Joana Ribeiro Hospital de Santa Maria, Lisboa

Joana Ribeiro Hospital de Santa Maria, Lisboa
O Papel do Oncologista no Tratamento das Metástases Ósseas dos Tumores Genitourinários Joana Ribeiro Hospital de Santa Maria, Lisboa Outubro/2011

“Bone metastasis is a catastrophic complication for most patients with cancer. Not only does it cause intractable pain and fracture after trivial injury, spinal cord compression and hypercalcemia, it also signifies that the malignant process is incurable.” — Gregory R. Mundy, MD Mundy GR. Cancer. 1997;80:

Sumário A Magnitude do Problema Biologia da Metastização Óssea
Agentes terapêuticos Bisfosfonatos Denosumab Estudos em curso Conclusões

Prevalência da doença óssea metastática
5-Year World Prevalence, thousands1 Incidence of Bone Metastases in Cancers, %2 Median Survival, months2-4 Myeloma 144 6 - 54 Renal 480 6 - 12 Melanoma 533 < 6 Bladder 1,000 40 6 - 9 Thyroid 475 60 48 Lung 1,394 Breast 3,860 Prostate 1,555 More Lytic More Blastic Bone disease in prostate cancer is not purely osteoblastic. 1. Parkin DM, et al. Int J Cancer. 2001;94(2): ; 2. Coleman RE. Cancer Treat Rev. 2001;27(3): ; 3. Coleman RE. Cancer. 1997;80(8 suppl): ; 4. Zekri J, et al. Int J Oncol. 2001;19(2): 5

Complicações esqueléticos associadas (SREs) à destruição óssea mediada pelo tumor
Desde a década de 90, os SREs foram definidos como: A taxa de SRE é utilizada para avaliar a eficácia dos agentes terapêuticos dirigidos ao tratamento das metástases ósseas Radiação óssea Fractura patológica Compressão medular Cirurgia óssea SREs are common among patients with metastatic bone disease, particularly those with lytic metastases (table 1). As an example, in a review of patients treated for metastatic breast cancer prior to the routine use of bisphosphonates, over 50 percent developed a SRE [2]. Other evidence suggests that in the absence of osteoclast inhibition, one SRE occurs on an average of every three to four months in women with lytic bone metastases from breast cancer SREs are clinical outcomes that can be distinctly measured; therefore, they are often used as endpoints in clinical trials investigating therapies for bone metastases, although not all studies include hypercalcemia. Bone metastases are also associated with pain, particularly with motion, which significantly impacts quality of life (QOL). However, the usual definition of a SRE does not include pain or changes in QOL, which are typically measured as separate outcomes in clinical trials. Coleman. Cancer Treat Rev 2001;27:

Prevalência de SREs em Doentes com Metástases Ósseas no Carcinoma da Próstata
Radiação óssea 33% Fractura ´patológica 25% Compressão medular 8% Cirurgia óssea 4% Bone metastases are associated with substantial morbidity in patients with cancer. Skeletal complications of bone metastases, often referred to as skeletal-related events (SREs), include fracture, skeletal instability/loss of skeletal integrity, spinal cord compression, the need for surgery or radiation therapy for a symptomatic bone metastasis, and hypercalcemia Saad, et al. J Urol 2003;169(Suppl).

Proportion of Patients With an Event, %
Prevalência de SREs em Doentes com Cancro na Ausência de Terapêutica Óssea Dirigida Proportion of Patients With an Event, % SREs são prevalentes em doentes com cancro na ausencia de terapeutica ossea dirigid Breast1 (n = 384) 24 months Prostate2 (n = 208) 24 months NSCLC 3 (n = 247) 21 months Cancer Type Data results from placebo arms of clinical trials. Abbreviations: NSCLC, non-small cell lung cancer; OST, other solid tumors; SRE, skeletal-related event. 1. Lipton A, et al. Cancer. 2000;88(5): ; 2. Saad F, et al. AUA 2003, abstract 1472; 3. Rosen LS, et al. Cancer. 2004;100(12):

