CPRC: enfoque terapéutico de la enfermedad ósea. Javier Cassinello, Hospital Universitario de Guadalajara

Transcripción

1 CPRC: enfoque terapéutico de la enfermedad ósea Javier Cassinello, Hospital Universitario de Guadalajara

2 AGENDA I Importancia del problema II Prevención o retraso de EREs en CPRC con metástasis óseas III Fármacos aprobados en CPRC con actividad sobre las metástasis óseas: son suficientes o es conveniente su combinarlos con los agente dirigidos al hueso? IV Prevención o retraso de metástasis óseas en CPRC

3 Bone Metastases Very Common in Prostate Cancer Estimated incidence (%) 1,a Myeloma Renal Melanoma Bladder 40 Thyroid 60 Lung Breast Prostate It is estimated that > 350,000 people die with bone metastases annually in the USA. 2 a Incidence of bone metastases at autopsy. Bone metastasis occurs in most prostate cancer patients during the natural course of their disease and typically targets the lumbar spine, vertebrae, and pelvis Coleman R. Cancer Treatment Rev. 2001;27: ; 2. Mundy G. Nat Rev Cancer. 2002;2: ; 3. Bubendorf L, et al. Hum Pathol. 2000;31:

4 Incidencia de complicaciones óseas (ERES) en Ensayos clínicos (%) Breast cancer 68 Multiple myeloma 51 Prostate cancer 49 Lung cancer/others Patients with SREs (%)* *Placebo arm of pamidronate or zoledronic acid randomized trials; 24 months; 21 months. Coleman RE. The Oncologist. 2004;9(suppl 4):14-27.

5 Skeletal-Related Events: A Serious Threat Requirement for surgery to bone Osteolytic lesion requiring palliative radiotherapy Vertebral collapse 33% 4% 8% 25% Pathologic fracture 5

6 Development of bone metastases in castration-resistant prostate cancer may be associated with increased mortality 56% No bone mets Bone mets 3% 5 year survival rate in patients without bone metastasis was 56% compared to 3% with bone metastasis 1. Nørgaard M et al. (2010) J Urol 184:162 n= 23,087 with median follow-up of 2.2 years (Danish National Patient Registry) BMFS (Jan2012) Sathiakumar N, et al Prostatic Dis 2011; 14:

7 Bone metastases in prostate cancer have a significant impact on healthcare costs Healthcare costs (US) in patients with prostate cancer: Increased costs due to treatment of metastatic disease and occurrence of SREs *1 Incremento > 100% Development of bone metastasis is associated with increased health resource utilization which leads to greater costs in: Hospital inpatient care Outpatient care including physician visits Outpatient pharmacy These costs are conservative, and do not include newer therapies A separate study demonstrated a 91% increase in the risk of hospitalization after development of bone mets 2 Preventing development of bone metastases in prostate cancer patients would result in substantial reduction of costs *Footnote: Retrospective cohort study of 215,702 PC patients using claims data from large, US health insurance plans between Oct 2002 and Dec Primary measure was total healthcare costs after bone metastases, secondary measures included components of total healthcare costs 1. Data on file, 2011; 2. Oglesby et al BMFS (Jan2012)

8 Costes en España de EREs (SRE) 2010 Radioterapia sobre hueso Cirugía ósea Fractura patológica Compresión medular N=93; 31 cáncer de mama: ; 21 cáncer de próstata; 41 cáncer de pulmón Durán I, Garzón C, Sánchez A, et al. Cost analysis of skeletal-related events in Spanish patients with bone metastases from solid tumours. Clin Transl Oncol 2014; 16:

9 I Tratamiento de las metástasis óseas Bisfosfonatos (Ac Zoledrónico) Denosumab Radioemisor de partículas alfa Radioterapia, Analgésicos, Cirugía ortopédica, etc.

