In healthy adult bone, RANK Ligand activity is tightly regulated to balance bone formation and resorption. 1 However, in the presence of tumour cells, a vicious cycle of bone destruction and tumour growth may develop. 2,3 Tumour cells that have invaded bone secrete factors that increase the expression of RANK Ligand by osteoblasts. Increased expression of RANK Ligand upregulates osteoclast activity. Excessive osteoclast activity drives increased bone resorption; this in turn releases growth factors from the bone matrix that may perpetuate tumour activity. This sequence of events drives a vicious cycle of bone destruction and tumour activity. The discovery of the RANK/RANK Ligand pathway and its role the regulation of bone turnover provides a molecular target for new therapies to interrupt bone destruction and potentially tumour growth in patients with advanced cancer. References Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655–64. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–93.
The clinical consequences of bone metastases include: Fractures The need for radiation to bone to treat pain or prevent fracture The need for surgery to bone to prevent or stabilize fractures Spinal cord compressions that can result in numbness or weakness, urinary or fecal incontinence, and paralysis These four consequences are collectively called skeletal-related events (SREs) Other clinical consequences include: Hypercalcemia, which often implies that the underlying bone metastases are not controlled Pain from the local bone destruction Coleman RE. Cancer Treat Rev . 2001;27:165–176
Key Points If patients with metastatic cancer are left untreated with a bone-targeting agent, nearly half will go on to develop an SRE. 1–3 In these untreated patients, the average numbers of SREs per patient per year ranges from approximately 1.47 in patients with prostate cancer to 3.70 in patients with breast cancer. 1 3 Background Percentages of SREs and mean number of patients developing SREs are based on data from the placebo arms of three IV bisphosphonate pivotal trials (breast: pamidronate vs placebo; prostate and lung/other solid tumours: zoledronic acid vs placebo) in patients with metastatic cancer involving bone. Results of the breast and prostate studies were taken over 24 months, 1,2 and the lung cancer and other solid tumour results were over 21 months. 3 References Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082 90. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879 82. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613 21.
Traditional approaches for treating patients with bone metastases include standard anticancer agents in conjunction with a variety of supportive and palliative therapies Radiotherapy and radionuclides are standard for severe bone pain palliation, and many patients also receive systemic analgesics Radiotherapy also stabilizes bone lesions and may prevent impending fractures Patients may also require orthopedic surgery either to treat existing fractures or to prevent impending fractures Intravenous (IV) bisphosphonate therapy has emerged in the last decade as another highly effective modality to reduce the incidence and delay the occurrence of skeletal complications. These bone-seeking agents inhibit tumor-induced osteolysis and maintain the strength and metabolic balance of the bone Intravenous bisphosphonates are extremely well tolerated and convenient. A single infusion once a month significantly reduces the risk of fractures and palliates bone pain, thereby reducing the need for radiation therapy
This was an international, multicenter, double-blind, randomized, phase III trial involving 1,648 patients Patients were randomized to receive ZOMETA ® (zoledronic acid 4 or 8 mg) or pamidronate disodium (90 mg) every 3 to 4 weeks for 25 months Patients also received supplemental calcium (500 mg) and vitamin D (400 International Units) open-label and were instructed to take 1 dose each day with food to prevent hypocalcemia Core analysis of the study results was at 13 months (after patients had received 12 months of therapy), and the final analysis detailed here was performed at 25 months Approximately 60% of patients (n = 606) completed the 12-month core phase and were given the option of continuing to receive study medication during an additional 12-month extension phase Of these patients, 350 completed 24 months of treatment Adverse events and death were the most frequent reasons for discontinuation, and the percentage of patients who did not complete the study was similar across all treatment groups. Final analyses were performed at 25 months This trial was designed to show noninferiority of zoledronic acid compared with pamidronate
Denosumab is a fully human monoclonal antibody of the immunoglobulin G 2 isotype that binds human RANK Ligand with high affinity and specificity. 1 By binding to RANK Ligand, denosumab prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts and their precursors, 1 thereby blocking RANK/RANK Ligand signaling. It is important to recognise that denosumab has been developed as two products with different dosing regimens that are appropriate for the pathophysiology of the condition being treated; the two products have different therapeutic indications: Denosumab at a dose of 60 mg subcutaneously (SC) every 6 months (Prolia ® ) is indicated for treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures, and treatment of osteoporosis in postmenopausal women at increased risk of fractures. 2 Denosumab at a dose of 120 mg SC every 4 weeks (XGEVA TM ) is approved in the USA for prevention of SREs in patients with bone metastases from solid tumours. References McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821–31. Prolia (Denosumab) Summary of product characteristics, Amgen.