Change/Standard Deviation
Complicações Esqueléticas Reduzem a Qualidade de Vida nos Doentes com Carcinoma da Próstata Total Physical Functional Emotional a Change/Standard Deviation a a FACT-G score: functional assesment cancer therapy – general (é um score) We examined the clinical relevance of skeletal-related events (SREs) for health state preferences, pain and health-related quality of life in patients with advanced prostate cancer and a history of bone metastases. Data were from a clinical trial of zoledronic acid versus placebo in the treatment of SREs associated with advanced prostate cancer metastatic to bone There were clinically meaningful and statistically significant declines in physical well-being after: radiation and pathologic fractures; functional well-being after radiation; and emotional well-being after radiation and pathologic fractures. There also were meaningful and significant declines in preference and utility scores after radiation and fracture. SREs have important and significant effects on measures of health-related quality of life in men with prostate cancer. Treatments that prevent SREs may not demonstrate corresponding effects on outcomes if the effects of SREs occur between scheduled outcome assessments. Implications for trial design are discussed. a a a a P < .05. Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4):

Fracturas patológicas afectam negativamente a sobrevivência
Risk increase P value 1.29 Prostate Cancer (n = 640) 29% .04 1.52 Breast Cancer (n = 1,130) 52% < .01 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Hazard Ratio Diminuição mortalidade Aumento mortalidade Data from Saad F, et al. Cancer. 2007;110(8):

SREs Aumentam o Risco de Morte nos Doentes com Cancro da Próstata
1 Sem SREs Um ou mais SREs 0.9 0.8 0.7 0.6 Probabilidade 0.5 0.4 0.3 As well as increasing morbidity, SREs can be fatal 0.2 0.1 90 180 270 360 Sobrevivência, dias dePuy, et al. Support Care Cancer 2007;15:

O Ciclo Vicioso das Metástases Ósseas
- Bone metastases are generally classified as either osteolytic, characterized by destruction of normal bone, or osteoblastic, with the deposition of new bone based upon the predominant radiologic appearance. This distinction is not absolute; many patients with bone metastases have both osteolytic and osteoblastic lesions, and individual metastatic lesions can contain both osteolytic and osteoblastic components (table 1).In both types of lesions there is a dysregulation of the normal bone remodeling process (figure 1). - The bone destruction observed in osteolytic metastases is primarily mediated by osteoclasts, and the benefits of osteoclast inhibition are easy to comprehend. In hormone refractory prostate cancer, the rationale for bisphosphonate therapy is still applicable, even though the bone metastases are predominantly osteoblastic (table 1). Nevertheless, fractures do occur, albeit less frequently than in cancers with predominantly osteolytic metastases, and bone resorption rates are typically increased to levels that may exceed those seen in breast cancer and myeloma

Opções para o Tratamento da Metastização Óssea
Radioterapia  Dor Óssea  Complicações Neurológicas Compressão Medular Radioisótopos  Dor Óssea Cirurgia  Cicatrização da Fractura Patológica Cimentoplastia  Estabilidade Analgesia Dor óssea Paliativa Among current tretment options for bone metastases, BPs are the only one shown to reduce the incidende of SREs. Prevenção Terapêutica Óssea  Dor óssea Dirigida  Incidência de SREs Potencial actividade antitumoral

Terapêutica Óssea Dirigida
Monica Fornier, JCO 2010

Indicações Aprovadas para Agentes Anti-Reabsortivos em Oncologia
Indicação Prevenção de SREs HCM Mieloma Múltiplo Cancro Mama Cancro Próstataa Outros Tumores Sólidos Clodronate (oral)  Pamidronate (EV) Ácido Zoledrónic (EV) Ibandronate (oral and EV) Denosumab – Não Zoledronic acid is currently approved for the prevention of SREs in the metastatic breast cancer setting worldwide, including the Middle East and Asia. a In the United States, prostate cancer must have progressed despite hormone therapy.  = Registo Europa  = Registo Generalizado  = Registo EUA Abreviaturas: HCM, hipercalcemia da malignidade; EV, via endovenosa; SRE, complicação esquelética.

