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 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 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 Denosumab 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. 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. RANKL madura y activa los osteoclastos Pre-fusion osteoclast CFU-GM RANK Ligand RANK M-CSF Multinucleated osteoclast Hormones Growth factors Cytokines Osteoblasts Activated osteoclast Bone formation CFU-GM = colony forming unit granulocyte macrophage M-CSF = macrophage colony stimulating factor. Adapted from Boyle WJ, et al. Nature 2003;423:337-42. Bone resorption Denosumab bloquea RANKL y la activación de osteoclastos Pre-fusion osteoclast CFU-GM RANK Ligand RANK M-CSF Multinucleated osteoclast Hormones Growth factors Cytokines Osteoblasts Activated osteoclast Bone formation CFU-GM = colony forming unit granulocyte macrophage M-CSF = macrophage colony stimulating factor. Adapted from Boyle WJ, et al. Nature 2003;423:337-42. Bone resorption 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. 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. Denosumab se une RANK-L y no se acumula en hueso Efecto reversible Denosumab: características farmacológicas – Biodisponibilidad próxima al 100% – Vida media 25-46 días – No precisa ajustar dosis por la función renal Denosumab en cáncer de próstata avanzado Mecanismo de acción de denosumab Espectro del problema Ensayos clave Efecto anti-tumoral Prevención de metástasis 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 Probability 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 90 180 Survival (days) SRE, skeletal related event dePuy, et al. Support Care Cancer 2007;15:869–76. 270 360 Denosumab en cáncer de próstata avanzado Mecanismo de acción de denosumab Espectro del problema Ensayos clave Efecto anti-tumoral Prevención de metástasis 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 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. Study Design: International, Randomised, Double-Blind, Active-Controlled Study N = 950 denosumab 120 mg SC and placebo IV Q4W Key Inclusion Criteria •Castration-resistant prostate cancer and 1 bone metastases Key Exclusion Criteria •Current or prior IV bisphosphonate treatment Supplemental calcium and vitamin D strongly recommended N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W Primary Endpoint • Time to first on-study skeletal-related event (SRE) (noninferiority) Secondary Endpoints • Time to first on-study SRE (superiority) • Time to first and subsequent on-study SRE(s) (superiority) *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. Baseline Characteristics Denosumab (N = 950) Zoledronic Acid (N = 951) 71 (64–77) 71 (66–77) 882 (93) 886 (93) PSA at randomisation 10 g/L, n (%) 805 (85) 806 (85) Recent chemotherapy ( 6 weeks before randomisation), n (%) 132 (14) 132 (14) Previous SRE, n (%) 232 (24) 231 (24) 3.94 (1.22– 15.67) 5.19 (1.31– 16.10) Characteristic Median age, years (IQR) ECOG performance status of 0 or 1, n (%) Stratification Factors Median time from diagnosis of bone metastasis to randomisation, months (IQR) IQR = interquartile range. ECOG = Eastern Cooperative Oncology Group. PSA = prostate-specific antigen. 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) Proportion of Subjects Without SRE 1.00 18% 0.75 Risk reduction 0.50 Kaplan-Meier Estimate of Median Months 0.25 20.7 17.1 Denosumab Zoledronic acid 0.00 0 3 6 9 733 758 544 582 407 472 Patients at Risk: Zoledronic acid 951 Denosumab 950 Fizazi K, et al. Lancet. 2011;377:813–822. 12 15 Study Month 299 361 207 259 18 21 24 27 140 168 93 115 64 70 47 39 Cumulative Mean Number of SREs per Patient Denosumab reduce la aparición del primero y subsecuentes eventos óseos 2.0 Rate ratio = 0.82 (95% CI, 0.71–0.94) 1.8 P = 0.009 (superiority) 1.6 18% 1.4 Risk reduction 1.2 1.0 0.8 0.6 Events 0.4 Denosumab Zoledronic acid 0.2 494 584 0.0 0 3 6 *Events occurring at least 21 days apart. Fizazi K, et al. Lancet. 2011;377:813–822. 9 12 15 18 21 Study Month 24 27 30 33 36 Summary of Adverse Events Denosumab (N = 943) n (%) Zoledronic Acid (N = 945) n (%) 916 (97) 918 (97) Anaemia 337 (36) 341 (36) Back pain 304 (32) 287 (30) Decreased appetite 267 (28) 274 (29) Nausea 272 (29) 245 (26) Fatigue 257 (27) 222 (23) CTCAE grade 3 or 4 AEs 678 (72) 628 (66) Serious AEs 594 (63) 568 (60) AEs leading to treatment discontinuation 164 (17) 138 (15) Patient Incidence Any adverse event (AE) Most Common AEs in Either Arm Summary of Adverse Events (continued) Denosumab (N = 943) n (%) Zoledronic Acid (N = 945) n (%) 402 (43) 375 (40) 79 (8) 168 (18) 139 (15) 153 (16) 22 (2) 12 (1) Year 1 10 (1) 5 (1) Year 2 22 (2) 8 (1) 121 (13) 55 (6) 18 (2) 10 (1) Patient Incidence Infectious AEs* Acute phase reactions (first 3 days) Renal AEs† Cumulative rate of osteonecrosis of the jaw (ONJ)‡ Hypocalcaemia New primary malignancy Osteonecrosis mandibular Denosumab n (%) Zoledronic Acid n (%) 22 (2) 12 (1) Tooth extraction, dental appliance, or poor oral hygiene 17 (77) 10 (83) Chemotherapy 14 (64) 9 (75) 10 (45) 3 (25) 2 (9) 1 (8) Patient Incidence Patients with positively adjudicated ONJ Risk Factors Treatment* Limited surgery (eg, debridement) Bone resection ONJ, osteonecrosis of the jaw *As of April 2010. 