed most of the mineral and organic matrix. Apoptosis of osteoclasts occurs in this phase and osteoblasts are recruited to the bone surface. 1-4 Formation phase : The removal of old bone by osteoclasts is followed by replacement with new, healthy osteoid (unmineralized collagen matrix) by osteoblasts. The collagen matrix provides the basic bone structure for mineral (predominantly hydroxyapatite) deposition. During the mineralization phase, these deposits gradually harden into the newly formed matrix, resulting in good quality bone. 1-4 Goldring S. Osteoporosis and Rheumatic Disease. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5 th ed. Washington, D.C: American Society for Bone and Mineral Research;2003;379-382. Holick MF, et al. Introduction to Bone and Mineral Metabolism. In: Harrison’s Online. Accessed 10/20/2004. Lindsay R, et al. Pathophysiology of bone loss. In: Lobo RA, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2 nd ed. New York, NY:Lippincott Williams & Wilkins 1999:305-314. Baron, R. General Principles of Bone Biology. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, D.C: American Society for Bone and Mineral Research;2003:1-8.
- Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
- Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
- Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
- The “vicious cycle” hypothesizes that tumor cells interact with the bone marrow microenvironment to drive bone destruction and tumor growth in a symbiotic relationship. Tumor cells secrete parathyroid-hormone-related peptide (PTHrP), which is the primary stimulator of osteoblast production of RANK Ligand 1 PTHrP induces both the production of RANK Ligand and down-regulates OPG production by osteoblasts, thereby stimulating osteoclastogenesis 2 Other factors produced and secreted by tumor cells (endothelin-1(ET-1), IL-6, prostaglandin E 2 , TNF, and macrophage colony-stimulating factor) also increase the expression of RANK Ligand 1,4 The increased expression of RANK Ligand in the tumor environment leads to increased formation, activation and survival of osteoclasts, and resulting osteolytic lesions 3 Osteolysis (process of bone resorption) then leads to the release of growth factors derived from bone, including: 1,2 transforming growth factor- β (TGF- β ) insulin-like growth factors (IGFs) fibroblast growth factors (FGFs) platelet-derived growth factor (PDGF) bone morphogenetic proteins (BMPs) These factors increase the production of PTHrP or promote tumor growth directly 1 Specifically, the growth factors bind to receptors on the surface of the tumor cells activating autophosphorylation and signaling through pathways involving SMAD (cytoplasmic mediators of most TGF- β signals) and mitogen-activated protein kinase (MAPK) 2 Bone destruction increases local extracellular calcium (Ca 2+ ) concentrations, which have also been shown to promote tumor growth and the production of PTHrP 2 Thus, tumor-cell proliferation and production of PTHrP through the signaling of these pathways is promoted and the cycle continues Roodman GD, N Engl J Med. 2004;350:1655-64. Mundy GR, et al. Nature Reviews Cancer. 2002;2:584-93. Kitazawa S, et al. J Pathol. 2002;198:228–36. Guise TA, et al. Endocrin Rev . 1998;19:18-54.
- Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
- Many different factors can affect osteoclast activity, but RANK ligand is required to mediate or permit their effects on bone resorption. Several factors (eg, parathyroid hormone [PTH], TNF, interleukin [IL]-1) stimulate the expression of RANK ligand by cells of the osteoblast lineage and other cells (eg, activated T cells), resulting in increased bone loss. 1-3 Evidence from gene deletion and other studies indicates that RANK ligand is an essential mediator of osteoclast activity. 1,2 RANK ligand is a key factor regulating osteoclastogenesis and bone resorption. 1,2 Consistent with this are the following observations: Within bone, most receptors for hormones, growth factors, and cytokines are present on osteoblasts rather than osteoclasts, regardless of whether the predominant action of these factors is bone formation or bone resorption. 2 Most osteotropic growth factors, hormones, and cytokines upregulate RANK ligand mRNA expression in osteoblast cell lines and primary cell cultures. 1,2 The anti-osteoclast effects of OPG, the natural endogenous inhibitor of RANK ligand, occur in normal animals and are consistent across various disease models. 2 This reproducibility supports the idea that most osteoclast activating factors act indirectly via RANK ligand. 2 Boyle WJ, et al. Nature. 2003;423:337-342. Kostenuik PJ, et al. C urr Pharm Des. 2001;7:613-635. Hofbauer LC, et al. JAMA . 2004;292:490-495.