Bisfosfonatos B Sato M, et al. J Clin Invest. 1991;88:2095-2105.
bisphosphonates decrease bone resorption and increase mineralization by inhibiting osteoclast activity There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, with somewhat different effects in killing osteoclast cells. The nitrogen containing bisphosphonates are more potent osteoclast inhibitors Exemplo: não nitrogenado: clodronato 3) Bisphosphonates have a direct apoptotic effect on osteoclasts, affect their differentiation and maturation, and thereby act as potent inhibitors of bone resorption. Nitrogenado: pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid Sato M, et al. J Clin Invest. 1991;88:

Mecanismo de Acção dos Bisfosfonatos Nitrogenados (BN)
HMG-CoA BNs inibem a FPP sintase, bloqueando, assim, a prenilação de metabolitos essenciais para a conexão de proteínas necessárias à função e sobrevivência da célula X Mevalonato Geranilpirofosfato + IPP FPP sinthase FPP – farnesil dfosfato sintase Prenilação - Interrupção da via HMG CoA-redutase, a nível de FPPs impede a formação de dois metabólitos (farnesol e geranylgeraniol) que são essenciais para a conexão de algumas pequenas proteínas para a membrana celular. Este fenômeno é conhecido como Prenilação, e é importante para o tráfico de proteína adequada sub-celular - In prostate cancer, it is unclear if bone destruction precedes the development of osteoblastic metastasis or is a consequence of the increased bone formation and remodeling. In vitro and in vivo studies in animal models suggest that zoledronic acid has an inhibitory effect on both osteolytic and osteoblastic prostate cancer metastases Farnesil difosfato (FPP) Ras S GGPP sinthase Geranilgeranil difosfato (GGPP) Rho S Kavanagh et al., PNAS, 2006; Rondeau et al., Chem Med Chem, 2006; Kavanagh et al., JBC, 2006

Bisfosfonatos ✓ Impacto na ocorrência de complicações esqueléticas
Carcinoma da Próstata ✓ Impacto na ocorrência de complicações esqueléticas ✓ Prevenção da ocorrência de metastização óssea ✓Prevenção da perda óssea associada à terapêutica anti- androgénea 3) Prevençao da perda de massa óssea – bifosfonatos estudados – pamidronato, zoladronato, alandronato – diminuem o turnover osseo e aumentam a densidade óssea

AZ Reduz todos os Tipos de SREs vs Placebo aos 2 anos em doentes com Metástases Ósseas no Ca Próstata P = .028 38 26 17 4 6 2 49 33 25 8 7 1 10 20 30 40 50 60 Any SRE Radiation to Bone Fractures Spinal Cord Compression Change in Antineoplastic Therapy Surgery to Bone HCM Zoledronic acid 4 mg (n = 214) Placebo (n = 208) Patients With SRE, % The strongest data supporting benefit for bisphosphonates is with zoledronic acid, which is approved by the United States Food and Drug Administration (FDA) for use in prostate cancer in men with bone metastases who are progressing on hormone therapy. The European Committee for Proprietary Medicinal Products has approved zoledronic acid for all men with prostate cancer and bone metastases. The benefit ofzoledronic acid in men with bone metastases from prostate cancer is supported by a trial in 643 men bone metastases that were progressing while on ADT [13]. Men were randomly assigned to one of two doses of zoledronic acid (4 mg or 8 mg) or placebo, each given every three weeks. The 8 mg dose of zoledronic acid was reduced to 4 mg early in the trial because of excessive renal toxicity At an average follow-up of 24 months, there was a significant reduction in the frequency of SREs in men receiving zoledronic acid compared to placebo (38 versus 49 percent), and the median time to develop an SRE was significantly longer with zoledronic acid (488 versus 321 days) [14]. Pain and analgesic scores were significantly higher in men who received placebo than in those who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups Abreviaturas: HCM, hypercalcemia of malignancy; SRE, skeletal-related event. Saad F, et al. Eur Urol Suppl. 2007;6(11): 21

AZ Reduz o Risco de SREs Independentemente de História Prévia de SRE
Redução Risco P Value Antes da inclusão estudo 0.670 Sem SRE prévio 33% .027 0.603 SRE prévio 40% .028 0.640 População Global do Estudo 36% .002 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Risk Ratio (ZOL 4 mg vs Placebo) Favorece o AZ Favorece o Placebo Abreviaturas: SRE, skeletal-related event; ZOL, zoledronic acid. Saad F, et al. Clin Genitourin Cancer. 2007;5(6): 22

Mean Change From Baseline in BPI Pain Score
AZ Obteve um Melhor Controlo da Dor vs Placebo aos 2 Anos em Doentes com Cancro da Próstata Time on Study, months Mean Change From Baseline in BPI Pain Score Mean n baseline BPI Zoledronic acid 4 mg Placebo 0.2 0.4 0.6 0.8 1 1.2 3 6 9 12 15 18 21 24 a In contrast to these results with zoledronic acid, trials with clodronate have yielded equivocal results [15-17], and two trials with pamidronate have failed to define a statistically significant benefit in terms of SREs or pain contro a P < .05. Abreviaturas: BPI, Brief Pain Inventory.; PC, prostate cancer; ZOL, zoledronic acid Saad F, et al. BJU Int. 2005;96(7): 23