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 Proportion of Patients Survived 1.00 0.75 0.50 0.25 Denosumab Zoledronic acid 0.00 0 3 6 9 12 635 519 401 645 552 427 Patients at Risk: Zoledronic 951 864 745 acid Denosumab 950 872 746 Fizazi K, et al. Lancet. 2011;377:813–822. 15 18 Study Month 21 24 27 30 297 207 143 98 55 54 310 233 156 99 Denosumab en cáncer de próstata avanzado Mecanismo de acción de denosumab Espectro del problema Ensayos clave Efecto anti-tumoral Prevención de metástasis RANK se expresa en células tumorales RANK SE EXPRESA EN CELULAS TUMORALES Jones, Nature 2006 RANK/RANKL en cáncer de mama Gonzalez Suarez, Clin Trasl Oncol 2011 RANK-L induce la expresión de genes implicados en el desarrollo de metástasis Amstrong, 2005 Denosumab en cáncer de próstata avanzado Mecanismo de acción de denosumab Espectro del problema Ensayos clave Efecto anti-tumoral Prevención de metástasis Denosumab vs placebo in non-metastatic CRPC Phase III Study 147 Key eligibility criteria • CRPC with PSA >8ng/ml or PSA doubling time <10 months • No bone metastases • No prior IV bisphosphonate use N=1435 • • R A N D O M I S A T I O N Denosumab 120 mg SC Q4W Placebo SC Q4W 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. Amgen Press Release December 13th, 2010 . http://www.amgennews.com/index.php/article/274/ Fecha acceso 12 Abril 11 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. Baseline characteristics Placebo (n = 716) Denosumab (n = 716) Age, years 74.0 74.0 Time from diagnosis to study entry, years 6.10 6.10 PSA, ng/mL 12.5 12.2 346 (48.3) 346 (48.3) 55 (7.7) 55 (7.7) 3.9 3.9 331 (46.2) 313 (43.7) ≤7 432 (60.3) 404 (56.4) 8–10 214 (29.9) 237 (33.1) 713 (99.6) 715 (99.9) Characteristic, n (%) or median PSA ≥8 ng/mL and PSADT ≤10 months Prior chemotherapy Duration of prior ADT, years Local therapy Gleason score at diagnosis ECOG performance status ≤1 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. Patient disposition at time of analysis Randomised patients 1432* Placebo 716 Denosumab 716 Discontinued, n (%) Discontinued, n (%) Bone metastasis Consent withdrawn Death Disease progression** Adverse event Other± On study 164 (23%) *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 297 (41.5) 92 (13) 53 (7.4) 22 (3) 25 (3) 63 (9) Bone metastasis Consent withdrawn Death Disease progression** Adverse event Other± 247 (34.5) 100 (14) 56 (7.8) 36 (5) 36 (5) 67 (9) On study 174 (24%) 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. Bone metastasis-free survival 1.0 HR = 0.85 (95% CI 0.73, 0.98) P = 0.028 Proportion of patients 0.8 0.6 0.4 0.2 Median months Events Placebo Denosumab 25.2 29.5 370 335 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Study month Placebo Denosumab 716 691 569 500 421 375 345 300 259 215 168 137 99 60 716 695 605 521 456 400 368 324 279 228 185 153 111 59 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. 36 35 Time to symptomatic bone metastasis* HR = 0.67 (95% CI 0.49, 0.92) P = 0.01 1.0 Proportion of patients 0.8 0.6 0.4 0.2 Events Placebo Denosumab 96 69 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Study month Placebo Denosumab 716 667 565 474 411 368 347 293 242 189 142 130 94 716 683 603 503 441 385 360 308 260 200 160 143 96 51 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. *Confirmed bone metastasis reported as symptomatic Studies of bone-targeted agents for bone metastases prevention in prostate cancer Study Patients Treatment arms Selected endpoints Results/ Status MRC PR041,2 M0; T24; WHO PS 02 Clodronate vs placebo Time to symptomatic bone mets or PCa death, OS Primary not met Smith et al 20053 M0 CRPC; rising PSA despite ADT ZOL vs placebo Time to first bone mets, OS, bone mets-free survival Terminated early Nelson et al 20084 M0 CRPC; rising PSA despite ADT (20, 50% in 6 mo, or rising in 12 mo) Atrasentan vs placebo Time to first mets, PSA progression, OS, bone mets-free survival, PSA doubling time Primary not met Enthuse M05 M0 CRPC; rising PSA despite ADT Zibotentan 10 mg vs placebo Progression-free survival, OS Terminated early Smith et al 2011. Study 1476 M0 CRPC with PSA >8ng/ml or PSA doubling time <10 mo Denosumab 120 mg SC Q4W vs placebo Time to first bone mets or death from any cause; time to first bone mets, OS Positive data reported 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. ZOL, zoledronic acid; 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 PCa, prostate cancer; Clin Oncol 2005;23:2918–5; 4. Nelson et al. Cancer 2008; 113:2478–87 5. AstraZeneca Press Release February 7th, 2011; OS, overall survival; QoL, quality of life 6. Smith MR et al. Presented at: American Urological Association Annual Meeting; May 14 –19, 2011; Washington, DC. Conclusiones 1. Denosumab reduce el riesgo de eventos esqueléticos frente ácido zoledrónico en cáncer de próstata mestastásico 2. 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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