- This was a phase III, multicenter, international, double-blind, placebo-controlled study in 643 men with prostate cancer and metastatic bone disease Patients were stratified on entry into the study according to the presence or absence of distant metastases at the time of the initial diagnosis of prostate cancer Patients were randomly assigned to receive either 4 or 8 mg ZOMETA or placebo via 5-minute infusion every 3 weeks The 8-mg dose was associated with a rise in serum creatine levels in some patients. Protocol amendments therefore increased the infusion time to 15 minutes and the infusate volume to 100 mL, and reduced the 8-mg dose to 4 mg; the group was thereafter referred to as the 8/4 mg group. No efficacy conclusions were drawn from the 8/4 mg group; however, this group was included in safety analyses Patients were also given supplemental calcium (500 mg) and vitamin D (400 International Units) open-label and instructed to take one dose each day with food to prevent hypocalcemia Core analysis of the study results was at 15 months. Patients who completed the core phase were given the option of continuing to receive study medication for another 9 months and 186 patients elected to continue. Of these, 122 patients completed 24 months of treatment. Final analyses were performed at 24 months
- In the presence of low levels of macrophage colony-stimulating factor (M-CSF), Receptor Activator of Nuclear Factor-kappa B (RANK) Ligand is essential for osteoclast formation, function, and survival. 1-4 Osteoclasts are the cells responsible for resorbing bone. Many different factors (e.g., PTH, TNF, IL-1) can lead to bone loss, but they all stimulate the expression of RANK Ligand by cells of the osteoblast lineage and other cells (e.g., activated T cells). 2,5 Maturation of pre-fusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANK Ligand binds to RANK on the preosteoclast and mature osteoclast. 5 In addition to being expressed on osteoclasts and osteoclast progenitors, RANK has been observed on cartilage cells (chondrocytes), mammary gland epithelial cells, and trophoblast cells. 6,7 The RANK Ligand polypeptide is a type II transmembrane protein found on the surface of expressing cells as well as in a proteolytically released (cleaved) soluble form. 3 1. Yasuda H, et al. Proc Natl Acad Sci USA. 1998;95:3597–3602. 2. Fuller K, et al. J Exp Med. 1998;188:997–1001. 3. Lacey DL, et al. Cell . 1998;93:165–176. 4. Lacey DL, et al. Am J Pathol. 2000;157:435-448. 5. Boyle WJ, et al. Nature. 2003;423:337-342. 6. Fata JE, et al. Cell. 2000:103:41-50. 7. Hsu H, et al. Proc Natl Acad Sci USA. 1999:96:3540-3545.
- RANK Ligand is expressed (both in a transmembrane and soluble form) from the osteoblast lineage cells. 1 RANK Ligand subsequently binds to RANK on immature and mature osteoclasts. 2 Maturation of pre-fusion osteoclasts to multinucleated osteoclasts and finally to activated osteoclasts is initiated when RANK Ligand binds to its receptor, RANK. The right side of the graphic depicts inhibition of RANK Ligand by naturally occurring osteoprotegerin (OPG). OPG, a member of the tumor necrosis factor (TNF) receptor family, binds to and neutralizes the effects of RANK Ligand, thereby inhibiting bone resorption. OPG is an important inhibitor of the terminal differentiation and function of osteoclasts. OPG acts as a decoy receptor by binding with RANK Ligand, thereby inhibiting osteoclastogenesis and the survival of pre-existing osteoclasts. 1-5 When RANK Ligand is bound and neutralized by OPG, osteoclasts cannot form 5,6 , function 6 or survive 7 . 1. Lacey DL, et al. Cell. 1998;93:165–176 2. Boyle WJ, et al. Nature. 2003;423:337-342. 3. Simonet WS, et al. Cell . 1997;89:309–319. 4. Bekker PJ, et al. J Bone Min Res. 2001;16:348-360. 5. Yasuda H, et al. Proc Natl Acad Sci USA . 1998;95:3597-3602. 6. Fuller K, et al. J Exp Med. 1998;188:997-1001. 7. Lacey DL, et al. Am J Pathol. 2000;157:435-448.