Ácido Zoledrónico: Efeito na Sobrevivência
Median P value ZOL 4 mg 546 d .103 Placebo 469 d No gráfico encontra-se representada a Overall survival of patients who received zoledronic acid or placebo Among patients with bone metastases from prostate cancer or renal cell carcinoma, zoledronic acid significantly delayed the onset and reduced the incidence of skeletal complications compared with placebo. Zoledronic acid is also the only bisphosphonate that has demonstrated a trend toward improved survival and delayed progression of bone lesions in patients with urologic malignancies. Furthermore, zoledronic acid reduced the incidence of pathologic fracture, a skeletal-related event known to be associated with reduced survival. Bisphosphonates have also demonstrated significant palliative benefits, and preclinical evidence indicates that bisphosphonates may have direct anti-tumour effects. AZ aumentou a sobrevivência global em ~ 2.75 meses (p = NS) Time, daysa Doentes, n ZOL 4 mg Placebo a After start of study drug. Abreviaturas: NS, not significant; ZOL, zoledronic acid. Saad F. Cancer Treat Rev. 2008;34(2):

AZ reduz todos os tipos de SREs em doentes com Cancro do Rim ou Bexiga
Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event; ZOL, zoledronic acid. Data from Mulders P, et al. EAU 2007, abstract 971.

Estudo Fase III em Doentes com Metástases Ósseas de Tumores Sólidos (excluindo Ca Mama e Ca Próstata) N = 507 LC and OTS Confirmed bone mets from solid tumors not including BC or PC ECOG PS ≤ 2 No prior BP treatment R 9% doentes (n = 46) com CCR 5% doentes (n = 26) com Ca Vesical Zoledronic acid 4 mg q 3 weeks + Daily oral vitamin D 400 IU and calcium 500 mg Placebo q 3 weeks + Daily oral vitamin D 400 IU and calcium 500 mg Patients were randomized to 4 or 8 mg zoledronic acid. Results are not shown for patients randomized to 8 mg. 9 months Core analysis 21 months Final analysis Abreviaturas: BC, breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; IU, International Units; LC, lung cancer; mets, metastases; OST, other solid tumors; PC, prostate cancer; RCC, renal cell carcinom. Rosen LS, et al. J Clin Oncol. 2003;21(16):

Subgrupo mCCR: AZ Significativamente o Tempo até Progressão da Doença Óssea
Median, days P value ZOL 4 mg Placebo 89 ZOL 4 mg Placebo Abreviaturas: RCC, renal cell carcinoma; ZOL, zoledronic acid. John Wiley & Sons, Inc., from Saad F, et al. BJU Int. 2005;96(7):

Subgrupo mCCR: AZ e Sobrevivência Global
Median, days P value ZOL 4 mg Placebo 216 ZOL 4 mg Placebo Abbreviations: RCC, renal cell carcinoma; ZOL, zoledronic acid. Data from Saad F, et al. BJU Int. 2005;96(7):

Toxicidade Renal no mCCR: Similar entre AZ e Placebo
Doentes, n (%) Evento adversos Ácid Zoledrónico, 4 mg (n = 27) Placebo (n = 19) Hematúria 2 1 Hiperuricémia Insuficiência Renala Dificuldade Micção Oligúria Total 4 (15%) 3 (16%) a Not otherwise specified.. Abreviaturas: mRCC, metastatic renal cell carcinoma; ZOL, zoledronic acid. Reprinted with permission from John Wiley & Sons, Inc., from Saad F, et al. BJU Int. 2005;96(7):

Estudo Fase II em Doentes com Metástases Ósseas por Carcinoma Vesical
Primary endpoint: Proportion of patients who developed ≥ 1 SRE at the 12-mo follow-up Secondary endpoints: Median time to first SRE, pain scores, and overall survival N = 40 Bladder cancer Confirmed bone involvement from primary bladder cancer Adequate liver and kidney function Karnofsky PS ≥ 60 Prior palliative radiotherapya Zoledronic acid 4 mg monthly Placebo Treatment duration: 6 months R Placebo-Controlled Trial; a Either 2 fractions of 650 cGy in 24 hours or 5 fractions of 400 cGy in 4 days (2000 cGy) according to the volume of irradiation and its vicinity to critical structures. Patients were randomized 1 week after radiotherapy . Abreviaturas: PS, performance status; SRE, skeletal-related events Zaghloul MS, et al. Int J Clin Oncol. 2010;15(4):

