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Denosumab en cáncer de próstata avanzado

Denosumab en cáncer de próstata avanzado . Begoña Mellado Servicio de Oncología Médica Hospital Clinic. Barcelona. Indicaciones de Denosumab aprobadas en metástasis óseas . EMA, 19 May 2011

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Denosumab en cáncer de próstata avanzado

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  1. Denosumab en cáncer de próstata avanzado Begoña Mellado Servicio de Oncología Médica Hospital Clinic. Barcelona

  2. Indicaciones de Denosumab aprobadas en metástasis óseas EMA, 19 May 2011 The approved indication is: “Prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours”. www.ema.europa.eu/docs/en_GB/document.../WC500106521.pdf

  3. Denosumab en cáncer de próstata avanzado • Mecanismo de acción y características farmacológicas • de denosumab • Espectro del problema • Ensayos clave • Efecto anti-tumoral • Prevención de metástasis

  4. Denosumab Bekker PJ, et al. J Bone Miner Res 2004;19:1059-66. Elliott R, et al. Osteoporos Int 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med 2006;354:821-31. Anticuerpo monoclonal totalment humanizado anti – RANK-L Immunoglobulina tipo IgG2 Alta afinidad Alta especificidad No unión a TNFα, TNFβ, TRAIL o CD40L No anticuerpos neutralizantes han sido detectados en los ensayos clínicos hasta el momento.

  5. RANKL madura y activa los osteoclastos RANK Ligand RANK Pre-fusionosteoclast CFU-GM M-CSF Multinucleatedosteoclast HormonesGrowth factors Cytokines Activated osteoclast Osteoblasts Bone formation CFU-GM = colony forming unit granulocyte macrophage M-CSF = macrophage colony stimulating factor. Bone resorption Adapted from Boyle WJ, et al. Nature 2003;423:337-42.

  6. Denosumab bloquea RANKL y la activación de osteoclastos RANK Ligand RANK Pre-fusionosteoclast CFU-GM M-CSF Multinucleatedosteoclast HormonesGrowth factors Cytokines Activated osteoclast Osteoblasts Bone formation CFU-GM = colony forming unit granulocyte macrophage M-CSF = macrophage colony stimulating factor. Bone resorption Adapted from Boyle WJ, et al. Nature 2003;423:337-42.

  7. Círculo vicioso de pogresión de las metástasis óseas RANK Ligand RANK OPG Tumour cell PTHrP, BMPs,TGF-β, IGF, FGF,VEGF, ET-1, WNT PDGF, BMPs TGF-β, IGFs FGFs Ca2+ Activated osteoclast Osteoblasts Adapted from Roodman D. NEJM 2004;350:1655.

  8. Denosumab romperia el círculo vicioso de pogresión de las metástasis óseas RANK Ligand RANK OPG Tumour cell PTHrP, BMPs,TGF-β, IGF, FGF,VEGF, ET-1, WNT PDGF, BMPs TGF-β, IGFs FGFs Ca2+ Activated osteoclast Osteoblasts Adapted from Roodman D. NEJM 2004;350:1655.

  9. Denosumab se une RANK-L y no se acumula en hueso Efecto reversible

  10. Denosumab: características farmacológicas • Biodisponibilidad próxima al 100% • Vida media 25-46 días • No precisa ajustar dosis por la función renal

  11. Denosumab en cáncer de próstata avanzado • Mecanismo de acción de denosumab • Espectro del problema • Ensayos clave • Efecto anti-tumoral • Prevención de metástasis

  12. Eventos esqueléticos se asocian a un riesgo aumentado de muerte en cáncer de próstata 1 No SREs One or more SREs 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 90 180 270 360 Survival (days) SRE, skeletal related event dePuy, et al. Support Care Cancer 2007;15:869–76.