- The “vicious cycle” hypothesizes that tumor cells interact with the bone marrow microenvironment to drive bone destruction and tumor growth in a symbiotic relationship. Tumor cells secrete parathyroid-hormone-related peptide (PTHrP), which is the primary stimulator of osteoblast production of RANK Ligand 1 PTHrP induces both the production of RANK Ligand and down-regulates OPG production by osteoblasts, thereby stimulating osteoclastogenesis 2 Other factors produced and secreted by tumor cells (endothelin-1(ET-1), IL-6, prostaglandin E 2 , TNF, and macrophage colony-stimulating factor) also increase the expression of RANK Ligand 1,4 The increased expression of RANK Ligand in the tumor environment leads to increased formation, activation and survival of osteoclasts, and resulting osteolytic lesions 3 Osteolysis (process of bone resorption) then leads to the release of growth factors derived from bone, including: 1,2 transforming growth factor- β (TGF- β ) insulin-like growth factors (IGFs) fibroblast growth factors (FGFs) platelet-derived growth factor (PDGF) bone morphogenetic proteins (BMPs) These factors increase the production of PTHrP or promote tumor growth directly 1 Specifically, the growth factors bind to receptors on the surface of the tumor cells activating autophosphorylation and signaling through pathways involving SMAD (cytoplasmic mediators of most TGF- β signals) and mitogen-activated protein kinase (MAPK) 2 Bone destruction increases local extracellular calcium (Ca 2+ ) concentrations, which have also been shown to promote tumor growth and the production of PTHrP 2 Thus, tumor-cell proliferation and production of PTHrP through the signaling of these pathways is promoted and the cycle continues Roodman GD, N Engl J Med. 2004;350:1655-64. Mundy GR, et al. Nature Reviews Cancer. 2002;2:584-93. Kitazawa S, et al. J Pathol. 2002;198:228–36. Guise TA, et al. Endocrin Rev . 1998;19:18-54.
- Forty subjects had responded (uNTx below 50 nM BCE/mM creatinine) up to the time of data cut off. For responders, the duration of response was defined as the time from the first occurrence of uNTx reducing below 50 to the first occurrence of uNTx rising above 50 nM BCE/mM creatinine. For responders who remained below 50 nM BCE/mM creatinine, the duration of response was censored at the time of last evaluation of uNTx. 1 Because more than 50% of responding subjects maintained below 50 in each of the 3 treatment arms, the median cannot be estimated. At the time of data cut off, 30%, 29% and 32% of subjects had uNTx rising above 50 nM BCE/mM creatinine in IV BP, denosumab Q4W, and denosumab Q12W, respectively. 1,2 Suarez T, et al. J Clin Oncol. 2006;24(18S):6S (abstract #8562). Amgen, data on file.
- Key Points This was an international, randomized, double-blind, active-controlled trial comparing denosumab with zoledronic acid for the treatment of bone metastases in patients with castration-resistant prostate cancer The primary endpoint was time to first on-study SRE comparing denosumab with zoledronic acid for noninferiority Secondary efficacy endpoints, evaluated only if noninferiority was demonstrated, were superiority tests comparing denosumab and zoledronic acid for time to first on-study SRE and time to first and subsequent SRE(s) (multiple-event analysis) Background Eligible patients were men 18 years old with histologically confirmed prostate cancer and current or prior radiographic evidence of at least one bone metastasis and documented failure of at least 1 hormonal therapy Patients were randomized 1:1 to receive either SC injections of denosumab 120 mg and an IV placebo Q4W, or an IV infusion (lasting no less than 15 minutes) of zoledronic acid 4 mg and an SC injection of placebo Q4W Daily supplementation with calcium and vitamin D was strongly recommended Key exclusion criteria included current or prior IV bisphosphonate or oral bisphosphonate administration to treat bone metastasis References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 815,Table 1 Fizazi K, et al. Lancet 2011;377: 815,A,2 XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2 XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 813,Methods Fizazi K, et al. Lancet 2011;377: 815,A,2 XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 814,A,2;B,1 XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 Fizazi K, et al. Lancet 2011;377: 814,B,5; 815,A,1 XGEVA™ PI 2010: 3,6.1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2
- Key Points A total of 1901 patients were randomized to receive denosumab (n = 950) or zoledronic acid (n = 951) Baseline age, race, and ECOG performance status variables were balanced between groups Background Randomization was stratified by previous SRE, PSA level ( 10 g/L vs 10 g/L), and chemotherapy for prostate cancer within 6 weeks before randomization Patients in the zoledronic acid arm had a slightly longer median time from bone metastases diagnosis to study randomization (denosumab, 3.94 months; zoledronic acid, 5.19 months) although the quartiles were similar Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 815,Table 1 Fizazi K, et al. Lancet 2011;377: 815,Table 1