Proportion of patients, %
Carcinoma Vesical: AZ Prolonga Significativamente a Sobrevivência Global em Doentes com Metástases Ósseas 100 Zoledronic acid Placebo 80 P = .004 60 Proportion of patients, % 40 Observed benefits are potentially through anticancer effects of ZOL ZOL was generally well tolerated (no generalized pain, no local reaction at injection site) 20 8 16 24 32 40 48 56 64 72 Patients at risk, n Time, weeks Placebo Zoledronic acid 20 20 18 20 3 11 9 9 7 4 1 Abreviaturas: OS, overall survival; ZOL, zoledronic acid. Zaghloul MS, et al. Int J Clin Oncol. 2010;15(4):

Denosumab ✗ Anticorpo monoclonal totalmente humano;
Modelo do Denosumab ✗ Anticorpo monoclonal totalmente humano; ✗ Alta afinidade e especificidade → RANK ligand ✗ Não detectados anticorpos neutralizadores nos estudos clínicos ✗ Administração SC The potential utility of denosumab for the prevention of osteoporosis in men with nonmetastatic, hormone-sensitive prostate cancer was demonstrated in a double-blind, trial in which 1468 men were randomly assigned to denosumab (60 mg subcutaneously every six months) or placebo [39,40]. Overall, 912 patients (62 percent) completed the three year trial. Data from Bekker PJ, et al. J Bone Miner Res. 2004;19(7): ; Elliott R, et al. Osteoporos Int. 2007;18(suppl 1):S54. Abstract P149; McClung MR, et al. N Engl J Med. 2006;354(8):

RANK Ligand is expressed by osteoblasts and promotes bone resorption
Mecanismo de Acção do Denosumab RANK Ligand is expressed by osteoblasts and promotes bone resorption Pre-fusion osteoclast Multinucleated osteoclast Hormones Growth factors Cytokines Activated osteoclast RANK ligand is an essential mediator for osteoclast formation, function and survival in both cortical and trabecular bone throughout the skeleton. RANK ligand is expressed (both in a transmembrane and soluble form) from the osteoblast cells. RANK ligand subsequently binds to its receptor, RANK, on immature and mature osteoclasts, which leads to maturation of pre-fusion osteoclasts to multinucleated osteoclasts, and finally to activated osteoclasts. RANK is another member of the tumour necrosis factor (TNF) receptor family and is expressed on osteoclasts and osteoclast progenitors. Growth factors, hormones and cytokines include: tumour necrosis factor-alpha (TNF-) parathyroid hormone-related peptide (PTHrP) parathyroid hormone (PTH) interleukins-1, -6 and -11 (IL-1, IL-6, IL-11) prostaglandin E2 (PGE2). References Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004;292:490–5. Osteoblasts Bone formation Bone resorption Adapted from Boyle WJ et al. Nature 2003;423:337–42. = RANK; = RANK ligand CFU-GM, colony forming unit granulocyte macrophage; RANK, receptor activator of nuclear factor κ B

RANK Ligand inhibition with denosumab
Mecanismo de Acção do Denosumab RANK Ligand inhibition with denosumab Osteoclast formation inhibited Pre-fusion osteoclast Osteoclast function and survival inhibited Hormones Growth factors Cytokines The discovery of the RANKL/RANK/OPG pathway and its implications for the pathogenesis of osteoporosis provides a molecular target for new therapies to improve bone health. Inhibition of RANK ligand offers the advantage of mimicing the endogenous pathway for inhibiting the formation, function and survival of osteoclasts. RANK ligand is an essential mediator in the formation, activation and survival of osteoclasts.1 OPG sequesters free RANK ligand thus preventing its binding to the RANK receptor.1 A suitable therapy for osteoporosis would: Mimic the activity and binding specificity of OPG for RANK ligand Be recognized by the body as ‘self’ Not be regulated by the normal bone homeostasis pathways. Reference 1. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. Osteoblasts Bone resorption inhibited Bone formation Boyle WJ et al. Nature 2003;423:337–42. = OPG; = RANK; = RANK ligand; = RANK ligand inhibition OPG, osteoprotogerin; RANK, receptor activator of nuclear factor κ B