10 DENOSUMAB BIFOSFONATOS Fornier MN et al. J Clin Oncol 2010;28:

11 BIFOSFONATOS PREVENCIÓN DE ERE Rosen LS et al. J Clin Oncol 2003:21: ZOL reduce el riesgo de ERE y retrasa su aparición Útiles en el control del dolor óseo Rosen LS et al. Cancer 2003;98: Eficacia en el tratamiento de la hipercalcemia Saad F et al. J Natl Cancer Inst 2004;96: Sin diferencias en SG

12 Ác. Zoledrónico en pacientes con metástasis óseas y cáncer de próstata sensible a castración CALGB N=645 ADT Zoledrónico Placebo Seguimiento 24 m NO diferencias en el tiempo al primer ERE ( 32.5 vs 29.8 m, HR 0.96) NO diferencias en SG ( HR 0.89, IC 95% ) Smith MR, HalabiS, Ryan CJ, et al. J Clin Oncol 2013; 31: ABSTRACT 27

13 CÍRCULO VICIOSO EN CÁNCER METASTÁSICO Célula tumoral Precursores del osteoclasto RANKL RANK OPG PTHrP, IL-1 IL-6, PGE2, TNFα, M-CSF PDGF, BMP, TGF-β, IGF, FGF Ca +2 Osteoclasto activado Osteoblastos RANKL, ligando del receptor activador del factor nuclear κb; RANK, receptor activador del factor nuclear κb; OPG, osteoprotegerina Adaptado de Boyle WJ et al. Nature 2003; 423:

14 DENOSUMAB BIFOSFONATOS Fornier MN et al. J Clin Oncol 2010;28:

15 ESTUDIO 103 The Lancet Febrero 2011

16 Proportion of Subjects Without SRE Time to First On-Study SRE SREs-met Prostate ( ) 1.00 HR 0.82 (95% CI: 0.71, 0.95) P = (Non-inferiority) P = (Superiority) 18% Risk Reduction Denosumab Zoledronic acid KM Estimate of Median Months Subjects at risk: Study Month Zoledronic Acid Denosumab Fizazi K. et al. J Clin Oncol 28:7s, 2010 (suppl. ASCO 2010). Abstract LBA4507 and Oral Presentation

17 Cumulative Mean Number of SREs per Patient Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) SREs-met Prostate ( ) Rate Ratio = 0.82 (95% CI: 0.71, 0.94) P = % Risk Reduction *Events occurring at least 21 days apart Study Month Events Denosumab 494 Zoledronic acid Fizazi K. et al. J Clin Oncol 28:7s, 2010 (suppl. ASCO 2010). Abstract LBA4507 and Oral Presentation

18 2-year Extended Analysis: Safety Summary 1 Phase No new safety signals were observed during open-label denosumb treatment Among patients who switched from zoledronic acid to denosumab a similar pattern and frequency of AEs was observed as in those who continued with denosumab The cumulative incidence of ONJ was 3.8% among denosumab/ denosumab patients when administered for up to 5.6 years 2.2% among patients who switched to denosumab with prior exposure to zoledronic acid for up to 3.4 years No neutralizing anti-denosumab antibodies were detected in either group Fizazi K, Brown JE, Carducci M. et al. ESMO 2012: abstract 937P and poster presentation.

19 Pain Interference: Summary 2 Phase Denosumab demonstrated consistent improvement in pain interference compared with zoledronic acid In the responder analysis of patients with no or mild pain at baseline, relative improvements were approximately twofold that reported for the full study group Fewer patients in the denosumab group shifted to strong opioid use during the course of the study The impact of treatment was greater on pain interference with activity than on pain interference with affect Patrick D, Cleeland C, Fallowfield L, et al. AUA 2011: abstract MP23 and poster presentation.

20 NNT: Summary 3 Phase Denosumab has a favorable NNT profile compared with zoledronic acid or placebo For first SRE vs. zoledronic acid, NNT=10 For multiple SREs vs. zoledronic acid, NNT=5 For first SRE vs. placebo, NNT=3 These low NNT values demonstrate the high therapeutic efficacy of denosumab Miller K, Fizazi K, Smith M, et al. AUA 2011: abstract 648 and oral presentation.