- Key Points Protocol-mandated dose adjustments of IV zoledronic acid for baseline creatinine clearance occurred in 213 (22%) patients per the Zometa prescribing information. One hundred forty-three (15%) patients required zoledronic acid doses to be withheld on study for serum creatinine increases per the Zometa prescribing information Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 817,B,1; 818,B,1 Fizazi K, et al. Lancet 2011;377: 817,B,1; 818,B,1
- Key Points Denosumab significantly delayed the time to first on-study SRE by 18% compared with zoledronic acid (HR = 0.82; 95% CI, 0.71–0.95; P .001 for noninferiority and P = .008 for superiority) 1 The median (95% CI) time to first on-study SRE was 20.7 months in the denosumab group and 17.1 months in the zoledronic acid group, a difference of 3.6 months 1 Between-group divergence is evident beginning at 3 months after initiation of treatment 2 References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ PI, 2010: 11,Table 2 XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 2
- Key Points Denosumab significantly delayed the time to first and subsequent on-study SREs (rate ratio = 0.82; 95% CI, 0.71–0.94; adjusted P = .009) 1 A total of 1078 events occurred, 494 in the denosumab treatment group, and 584 in the zoledronic acid treatment group 2 References XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 XGEVA™ PI, 2010: 11,Table 2
- Key Point Overall disease progression (HR = 1.06; 95% CI, 0.95–1.18; P = .30) was similar between study groups Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 817,Figure 4,B Fizazi K, et al. Lancet 2011;377: 817,Figure 4,B
- Key Points Overall survival (HR = 1.03; 95% CI, 0.91–1.17; P = .65) was similar between study groups 1 Overall survival and progression-free survival were similar between arms in all three trials 1 Mortality was higher with denosumab in a subgroup analysis of patients with multiple myeloma (HR = 2.26; 95% CI, 1.13–4.50; n = 180) 2 References Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. XGEVA™ (denosumab) prescribing information, Amgen. Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A XGEVA™ PI, 2010: 10-14
- Key Points Overall rates of AEs and serious AEs were similar between the two study groups (97% in the denosumab and zoledronic acid groups) The most common AEs were anemia, back pain, decreased appetite, nausea, and fatigue Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,Table 4
- Key Point The incidence of AEs of interest was similar between the two study treatment groups Background During the first 3 days of treatment, AEs potentially associated with acute phase reactions occurred in 8% of denosumab and 18% of zoledronic acid patients AEs potentially associated with renal impairment occurred in 15% of the denosumab group and 16% of the zoledronic acid group Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group ( P = .09) AEs of hypocalcemia were reported in 121 (13%) patients in the denosumab group and 55 (6%) patients in the zoledronic acid group New primary malignancies were identified in 18 (2%) patients in the denosumab group and 10 (1%) patients in the zoledronic acid group Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 819,A,3 Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 819,A,3 Fizazi K, et al. Lancet 2011;377: 818,Table 4
- Key Point ONJ occurred infrequently in both treatment groups, and was usually associated with risk factors Background Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group ( P = .09) A history of tooth extraction, poor oral hygiene, and/or dental appliance utilization was present in 17 (77%) of the patients with ONJ in the denosumab group and 10 (83%) of the patients with ONJ in the zoledronic acid group On-study chemotherapy use was reported by 14 (64%) of patients with ONJ in the denosumab group and nine (75%) of the patients with ONJ in the zoledronic acid group As of April 2010, 10 (45%) patients with ONJ in the denosumab group had undergone limited surgeries and two (9%) had bone resections compared with three (25%) patients in the zoledronic acid group who received limited surgical treatment and one (8%) who underwent bone resection Reference Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet . 2011;377:813-822. Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,B,5 Fizazi K, et al. Lancet 2011;377: 818,B,5; 819,A,1 Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,B,5 Fizazi K, et al. Lancet 2011;377: 818,B,5; 819,A,1
- Key Points The results of this study demonstrated that denosumab was superior to zoledronic acid in delaying time to first and subsequent SRE(s) in advanced prostate cancer patients with bone metastases Denosumab had several potentially beneficial characteristics
- ZD4054 is a specific endothelin A receptor antagonist with no effect on the B receptor. This means that the beneficial effects of endothelin receptor B mediated apoptosis are unaffected while the endothelin receptor A mediated stimulation of progression, angiogenesis and osteoblasts are blocked.
- Although based on only 40 deaths in total, a marked improvement in overall survival was seen.
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