Denosumab precisely binds to and sequesters free RANK Ligand, thus preventing activation of the RANK receptor and blocking the development of activated osteoclasts. Inhibiting RANK Ligand in this way mimics the endogenous action of OPG on the RANK/RANK Ligand pathway in inhibiting the formation, function and survival of bone-resorbing osteoclasts. Because bone destruction may lead to SREs, it can be hypothesised that targeting RANK Ligand with denosumab to break the vicious cycle could prevent or delay SREs in patients with bone metastases. References Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655–64. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–93.
The primary endpoint is represented on a Kaplan Meier curve Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to 0.95. The P value was less than 0.0001 for noninferiority and equal to 0.01 for superiority The median time to first on-study SRE was not reached for denosumab and was 26.5 months for zoledronic acid The 2 most common components of SREs were fractures and radiation to bone Approximately 30-37% of subjects experienced an on-study SRE Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.
For the secondary endpoint of time to first and subsequent SRE, otherwise known as the multiple event analysis, denosumab was also superior to zoledronic acid and reduced the risk of multiple events by 23% (rate ratio: 0.77; 95% CI: 0.66–0.89; P=0.001) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.
Overall disease progression was also similar between groups (hazard ratio: 0.99; 95% CI: 0.89–1.11; P=0.90) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.
Overall survival was similar between groups (hazard ratio: 0.95; 95% CI: 0.81–1.11; P=0.50) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.
Additional safety results of note include infectious AEs and infectious serious AEs, both of which were approximately balanced on the 2 arms A prespecified analysis of adverse event terms that could represent a flu-like illness or acute phase reactions reported in the first 3 days after treatment occurred was performed. These adverse events occurred much less frequently with denosumab than with zoledronic acid In another prespecified analysis, adverse event terms that could represent renal toxicity also occurred less frequently with denosumab despite appropriate renal dosing with zoledronic acid per the prescribing information Osteonecrosis of the jaw occurred infrequently and was not significantly different between treatment arms (prespecified P value of 0.39) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.
Rob Coleman YCR Professor of Medical Oncology Weston Park Hospital University of Sheffield Bone Metastases ABC-01 – Lisbon 2 nd – 5 th November 2011
A Vicious Cycle Of Bone Destruction May Develop In The Presence Of Tumour Cells Overexpression of RANK Ligand drives increased formation, function and survival of osteoclasts, leading to excessive bone resorption Osteoblasts Tumour cells produce factors that stimulate osteoblasts to secrete RANK Ligand RANK Ligand Tumour Osteoblasts and other bone cells increase expression of RANK Ligand Osteoclast Bone resorption releases growth factors from the bone matrix that may perpetuate tumour activity Adapted from Roodman GD. N Engl J Med 2004;350:1655–64; Mundy GR. Nat Rev Cancer 2002;2:584 93.