21 GUIAS ESMO 2014

22 GUIAS ESMO 2014 A: unánimemente recomendado B: generalmente recomendado

23 Agentes aprobados para hueso β-emitters Bisphosphonates Osteoclast inhibitor Strontium-89; 1 Zoledronic acid 3 6 Denosumab 6,7 Samarium Proven impact on pain Proven impact on SREs Proven impact on overall survival Key safety issues NO NO NO Bone marrow suppression Fatigue, anemia; Rare but serious: osteonecrosis of the jaw Hypocalcemia; Rare but serious: osteonecrosis of the jaw 1. Lewington et al. Eur J Cancer 1991;27: Sartor et al. Urology 2004;63: Saad et al. J Natl Cancer Inst 2002;94: Saad et al. J Natl Cancer Inst ;96: Smith et al. J Urol 2003;169: Fizazi et al. Lancet 2011;377: Smith et al. N Engl J Med 2009;361:

24 223 Ra ( Radium-223) Emisor alfa Afinidad ósea por su parecido al Calcio

25 ALSYMPCA: Fase III Diseño Randomized 2:1 and stratified by total ALP (< vs 220 U/L), bisphosphonate use (yes vs no), and previous docetaxel (yes vs no) Patients with: Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel (N = 921) Radium kbq/kg + Best Standard of Care Placebo (saline) + Best Standard of Care 6 injections at 4-wk intervals Planned follow-up: 3 yrs Clinicaltrials.gov. NCT Parker C, et al ASCO GU Cancers Symposium. Abstract 8.

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27 3.6 m

28 7.8 m

29 Conclusiones Radium-223: de la paliación al aumento de supervivencia Radium-223 es el primer radiofármaco alfa aprobado para el CPRC con metástasis óseas sintomáticas Radium-223 aumenta la supervivencia global y retrasa la aparición de complicaciones óseas Está indicado tanto en pacientes que ya hayan recibido docetaxel como en aquellos no aptos, frágiles o que hayan rechazado su uso

30 Radium-223 has now been in november 15, 2013 approved by the European Commission

31 Nuevos datos con Radium-223 Oliver Sartor, et al Lancet Oncology 2014: 15: Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention.

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34 Mayor eficacia en 2 EREs: Disminución de RT y de compresión medular NO reduce con significación estadística -el riesgo de fractura patológica -la necesidad de cirugía ortopédica

35 Seguridad de Rsdium-223 a largo plazo ASCO 2014 Abs # 5070

36 Objetivo primario: respuestas por bone scan a 24 semanas de BSLA (bone scan lesion area, medición cuantitativa similar a RECIST Objetico secundario: testar la combinación de Radium-223, abiraterona y enzalutamida

37 Changing treatment paradigm for ADT Suppression of gonadal androgens by medical or surgical castration 1 mcrpc Cabazitaxel EMA approved in 2011 for hormone-refractory metastatic prostate cancer previously treated with docetaxel s Docetaxel FDA and EMA approved for treatment of hormone-refractory metastatic prostate cancer 2,3 *Not approved in Europe. ADT=androgen-deprivation therapy; EMA=European Medicines Agency; FDA=Food and Drug Administration; mcrpc=metastatic castration-resistant prostate cancer. 1. Higgins C, et al. Arch Surg 1941;43: Taxotere (docetaxel). Prescribing information. April Taxotere (docetaxel). Summary of product characteristics. August Provenge (sipuleucel-t). Prescribing information. June EMA Press release 28 June Last accessed September Sipuleucel-T FDA and EMA approved for treatment of asymptomatic or minimally symptomatic mcrpc 4,5 Abiraterone EMA approved for treatment of men with mcrpc previously treated with docetaxel 7 6. Jevtana (cabazitaxel). Summary of product characteristics. September Zytiga (abiraterone). Summary of product characteristics. August Xofigo (radium 223). Prescribing information. May Xtandi (enzalutamide). Summary of product characteristics. July Xtandi (enzalutamide). Prescribing information. August Enzalutamide FDA and EMA approved in 2012 and 2013 for treatment of men with mcrpc previously treated with docetaxel 9,10