Estudos de Fase III de Denosumab em Doentes com Metástases Ósseas
Prostate cancer (n = 1870) Breast cancer (n = 2046) Solid tumor & MM (n = 1776) R A N D O M I S A T I O N Key inclusion Adults with confirmed bone metastases from advanced cancer Key exclusion Current or prior intravenous bisphosphonate Denosumab 120 mg SC Q4W + Placebo IV Q4W Supplemental calcium and vitamin D Zoledronic acid 4 mg IV Q4W + Placebo SC Q4W Endpoint primário : - Tempo até ocorrência de 1º SRE no estudo MM, multiple myeloma

Risk reduction favours
A Redução do Risco de Ocorrência do 1º SRE Favoreceu Consistentemente o Denosumab 18% P = 0.01 P = 0.008 16% P = 0.06 17% P < Risk reduction P value (superiority) Breast cancer1 Prostate cancer2 Solid tumours + multiple myeloma3 Denosumab consistently reduced risk of first SRE across different tumour types. 18% risk reduction over zoledronic acid in patients with breast cancer (P = 0.01).1 18% risk reduction over zoledronic acid in patients with prostate cancer (P = 0.008).2 16% risk reduction over zoledronic acid in patients with solid tumours and multiple myeloma (P = 0.06).3 17% risk reduction over zoledronic acid in the integrated analysis combining data from all three studies (P < ).4 References Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9. 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;377:813–22. Henry DH, Costa L, Goldwasser F et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:112532. Lipton A, Siena S, Rader M et al. Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials [Abstract 1249P]. Ann Oncol 2010;21(Suppl 8):viii379. Integrated analysis4 0.5 1.0 0.5 2.0 Risk reduction favours Zoledronic acid Denosumab 1. Stopeck AT et al. J Clin Oncol 2010;28:5132–9; 2. Fizazi K et al. Lancet 2011;377:813–22; 3. Henry DH et al. J Clin Oncol 2011;29:112532; 4. Lipton A et al. Ann Oncol 2010;21(Suppl 8):viii379 [Abstract 1249P]. 36

Proportion of Patients Without SRE
Denosumab Atrasa Significativamente a Ocorrência do 1º SRE vs Ácido Zoledrónico 1.00 Risk Reduction HR = 0.82 (95% CI = 0.71, 0.95) P = (Non-inferiority) P = .008 (Superiority) 0.75 18% 0.50 Proportion of Patients Without SRE KM Estimate of Median Months 0.25 Denosumab Zoledronic acid 20.7 17.1 3 6 9 12 15 18 21 24 27 Patients at risk Study Month Zoledronic acid Denosumab 951 950 733 758 544 582 407 472 299 361 207 259 140 168 93 115 64 70 47 39 Abreviaturas: CI, confidence interval; HR, hazard ratio; SRE, skeletal-related event. Reprinted from Fizazi K, et al. ASCO 2010, abstract LBA4507.

21-month cut-off (event-driven analysis)
Denosumab vs Ácido Zoledrónico em Tumores Sólidos e Mieloma Múltiplo (excepto Ca Mama e Próstata) Solid tumor (other than breast or prostate cancer) or multiple myeloma M/F ≥18 years of age ≥ 1 bone metastasis or osteolytic lesion ECOG PS 0, 1, or 2 Adequate organ function Dmab 120 mg SC + placebo IV infusion q4wk (n = 886) R ZOL 4 mg IV + placebo SC injection q4wk (n = 890) N = 1,776 21-month cut-off (event-driven analysis) n = 155 with CCR Primary endpoint: Time to first on-study SRE (non-inferiority) Secondary endpoints: Time to first on-study SRE (superiority), time to first and subsequent on-study SREs (superiority), changes in laboratory values, safety, incidence of formation of anti-Dmab antibodies Abreviaturas: Dmab, denosumab; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; M/F, male/female; q4wk, every 4 weeks; RCC, renal cell carcinoma; SC, subcutaneous; SRE, skeletal-related event; ZOL, zoledronic acid. Henry D, et al. ECCO/ESMO 2009, abstract 20LBA.