Consequences of Bone Metastases Economic Burden Poor functional capacity Impaired mobility Long and painful recovery from fractures Severe bone pain Hypercalcaemia Inconvenient hospital/clinic visits Pain and paralysis from spinal cord compression Metastatic Bone Disease
Skeletal Morbidity from Bone Metastases in Advanced Cancer Surgery to Bone Pathologic Fracture Spinal Cord Compression Radiotherapy to B one Skeletal Related Events (SREs) + HYPERCALCAEMIA
Frequency of Skeletal Morbidity (SREs) in Advanced Cancer with Bone metastases Percentage of patients Percentage of patients developing SREs Mean number of SREs per patient per year 1. Lipton A, et al. Cancer 2000;88:1082 90. Data are from the placebo arms of trial of placebo vs. IV pamidronate Mean number of SREs/patient/year Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression SREs Any
Multi-Disciplinary Treatment of Metastatic Bone Disease
Radiotherapy/radionuclides Palliate bone pain
Endocrine treatment A nti-tumour
Chemotherapy A nti-tumour
Targeted therapies Anti-tumour
Orthopaedic intervention S tabilize/re pair bone
Interventional radiology Pain relief
Analgesic s Pain management
Bone Targeted Treatments Inhibit bone cell function
Zoledronic Acid for Bone Metastases Trial Designs Zoledronic acid 4/8 mg q 3 to 4 wk + daily oral vitamin D 400 IU and calcium 500 mg Pamidronate 90mg/ + daily oral vitamin D 400 IU and calcium 500 mg
Proportion of patients experiencing ≥ 1 SRE
Time to first SRE
Risk of events (multiple event analysis)
Advanced breast cancer
At least 1 bone metastasis
ECOG 0, 1, or 2
Adequate organ function
N = 1130
Incremental Benefit of Zoledronic Acid Over Pamidronate Cumulative expected SREs, (n) per 100 patients Months Rosen LS, et al. Cancer , 2003;98:1735-1744. Pamidronate Zoledronic acid 4 mg P = .046 3 6 9 12 15 18 21 25 0 20 40 60 100 120 0 80
Zoledronic Acid Significantly Reduces Bone Pain Mean change from baseline 2 4 8 12 16 20 24 28 32 36 40 44 48 52 Time on study, weeks * * * * * * * * * * * * P < .05 0 * * BPI = Brief Pain Inventory. Adapted with permission from Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.
Consider extending interval after 2 years if in remission
Revert to monthly on progression
Use most potent effective agent available
Use monthly schedule
Bone markers may allow use of less frequent schedule
Clinical Benefits of Normalising Bone Resorption NTX = N-telopeptide of type I collagen; SRE = Skeletal-related event; BC = Breast cancer; E-E = Patients whose NTX levels remained elevated at 3 months. Lipton A, et al. Cancer 113: 193-201, 2008. First SRE Breast cancer 0 Death 49 0.505 0.473 0.821 Risk reduction, % 53 .002 P value .002 48 .002 0.5 1.0 1.5 2.0 Increased risk versus E-E Decreased risk versus E-E 1st Fracture/Bone surgery Bone lesion progression 0.517 18 NS
Denosumab is a fully human monoclonal antibody that binds human RANK Ligand with high affinity and specificity 1
1. McClung MR et al. New Engl J Med 2006;354:821–31. 2. Prolia ® (Denosumab) Summary of product characteristics, Amgen. Prolia ® (denosumab) 2 XGEVA ™ (denosumab) Dose 60 mg SC 120 mg SC Regimen Every 6 months Every 4 weeks Indication(s) Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures Treatment of osteoporosis in postmenopausal women at increased risk of fractures Approved in USA for prevention of SREs in patients with bone metastases from solid tumors
Denosumab Targets RANK Ligand To Break The Vicious Cycle By binding to RANK Ligand denosumab inhibits osteoclast formation, function, and survival Osteoblasts Osteoclast Denosumab precisely binds to RANK Ligand, preventing activation of the RANK receptor on osteoclasts Denosumab prevents the maturation of osteoclasts, decreasing bone resorption and breaking the vicious cycle of bone destruction Tumour RANK Ligand Denosumab Adapted from Roodman GD. N Engl J Med 2004;350:1655–64; Mundy GR. Nat Rev Cancer 2002;2:584 93.