38 Tiempo hasta al aparición del 1er evento esquelético COU-AA-301 AFFIRM TROPIC ALSYMPCA 25 meses vs 20,3 meses 16,7 meses vs 13,3 meses No evaluado 15.6 meses vs 9,8meses HR=0,615 HR=0,69 No evaluado HR=0,66 P=0,0001 P<0,001 No evaluado P = 0,00037 Logothetis et al. Lancet Oncol 2012: 2012; 13: ; Bahl et al. Cancer Treat Rev Feb;40(1):170-7; Scher et al. N Engl J Med 2012;367:

39 Abiraterona: Retraso en la aparición de eventos esqueléticos y mejoría del dolor en 2ª línea Eventos óseos en el CaP: - Fractura patológica - Compresión medular - RT paliativa - Cirugía ósea

40 Tiempo para SRE Una proporción menor de pacientes tiene SRE a los 6, 12 y 18 meses en el grupo de abiraterona + prednisona versus placebo + prednisona La tasa global de SREs ajustada para la duración de la exposición al tratamiento fue menor en el grupo de abiraterona Abiraterona + Prednisona Placebo + Prednisona 6 meses libres de eventos 82.2% 72.1% 12 meses libres de eventos 71.1% 59.1% 18 meses libres de eventos 63.3% 57.2% Logothetis et al. Lancet Oncol 2012: 2012; 13:

41 Uso concomitante de abiraterona con terapias dirigidas al hueso (TDH) en población general: COU-AA-302 TDH Abiraterona/PDN (n=546) PDN (n=542) Total (N=1088) Ácido zoledrónico 172 (31.5%) 158 (29.2%) 330 (30.3%) Otros bifosfonatos 7 (1.3%) 8 (1.5%) 15 (1.4%) Denosumab 16 (2.9%) 6 (1.1%) 22 (2.0%) Otros TDH 2 (0.4%) 3 (0.6%) 5 (0.5%) Cortesía Dr Joan Carles Saad et al. Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mcrpc) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).ASCO 2013

42 Impacto de uso concomitante de Abiraterona con terapias dirigidas al hueso (TDH) en población general: COU-AA-302 Objetivo Sí TDH, meses (95% IC) No TDH, meses (95% IC) Hazard ratio (95% IC) p SLPr ( ) ( ) ( ) SG NE (30.88-NE) ( ) ( ) Tiempo para opiáceos Tiempo para quimioterapia Tiempo para ECOG PS Tiempo para progresión PSA NE (27.63-NE) 27.86( ) 0.801( ) ( ) 21.06( ) 0.916( ) ( ) 11.07( ) 0.750( ) < ( ) 8.31 ( ) 0.878( ) Cortesía Dr Joan Carles Saad et al. Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mcrpc) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).ASCO 2013

43 Impacto de uso concomitante de Abiraterona con terapias dirigidas al hueso (TDH) en población general: COU-AA-302 Objetivo Sí TDH, meses (95% IC) No TDH, meses (95% IC) Hazard ratio (95% IC) p SLPr ( ) ( ) ( ) SG NE (30.88-NE) ( ) ( ) Tiempo para opiáceos Tiempo para quimioterapia Tiempo para ECOG PS Tiempo para progresión PSA NE (27.63-NE) 27.86( ) 0.801( ) ( ) 21.06( ) 0.916( ) ( ) 11.07( ) 0.750( ) < ( ) 8.31 ( ) 0.878( ) Cortesía Dr Joan Carles Saad et al. Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mcrpc) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).ASCO 2013

44 II Prevención del desarrollo de metástasis óseas en el cáncer de próstata MR Smith, F Saad, R Coleman et al Lancet 2012; 379: 39-46