Proportion of Patients Without SRE KM estimate of median months
Tempo até 1º SRE em doentes com Tumores Sólidos (excepto Carcinoma da Mama e Próstata) 1.00 Primary: HR = 0.84 (95% CI = 0.71, 0.98) P = (Non-inferiority) Secondary: Unadjusted P = .03 Superiority Adjusted P = .06 0.75 Proportion of Patients Without SRE 0.50 KM estimate of median months 0.25 Dmab ZOL 20.6 16.3 3 6 9 12 15 18 21 24 Study month Subjects at risk ZOL Dmab 890 886 578 582 376 387 261 266 194 202 126 134 86 96 47 55 Abreviaturas: CI, confidence interval; Dmab, denosumab; HR, hazard ratio; KM, Kaplan-Meier; SRE, skeletal-related event; ZOL, zoledronic acid. Henry D, et al. ECCO/ESMO 2009, abstract 20LBA.

Proportion of Subjects Surviving Proportion of Subjects Surviving
Sobrevivência Global e Progressão da Doença em Tumores Sólidos (excepto Carcinoma da Mama e Próstata) Dmab ZOL Dmab ZOL 1.00 1.00 0.75 0.75 Proportion of Subjects Surviving 0.50 Proportion of Subjects Surviving 0.50 0.25 0.25 HR = (95% CI = 0.83, 1.08) P = .43 HR = 1.00 (95% CI = 0.89, 1.12) P = 1.0 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27 Months Study month Subjects at risk Subjects at risk ZOL 890 727 540 410 343 232 176 118 64 ZOL 890 565 356 248 189 136 98 66 34 Dmab 886 726 557 420 340 247 182 127 66 Dmab 886 563 352 235 173 127 96 60 26 Abreviaturas: CI, confidence interval; Dmab, denosumab; HR, hazard ratio; ZOL, zoledronic acid. Henry D, et al. ECCO/ESMO 2009, abstract 20LBA.

Segurança: Denosumab vs Ácido Zoledrónico
Zoledronic Acid (n = 878) (%) Denosumab (n = 878) (%) Efeitos adversos infecciosos 349 (39.7) 358 (40.8) Efeitos adversos infecciosos graves 118 (13.4) 128 (14.6) Reacção de fase aguda (primeiros 3 dias) 127 (14.5) 61 (6.9) Toxicidade renal 96 (10.9) 73 (8.3) Insuficiência Renal 25 (2.8) 20 (2.3) Insuficiência Renal Aguda 16 (1.8) 11 (1.3) Taxa cumulativa de Osteonecrose Mandíbula 10 (1.1) Ano 1 Ano 2 5 (0.6) 8 (0.9) 4 (0.5) 2º Tumor Primário 3 (0.3) Hipocalcémia 49 (5.6) 93 (10.6) Abreviaturass: AE, adverse event; ONJ, osteonecrosis of the jaw; ZOL, zoledronic acid. Henry D, et al. ECCO/ESMO 2009, abstract 20LBA.

Estudos em Curso no Carcinoma da Próstata
Questão Recrutamento ZEUS AZ pode reduzir a ocorrência de metástases ósseas nos doentes de alto risco M0 disease ± ADT? 1.433 RADAR AZ pode melhorar a sobrevivência livre de recorrência combinado com ADT a curto ou médio prazo? 1.071 STAMPEDE AZ pode melhorar a sobrevivência livre de recorrência combinado com ADT? 3.300a AMG 147 Dmab pode atrasar o tempo até ocorrência de metástases ósseas ou morte? 1.435 a Planned enrollment. Current enrollment is at 1,469 patients. Abreviaturas: ADT, androgen-deprivation therapy; AMG, Amgen; Dmab, denosumab; ZOL, zoledronic acid.

ZEUS: Ácido Zoledrónico na prevenção de Metástases Ósseas no Carcinoma da Próstata
Primary endpoint: Time to bone metastases Secondary endpoints: Overall survival, PSA doubling time, substudies on bone markers, adverse events N = 1,433 Prostate cancer, M0 ± previous local curative treatment, ± ADT High-risk PC with ≥ 1 of the following criteria: Gleason Score 8-10 pN+ PSA  20 at diagnosis R Zoledronic acid 4 mg q 3 months No zoledronic acid Treatment duration: 4 years Accrual complete Abreviaturas: ADT, androgen-deprivation therapy; PC, prostate cancer; PSA, prostate-specific antigen.