  13. Denosumab en cáncer de próstata avanzado • Mecanismo de acción de denosumab • Espectro del problema • Ensayos clave • Efecto anti-tumoral • Prevención de metástasis

  14. Denosumab reduce marcadores de actividad ósea en pacientes con metástasis óseas con tratamiento previo con bifosfonatos Fase II aleatorizado Pacientes con cáncer con > 1 M1 ósea y niveles de uNTx > 50 nmol/L a pesar de tratamiento previo con bifosfonatos N= 111 pts (50% c de próstata) Reducción uNTx < 50nmol/L 71% (D) vs 29%(Z), p<0.01 SREx 7% (D) vs 10% (Z) Fizazi K et al. JCO 2009;27:1564-1571

  15. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study Fizazi k et al. Lancet. 2011 March 5; 377(9768): 813–822. doi:10.1016/S0140-6736(10)62344-6.

  16. Study Design: International, Randomised, Double-Blind, Active-Controlled Study *Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine. Fizazi K, et al. Lancet. 2011;377:813–822. • Key Inclusion Criteria • Castration-resistant prostate cancer and 1 bone metastases • Key Exclusion Criteria • Current or prior IV bisphosphonate treatment N = 950 denosumab 120 mg SC and placebo IV Q4W Supplemental calcium and vitamin D strongly recommended N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W

  17. Baseline Characteristics IQR = interquartile range. ECOG = Eastern Cooperative Oncology Group. PSA = prostate-specific antigen. Fizazi K, et al. Lancet. 2011;377:813–822.

  18. Fizazi K, et al. Lancet. 2011;377:813–822. Denosumab retrasa la aparición del primer evento óseo HR = 0.82 (95% CI, 0.71–0.95)P 0.001 (noninferiority) P = 0.008 (superiority) 1.00 Risk reduction 18% 0.75 0.50 Proportion of Subjects Without SRE Kaplan-Meier Estimate of Median Months 0.25 20.7 Denosumab Zoledronic acid 17.1 0.00 0 3 6 9 12 15 18 21 24 27 Study Month Patients at Risk:

  19. *Events occurring at least 21 days apart. Fizazi K, et al. Lancet. 2011;377:813–822. Denosumab reduce la aparición del primero y subsecuentes eventos óseos 2.0 Rate ratio = 0.82 (95% CI, 0.71–0.94) P = 0.009 (superiority) 1.8 Risk reduction 18% 1.6 1.4 1.2 1.0 Cumulative Mean Number of SREs per Patient 0.8 0.6 Events 0.4 Denosumab 494 0.2 Zoledronic acid 584 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Study Month

  20. Summary of Adverse Events

  21. Summary of Adverse Events (continued)

  22. Osteonecrosis mandibular ONJ, osteonecrosis of the jaw *As of April 2010.Fizazi K, et al. Lancet. 2011;377:813–822.

  23. Fizazi K, et al. Lancet. 2011;377:813–822. No observaron diferencias en la evolución de PSA, supervivencia libre de progresión o supervivencia global (análisis exploratorio) HR = 1.03 (95% CI, 0.91–1.17) P = 0.65 1.00 0.75 Proportion of Patients Survived 0.50 0.25 Denosumab Zoledronic acid 0.00 0 3 6 9 12 15 18 21 24 27 30 Study Month Patients at Risk:

  24. Denosumab en cáncer de próstata avanzado • Mecanismo de acción de denosumab • Espectro del problema • Ensayos clave • Efecto anti-tumoral • Prevención de metástasis

  25. RANK se expresa en células tumorales RANK SE EXPRESA EN CELULAS TUMORALES Jones, Nature 2006

  26. RANK/RANKL en cáncer de mama Gonzalez Suarez, Clin Trasl Oncol 2011

  27. RANK-L induce la expresión de genes implicados en el desarrollo de metástasis Amstrong, 2005

  28. Denosumab en cáncer de próstata avanzado • Mecanismo de acción de denosumab • Espectro del problema • Ensayos clave • Efecto anti-tumoral • Prevención de metástasis