45 Prostate cancer Prevention/delay bone metas. Prostate ( ) Randomized, Double-Blind, Placebo-controlled, Phase 3 trial Key Eligibility Criteria Histologically-confirmed prostate cancer No prior or current radiographic evidence of bone metastasis Hormone refractory with PSA > 8 or PSA doubling time < 10 months No prior IV bisphosphonate use E N R O L L M E N T N = 1400 Denosumab 120 mg SC Q4W Placebo E N D O F S T U D Y Screening/Enrollment Treatment Period Primary Objective Efficacy of denosumab compared to placebo to prolong bone metastasis-free survival Secondary Objectives To compare the treatment effect of denosumab with placebo on: time to first bone metastasis excluding deaths overall survival EOS * Accessed, 13/May/2010 Event Driven. * End Of Study, Q4W: every 4 weeks. SC, subcutaneous; IV, intravenous

46 Eligibility criteria Key inclusion criteria Men with castration-resistant prostate cancer Total serum testosterone level 50 ng/dl High risk for development of bone metastasis PSA value 8.0 µg/l within 3 months before randomisation, And/or PSA doubling time 10.0 months Key exclusion criteria Radiographically detectable bone metastasis Any metastatic involvement of distant organs (lymph node metastases acceptable) IV bisphosphonate administration History or evidence of osteonecrosis or osteomyelitis of the jaw PSA, prostate-specific antigen; IV, intravenous. Smith MR, et al. Lancet 2012;379: Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting.

47 Proportion of patients The primary endpoint was met: denosumab demonstrated improved bone metastasis-free survival HR 0.85 (95% CI, ); P = % risk reduction Number at risk Denosumab Placebo Denosumab Placebo Median survival (months) Events Month Smith MR, et al. Lancet 2012;379: Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting.

48 Proportion of patients Denosumab demonstrated improved time to symptomatic bone metastasis* 1.0 HR 0.67 (95% Cl, ) P = % risk reduction Number at risk Denosumab Placebo Denosumab Placebo Events Month *Bone metastases that were symptomatic at the time of radiological detection. Smith MR, et al. Lancet 2012;379: Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting.

49 Proportion of patients An overall survival benefit was not demonstrated 1.0 HR 1.01 (95% Cl, ) P = Number at risk Denosumab Placebo Denosumab Placebo Month Smith MR, et al. Lancet 2012;379: Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting.

50 Relative Risk for Bone Metastasis or Death Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death PSA DT eligibility criteria Median PSA DT at study entry Post hoc analyses of sub-groups of Product A data were conducted in patients with shorter PSA doubling time 1.4 Placebo arm, N = PSA Doubling Time in Months Placebo arm of the Denosumab study demonstrates shortening PSA doubling time as a predictor of increasing risk for bone metastases development In a separate study, PSA was a key risk factor for bone metastasis and a PSADT 6 months was significantly associated with shorter bone metastasis-free survival 1 Smith et al (2005)

51 Relative Risk for Bone Metastasis or Death Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death PSA DT eligibility criteria Median PSA DT at study entry Post hoc analyses of sub-groups of Product A data were conducted in patients with shorter PSA doubling time 1.4 Placebo arm, N = PSA Doubling Time in Months Placebo arm of the Denosumab study demonstrates shortening PSA doubling time as a predictor of increasing risk for bone metastases development In a separate study, PSA was a key risk factor for bone metastasis and a PSADT 6 months was significantly associated with shorter bone metastasis-free survival 1 Smith et al (2005)

52 Denosumab is markedly effective at prolonging bone metastasis free survival in patients with shorter PSA doubling times Population Median BMFS time: Placebo (mo) Median delay to bone met: Product A (mo) Crude incidence reduction (%) Hazard Ratio P-value Overall (N = 1,432) 10 month PSA DT (~80% of pop) 6 month PSA DT (~60% of pop) 4 month PSA DT (~40% of pop) The median bone metastasis free survival continues to improve with increasing risk (as determined by reducing PSA doubling time)