Prevenção de Metástases Ósseas no Carcinoma da Próstata: Estudo de Fase III (AMG 147)
Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) R Prostate cancer (nonmetastatic) Hormone-refractory disease High risk of bone metastases Adequate organ function N = 1,435 Denosumab 120 mg SC every 4 weeks Placebo Event-driven study: time to bone metastasis or death Data expected 2011 Abreviaturas: AMG, Amgen; PC, prostate cancer; SC, subcutaneous. 45

Tratamento Médico das Metástases Ósseas
Alvo Tratamento Endpoints Tumor cell Agentes Citotóxicos Agentes Endócrinos Novos Agentes Remissão objectiva (critérios WHO, UICC) Tempo até progressão Sobrevivência Osteoclast Bisfosfonatos Denosumab Complicações (SREs) Controlo da dor Survival?

Conclusões Doença óssea metastática e SREs são eventos com grande impacto nos doentes com doença oncológica SREs estão associados a ↑ morbilidade e↓ qualidade de vida Fracturas ósseas podem ↓ sobrevivência Opções terapêuticas médicas actuais para ↓ risco de SREs: Bisfosfonatos Denosumab Perfil de toxicidade: Bisfosfonatos: bem definido; geralmente bem tolerado Denosumab: desconhecidos a longo prazo

Conclusões Preclinical data suggest ZOL may impede tumor progression
Inhibiting tumor cell invasion/migration, inducing apoptosis, and enhancing host antitumor immune respons Clinical data in patients with GU malignancies suggest that adding ZOL to standard care Inhibits disease progression Improves overall survival In addition to maintaining bone health, ZOL has potential anticancer activity Clinical trials to explore and clarify the anticancer activity of bone-targeted agents in this patient population is ongoing Abbreviations: GU, genitourinary; NTX, N-telopeptide of type I collagen; PC, prostate cancer; ZOL, zoledronic acid.

Bisphosphonate Therapy: Potential Mechanisms for Improved Outcomes
Bisphosphonates  Skeletal-related eventsa Anticancer effects  Therapy options (preservation of function)  Mortality associated with skeletal-related events Anticancer effects in bone microenvironment Effects on cancer cells (alone or with chemotherapy) Improved disease outcomes Delayed disease progression Prolonged survival a Zoledronic acid has also demonstrated activity in preventing bone loss in women with hormone-sensitive early breast cancer receiving endocrine therapy.

Smith MR, et al. N Engl J Med. 2009;361:745-755.
Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer Smith MR, et al. N Engl J Med. 2009;361:

Study Schema Denosumab 60 mg SC Q6M ( 6 doses) (n=734)
Design: Randomised, double-blind, placebo-controlled, multicentre Study protocol amended from 2 to 3 years to extend period for safety and fracture evaluation Men with nonmetastatic prostate cancer receiving continuous ADT (n=1468) Stratified by Age (<70 y vs 70 y) Prior ADT duration (6 mo vs >6 mo) Denosumab mg SC Q6M ( 6 doses) (n=734) R A N D O M I S E Placebo SC Q6M ( 6 doses) (n=734) Baseline 36 months This is a randomized, double-blind, placebo-controlled, multicenter study conducted in the United States, Canada, Mexico, and Europe of denosumab in 1468 men receiving ADT for hormone-sensitive, nonmetastatic prostate cancer. Background An equal number of patients were randomized to: SC denosumab 60 mg via 1 mL injection every 6 months (n = 734) Placebo every 6 months (n = 734) All patients were instructed to take daily supplements of ≥1 g of calcium and ≥400 IU of vitamin D. In July 2006, the study protocol was amended from 2 to 3 years to extend the treatment period for safety and fracture evaluation. Exploratory end points included: percent changes in BMD of the whole body and distal ⅓ radius, and changes over time in levels of PSA and markers of bone turnover. End points Primary Percentage change from baseline at month 24 in lumbar spine BMD Secondary Incidence of new vertebral fractures over 36 months Percentage change from baseline at month 36 in lumbar spine BMD Percentage change from baseline at 24 and 36 months in total hip and femoral neck BMD Fracture at any site (morphometric/clinical vertebral or nonvertebral) Time to first clinical fracture Safety events Supplemental calcium and vitamin D Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361: Smith MR, Egerdie B, Toriz NH, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med Aug 11. [Epub ahead of print]. doi: /NEJMoa

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