  29. Denosumab vs placebo in non-metastatic CRPC R A N D O M I S A T I O N Phase III Study 147 Denosumab 120 mg SC Q4W • Key eligibility criteria • CRPC with PSA >8ng/ml or PSA doubling time <10 months • No bone metastases • No prior IV bisphosphonate use PlaceboSC Q4W N=1435 • Primary endpoint: Time to first occurrence of bone metastases or death from any cause • Secondary endpoints: Time to first occurrence of bone metastasis (excluding death), overall survival Smith MR, Saad F, Coleman R, et al. Presented at: American Urological Association Annual Meeting; May 14 –19, 2011; Washington, DC. Denosumab (120 mg Q4W) is not approved in the EU for use in patients with advanced cancer to treat or delay bone metastases. Denosumab is investigational in that setting. Amgen Press Release December 13th, 2010 . http://www.amgennews.com/index.php/article/274/ Fecha acceso 12 Abril 11

  30. Baseline characteristics PSA (prostate specific antigen); PSADT (PSA doubling time) Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C. Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

  31. Patient disposition at time of analysis Randomised patients 1432* Placebo 716 Denosumab 716 Discontinued, n (%) Bone metastasis 297 (41.5) Consent withdrawn 92 (13) Death 53 (7.4) Disease progression** 22 (3) Adverse event 25 (3) Other± 63 (9) Discontinued, n (%) Bone metastasis 247 (34.5) Consent withdrawn 100 (14) Death 56 (7.8) Disease progression** 36 (5) Adverse event 36 (5) Other± 67 (9) On study 164 (23%) On study 174 (24%) *Does not include three patients with insufficient IRB (international review board) oversight **Not in bone ±Administrative decision, noncompliance, lost to follow-up, protocol deviation, ineligibility determined Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C. Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

  32. Bone metastasis-free survival 1.0 HR = 0.85 (95% CI 0.73, 0.98) P = 0.028 0.8 0.6 Proportion of patients 0.4 0.2 Median months Events 25.2 370 Placebo Denosumab 29.5 335 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Study month Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 36 Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59 35 Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C. Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

  33. Time to symptomatic bone metastasis* HR = 0.67 (95% CI 0.49, 0.92) P = 0.01 1.0 0.8 0.6 Proportion of patients 0.4 0.2 Events 96 Placebo Denosumab 69 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Study month *Confirmed bone metastasis reported as symptomatic Placebo 716 667 565 474 411 368 347 293 242 189 142 130 94 51 Denosumab 716 683 603 503 441 385 360 308 260 200 160 143 96 47 Smith MR, Saad F, Coleman R, et al. Oral Plenary Session, May 2011, AUA Annual Meeting 2011 Washington, D.C. Denosumab (120 mg Q4W) is currently not approved outside the US. Denosumab is investigational in that setting.

  34. Studies of bone-targeted agents for bone metastases prevention in prostate cancer Denosumab (120 mg Q4W) is not approved in the EU for use in patients with advanced cancer to delay SREs. Denosumab is investigational in that setting. 1. Mason, et al. J Natl Cancer Inst 2007;16;99:744–5; 2. Dearnaley, et al. Lancet Oncol 2009;10:872–6; 3. Smith, et al. J Clin Oncol 2005;23:2918–5; 4. Nelson et al. Cancer 2008; 113:2478–87 5. AstraZeneca Press Release February 7th, 2011; 6. Smith MR et al. Presented at: American Urological Association Annual Meeting; May 14 –19, 2011; Washington, DC. ZOL, zoledronic acid;PCa, prostate cancer;OS, overall survival; QoL, quality of life

  35. Conclusiones • Denosumab reduce el riesgo de eventos esqueléticos frente ácido zoledrónico en cáncer de próstata mestastásico • Denosumab está aprobado por la FDA y EMA en esta indicación, ofreciendo una opción novedosa para mejorar la calidad de vida de los pacientes. 3. Denosumab retrasa la aparición de metastásis óseas en pacientes con recidiva bioquímica resistente a la castración

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