53 Summary The first large randomised study to demonstrate that targeting the bone microenvironment can prevent bone metastasis in men with prostate cancer Denosumab significantly increased bone metastasisfree survival and time to symptomatic bone metastasis Overall adverse events were similar between groups Denosumab was associated with increased incidence of osteonecrosis of the jaw and hypocalcaemia vs placebo This study provides clinical evidence for the important role of the bone microenvironment and RANKL signaling in the development of bone metastases in men with prostate cancer RANK, receptor activator of nuclear factor κ B ligand. Smith MR, et al. Lancet 2012;379: Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting.

54 GUIAS ESMO 2014 A: unánimemente recomendado B: generalmente recomendado

55 Nuevos agentes en el CPRC con metastasis óseas Cabozantinib es un nuevo inhibidor tirosin-quinasa que inhibe el c-met, el factor de crecimiento hepatocitario y VEGFR-2, receptor del factor de crecimiento vásculo-endolelial 2. 2 estudios fase III en marcha: el COMET-2 (CabOzantinib MET Inhibition CRPC Efficacy Trial) que enfrenta cabozantinib con mitoxantrone y prednisona y que ya ha demostrado cumplir un objetivo principal de reducción del dolor [ClinicalTrials.gov: NCT ]; y el COMET-1, [ClinicalTrials.gov identifier: NCT ], DC Smith, et al J Clin Oncol 2013; 31(4): Dasatinib es un inhibidor de tirosinquinasa que actúa sobre Src, mediador de actividad osteoclástica, del crecimiento tumoral y del desarrollo de metástasis Araujo DC, et al Cancer 2012; 118:63-71

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58 Pendiente de los fases III COMET-1 y COMET-2 Conclusions: Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans and reductions in bone turnover markers, pain and narcotic use

59 Conclusiones enfermedad óseas en CPRC 1. Denosumab más eficaz que ácido zoledrónico en la prevención de EREs 2. Radium-223 retrasa el desarrollo de EREs y aumenta la supervivencia en pacientes con sólo metástasis óseas sintomáticas. 3. Los agentes aprobados en CPRC también reducen o retrasan los EREs, si bien datos iniciales favorecen su combinación con las terapias dirigidas al hueso. 4. Denosumab retrasa el desarrollo de metástasis óseas en pacientes con CPRC de alto riesgo ( PSADT < 10 ó menos meses)

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64 Proportion of patients Secondary endpoint was met: denosumab demonstrated improved time to first bone metastases HR 0.84 (95% Cl, ) P = % risk reduction Number at risk Denosumab Placebo Denosumab Placebo Median time (months) Month Events Smith MR, et al. Lancet 2012;379: Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting.

65 Conclusiones Radium-223: de la paliación al aumento de supervivencia Radium-223 presenta un excelente perfil de seguridad, lo que permite estudiar su combinación con otros agentes terapéuticos en el CPRC Radium-223 ha sido aprobado el 15 de noviembre de 2013 por la EMA para el tratamiento del CPRC con metástasis óseas sintomáticas

66 Conclusions from ALSYMPCA In CRPC patients with bone metastases Radium Ra 223 dichloride significantly prolonged overall survival 14.9 months vs months placebo (P = ; HR 0.695, 95% CI ) Radium Ra 223 dichloride significantly prolonged time to first SRE 12.2 months vs. 6.7 months placebo (P < ; HR = 0.64 [95% CI: ]) Radium Ra 223 dichloride was very well tolerated Radium Ra 223 dichloride may provide a new standard of care for the treatment of CRPC patients with bone metastases

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68 Penetration of Ionizing Radiation Types α β γ Paper Aluminum Lead or concrete α-radiation consists of helium ( 4 He) nuclei and is stopped by a sheet of paper or skin β-radiation, consisting of electrons, is halted by an aluminum plate or plastic γ-radiation, consisting of energetic photons, is only attenuated by dense material