Phase III Trial of Denosumab vs Zoledronic Acid in Patients Advanced Breast Cancer Abbreviations: Dmab, denosumab; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; MM, multiple myeloma; OST, other solid tumors; q, every; R, randomization; SC, subcutaneous; SRE, skeletal-related event. Primary endpoint: Time to first on-study SRE (non-inferiority trial) Secondary endpoints: Time to first on study SRE (superiority), time to first and subsequent on-study SREs (superiority)
Time to First On-Study SRE Months Subjects at risk: 0 1.00 Proportion of Subjects Without SRE 0 3 6 9 12 15 18 21 24 27 30 0.25 0.50 0.75 KM Estimate of Median Months Denosumab Zoledronic Acid Not reached 26.5 HR 0.82 (95% CI: 0.71, 0.95) P <0.0001 (Non-inferiority) P = 0.01 (Superiority)* * Adjusted for multiplicity Stopeck AT et al. J Clin Oncol 2010;28:5132–9 Zoledronic Acid 1020 829 676 584 498 427 296 191 94 29 Denosumab 1026 839 697 602 514 437 306 189 99 26
Time to First and Subsequent On-Study SRE* 0 3 6 9 12 15 18 21 24 27 30 0 0.5 1.0 1.5 Cumulative Mean Number of SRE Months Events (n) Denosumab Zoledronic Acid 474 608 Rate Ratio 0.77 (95% CI: 0.66, 0.89) P = 0.001 † * Events that occurred at least 21 days apart † Adjusted for multiplicity Stopeck AT et al. J Clin Oncol 2010;28:5132–9 Multiple Event Analysis
Not All Skeletal Related Events Are Equal - Quality and Quantity Ignored RIB FRACTURE SPINAL CORD COMPRESSION SPINAL STABILISATION POST-OP RADIOTHERAPY ≠
Incremental Benefits of Bone Resorption Inhibitors 64% risk of skeletal complication with no bisphosphonate at 2 years 1 64% (2 trials; placebo n=384) 2-yr risk of any SRE
Lipton A, et al. Cancer 2000; 88(12 Suppl):3033-–7.
SRE, skeletal-related event
Incremental Benefits of Bone Resorption Inhibitors Additional 23% risk reduction with Denosumab 3 64% risk of skeletal complication with no bisphosphonate at 2 years 1 Approx 33% risk reduction with pamidronate 1 64% (2 trials; placebo n = 384) – 33% (2 trials; N = 754) – 20% (1 trial; n = 1130) Lipton A, et al. Cancer 2000; 88(12 Suppl):3033–7; 2. Rosen LS, et al. Cancer 2003;100:36–43; 3. Stopeck AT et al. J Clin Oncol 2010;28:5132–9 Further 20% risk reduction with zoledronic acid 2 – 23% (1 trial; N = 2046) 2-yr risk of any SRE (P < .001) HR for all SREs vs prior standard of care (P < .037) (P = .001)
Time to Experiencing Moderate or Severe Pain (Worst Pain Score > 4 Points per Brief Pain Inventory) Months 0 Proportion of Subjects 1.00 0.25 0.50 0.75 Subjects at risk: 0 3 6 9 12 15 18 21 24 27 KM Estimate of Median Days Denosumab Zoledronic acid 88 64 HR 0.87 (95% CI: 0.79, 0.97) P = 0.009 Stopeck AT et al. J Clin Oncol 2010;28:5132–9 . Zoledronic Acid 1020 463 318 250 209 172 126 93 56 17 Denosumab 1026 511 378 312 256 214 159 109 59 27
Adverse Events of Interest † P = 0.39 * Includes blood creatinine increased, hypercreatininemia, oliguria, renal impairment, proteinuria, renal failure, urine output decreased, creatinine renal clearance decreased, renal failure acute, renal function test abnormal, anuria, blood urea increased, renal failure chronic No neutralizing anti-denosumab antibodies were detected Stopeck AT et al. J Clin Oncol 2010;28:5132–9
Can we Prevent Metastasis With Bone Targeted Treatment? Coleman et al. N Engl J Med 2011; 365:1396-1405 Invasive DFS AZURE trial results 1 2 3 4 5 6 7 20 40 60 80 TIME (YEARS) Zoledronic acid N= 1681 No. at risk: 1681 1578 1443 1337 1224 570 82 1678 1574 1426 1316 1221 544 68 Control N= 1678 Adjusted HR = 0.98 95% CI [0.85,1.12] p=0.73
Divergent ZOL Treatment Effects on First Recurrence Outside Bone by Menopausal Status Typical Odds Ratio Menopausal Group Description 2 1 (heterogeneity) = 14.00; P = .0002 a Adjusted for imbalances in ER, lymph node status and T stage. HR: 0.70 (95% CI 0.54-0.92) 1.32 (95% CI 1.09-1.59) Pre + < 5 years post + unknown status >5 years postmenopausal 1 1.2 1.4 1.6 1.8 2.0 0.2 0.4 0.6 0.8 Coleman et al. N Engl J Med 2011; 365:1396-1405