69 Características Físicas Rotura simple Reparables Baja letalidad Rotura doble Apoptosis Alt. Mitótica Fase G0 Cortesía Dra. Méndez

70 Summary Phase Denosumab was superior to zoledronic acid in delaying the time to First SRE First and subsequent SRE(s) Notable adverse events occurring in both treatment groups included ONJ and hypocalcemia Hypocalcemia was more frequent in the denosumab arm Incidence of ONJ was similar between arms and not statistically significantly different Denosumab had several select attributes Administered as a 120 mg SC injection once every 4 weeks No dose adjustment necessary for patients with renal impairment Fewer acute phase reactions in the denosumab arm Fizazi K, Carducci M, Smith M, et al. Lancet 2011;377:

71 SREs Total de pts con SREs Uno Dos Tres Total número de SREs Radiación ósea Fractura patológica Cirugía en el hueso Compresión del núcleo espinal Tasa SRE por 100 pacientes-año de exposición Radiación ósea Fractura patológica Cirugía en el hueso Compresión del núcleo espinal Abiraterona + Prednisona (n=797) 22.6% 17.2% 4.4% 1.0% % 15.3% 4.3% 19.1% 38.9% 24.0% 6.0% 1.7% 7.3% Placebo + Prednisona (n=398) 24.6% 18.6% 5.0% 1.0% % 6.2% 1.5% 21.5% 65.1% 46.1% 4.0% 1.0% 14.0% Investigación adicional necesaria para evaluar si el tratamiento con abiraterona podría estar asociado con un mayor riesgo de fracturas patológicas (números pequeños en este estudio) Logothetis et al. Lancet Oncol 2012: 2012; 13:

72 Different Classes of Ionizing Radiation Radiation Type Composition Range in Air Alpha α Helium nuclei A few inches (several centimeters) Beta β Electrons Several feet (many centimeters) Gamma γ Electromagnetic waves (photons) Many yards (many meters) Radiation ranges (ie, distances over which energy is deposited): γ >> β > α

73 223 RaCl 2 Datos generales Vida media 11, 4 días Detectable con equipos convencionales No residuos radioactivos de larga vida

74 223 RaCl 2 Conclusiones Agente emisor alfa con tropismo óseo Baja irradiación de médula ósea y otros tejidos Fácil manejo y administración Pacientes ambulatorios

75 Overview of Phase II/III Clinical Development to Date BC1-03 (n = 100)1 CRPC with painful bone metastases Single doses: 5, 25, 50 or 100 kbq/kg BC1-04 (n = 122)2 CRPC with bone metastases Multiple doses: 3 x 25, 50 or 80 kbq/kg at 6-week intervals BC1-02 (n = 64)3,4 CRPC with bone metastases requiring EBRT Multiple doses: 4 x 50 kbq/kg or placebo at 4-week intervals ALSYMPCA5 Randomized Phase III Study EBRT, external beam radiation therapy 1. Nilsson S, et al. Eur J Can Supp 2009;7:409 Abstract Parker C, et al. Eur J Can Supp 2009;7:406 Abstract Nilsson S, et al. Lancet Oncol. 2007;8(7): Nilsson S, et al. Eur J Cancer Suppl. 2009;7:412 P NCT

76 Bone metastases in prostate cancer have a significant impact on healthcare costs Healthcare costs (US) in patients with prostate cancer: Increased costs due to treatment of metastatic disease and occurrence of SREs *1 $16,998 42% Development of bone metastasis is associated with increased health resource utilization which leads to greater costs in: Hospital inpatient care Outpatient care including physician visits Outpatient pharmacy These costs are conservative, and do not include newer therapies A separate study demonstrated a 91% increase in the risk of hospitalization after development of bone mets 2 Preventing development of bone metastases in prostate cancer patients would result in substantial reduction of costs *Footnote: Retrospective cohort study of 215,702 PC patients using claims data from large, US health insurance plans between Oct 2002 and Dec Primary measure was total healthcare costs after bone metastases, secondary measures included components of total healthcare costs 1. Data on file, 2011; 2. Oglesby et al BMFS (Jan2012)

77 Etapas en el desarrollo de las metástasis óseas

78 SREs-met Prostate ( ) Prostate cancer Randomized, Double-Blind, Active-Controlled study, phase 3 trial Key Eligibility Criteria Adult histologically confirmed prostate cancer Prior or current radiographic evidence of at least 1 bone metastasis Documented failure of at least one hormonal agent, evidenced by rising PSA Serum testosterone < 50 ng/dl ECOG 1 performance status of 0, 1, or 2 No prior or current IV bisphosphonate use E N R O L L M E N T N = 1901 Denosumab 120 mg SC + Placebo IV infusion over 15 minutes Q4W Placebo SC + Zoledronic acid 4 mg IV infusion over 15 minutes Q4W E N D O F S T U D Y Study Week EOS * Screening/Enrollment Treatment Period 1 Eastern Cooperative Oncology Group. Event Driven. * End Of Study. SRE, Skeletal Related Event; Q4W, Every 4 weeks; IV, intravenous; SC, Subcutaneous Accessed 28/April/10 Accessed 28/April/10 Fizazi K. et al. J Clin Oncol 28:7s, 2010 (suppl. ASCO 2010). Abstract LBA4507 and Oral Presentation

79 Denosumab is markedly effective at prolonging bone metastasis free survival in patients at higher risk of developing bone mets Bone Metastasis-Free Survival in Patients with PSA Doubling Time (PSADT) 6 Months Post Hoc Analysis Denosumab [n=419] PLACEBO [n=427] Median time: 18.7 months Median time: 25.9 months 7.2 MONTHS 23% RISK REDUCTION HR:0.77 (95% CI: 0.64, 0.93) p= Patients with PSADT 6 months constitute 60% of the Product A trial population Median bone metastasis free survival in the placebo group with PSADT 6 months (18.7 months) was 6.5 months shorter than for the placebo group in the full population (25.2 months), indicating that these men are at particularly high risk N = Number of subjects randomized with baseline PSA doubling time <6 months

80 223 RaCl 2 Mecanismo de acción Administración intravenosa Forma complejos con la Hidroxiapatita (Ca 10 (PO 4 ) 6 (OH) 2 ) en áreas de elevado turn-over óseo (metastasis óseas ) 40-60% dosis administrada se localiza en esqueleto Escasa redistribución extraósea Escasa exposición de médula ósea

81 ALSYMPCA OS : Prior Docetaxel Use Prior docetaxel use HR = % CI, 0.565, P = NO prior docetaxel use HR = % CI, 0.562, P = % Radium-223, n = 352 Median: 14.4 months % Radium-223, n = 262 Median: 16.1 months Placebo, n = 174 Median: 11.3 months Placebo, n = 133 Median: 11.5 months 0 Month Radium Placebo Month Radium Placebo

82 ALSYMPCA Updated Analysis OS by Stratification Variables: Bisphosphonate Use Current bisphosphonate use Placebo, n = 124 Median: 11.5 months HR = % CI, 0.525, P = % % Radium-223, n = 250 Median: 15.3 months NO current bisphosphonate use 100 HR = % CI, 0.587, P = Placebo, n = 183 Median: 11.0 months Radium-223, n = 364 Median: 14.5 months 0 Month Radium Placebo Month Radium Placebo

83 ALSYMPCA SG y Fosfatasa alcalina basal Total ALP < 220 U/L HR = % CI, 0.635, P = % % Placebo, n = 169 Median: 15.8 months Radium-223, n = 348 Median: 17.0 months Total ALP 220 U/L Placebo, n = 138 Median: 8.1 months HR = % CI, 0.486, P = Radium-223, n = 266 Median: 11.4 months 0 Month Radium Placebo Month Radium Placebo

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85 Trial profile