Denosumab en cáncer de próstata avanzado

Presentación del tema: "Denosumab en cáncer de próstata avanzado"— Transcripción de la presentación:

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”.

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 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. Dougall FHCRC 2009; UW Dental School talk 2010 Denosumab, an investigational fully human monoclonal antibody (IgG2), binds with high affinity and specificity to human RANK (receptor activator of nuclear factor kappa B) ligand, an essential mediator of osteoclast activity.1-3 No neutralizing antibodies have been detected in clinical trials to date.1,3 Binding of denosumab to RANK Ligand was investigated in an in-vitro study using flow cytometry and ELISA. Binding affinity was measured using BIAcore and a kinetic exclusion assay. Denosumab bound both soluble and membrane-bound forms of human RANK Ligand. This binding was inhibited by excess human RANK Ligand, but not by TNF-, TNF-, TRAIL or CD40 Ligand. The dissociation constants of denosumab were calculated to be 9.5 x 10-11M and x 10-12M using the BIAcore and kinetic exclusion assay, respectively.2 No neutralizing antibodies have been detected in clinical trials to date: In a phase 1, double-blind study, 49 healthy postmenopausal women were randomized to receive a single dose of denosumab 0.01, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg or placebo. No anti-denosumab antibodies were detected in subjects enrolled in this study.1 In a phase 2 study, 412 postmenopausal women with low bone mineral density (BMD) were randomized to receive denosumab SC either every three months (6, 14, or 30 mg) or every six months (14, 60, 100, or 210 mg), open-label alendronate (70mg orally once weekly), or placebo. Denosumab-binding antibodies were observed in two subjects—one at 1 month and the other at 12 months. These antibodies were not neutralizing and were not detected in subsequent samples in either subject.3 The effects of denosumab on bone resorption appear reversible.3 Note: The graphic in the slide is a ribbon depiction of denosumab. Bekker PJ, et al. J Bone Miner Res. 2004;19: Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354: Bekker PJ, et al. J Bone Miner Res 2004;19: Elliott R, et al. Osteoporos Int 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med 2006;354:

5 RANKL madura y activa los osteoclastos
CFU-GM Pre-fusion osteoclast RANK Ligand RANK M-CSF Multinucleated osteoclast Hormones Growth factors Cytokines This slide gives an overview of current knowledge of the RANK Ligand pathway Growth factors act on osteoblasts to stimulate production of RANK Ligand RANK Ligand interacts with its receptor, RANK This interaction drives osteoclastogenesis The resulting activated osteoclasts turn over bone The effect of RANK Ligand on osteoclasts is three fold, promoting: Differentiation Activation Survival CFU-GM = colony forming unit granulocyte macrophage; M-CSF = macrophage colony stimulating factor Activated osteoclast Osteoblasts Bone formation CFU-GM = colony forming unit granulocyte macrophage M-CSF = macrophage colony stimulating factor. Adapted from Boyle WJ, et al. Nature 2003;423: Bone resorption

6 Denosumab bloquea RANKL y la activación de osteoclastos
CFU-GM Pre-fusion osteoclast RANK Ligand RANK M-CSF Multinucleated osteoclast Hormones Growth factors Cytokines This slide gives an overview of current knowledge of the RANK Ligand pathway Growth factors act on osteoblasts to stimulate production of RANK Ligand RANK Ligand interacts with its receptor, RANK This interaction drives osteoclastogenesis The resulting activated osteoclasts turn over bone The effect of RANK Ligand on osteoclasts is three fold, promoting: Differentiation Activation Survival CFU-GM = colony forming unit granulocyte macrophage; M-CSF = macrophage colony stimulating factor Activated osteoclast Osteoblasts Bone formation CFU-GM = colony forming unit granulocyte macrophage M-CSF = macrophage colony stimulating factor. Adapted from Boyle WJ, et al. Nature 2003;423: Bone resorption

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+ The vicious cycle model predicts that by blocking RANK Ligand, not only will tumour-induced osteolysis be blocked, but the skeletal tumour burden will also be reduced This prediction can be tested in an animal model BMPs = bone morphogenetic proteins; ET-1 = endothelin-1; FGF = fibroblast growth factor; IGF = insulin-like growth factor; OPG = osteoprotegerin; PDGF = platelet-derived growth factor; PTHrP = parathyroid hormone related peptide; TGF-β = transforming growth factor-beta; VEGF = vascular endothelial growth factor 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+ The vicious cycle model predicts that by blocking RANK Ligand, not only will tumour-induced osteolysis be blocked, but the skeletal tumour burden will also be reduced This prediction can be tested in an animal model BMPs = bone morphogenetic proteins; ET-1 = endothelin-1; FGF = fibroblast growth factor; IGF = insulin-like growth factor; OPG = osteoprotegerin; PDGF = platelet-derived growth factor; PTHrP = parathyroid hormone related peptide; TGF-β = transforming growth factor-beta; VEGF = vascular endothelial growth factor 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 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 As well as increasing morbidity, SREs are associated with reduced survival. Reference DePuy V, Anstrom KJ, Castel LD et al. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer. Support Care Cancer 2007;15:869–76. 0.2 0.1 90 180 270 360 Survival (days) SRE, skeletal related event dePuy, et al. Support Care Cancer 2007;15:869–76. 12 12

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

14 óseas con tratamiento previo con bifosfonatos
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) (A) Proportion of patients in each treatment arm achieving urinary N-telopeptide (uNTx) levels lower than 50 nmol/L BCE/mM creatinine at week 13. (B) Median percent change (Q1, Q3) from baseline in uNTx corrected by creatinine from baseline to week 25. (B) Number of patients assessed at week 13: IV BP every 4 weeks (Q4W), n = 30; denosumab 180 mg every 12 weeks (Q12W), n = 28; denosumab 180 mg Q4W, n = 30; pooled denosumab, n = 58 and at week 25; IV BP Q4W, n = 23; denosumab 180 mg Q12W, n = 25; denosumab 180 mg Q4W, n = 26; pooled denosumab, n = 51. (C) Median time to reduction of uNTx levels lower than 50 nmol/L BCE/mM creatinine. Fizazi K et al. JCO 2009;27:

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 March 5; 377(9768): 813–822. doi: /S (10)

16 Study Design: International, Randomised, Double-Blind, Active-Controlled Study
XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 815,Table 1 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 XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2 Supplemental calcium and vitamin D strongly recommended Fizazi K, et al. Lancet 2011;377: 815,A,2 N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 813,Methods Key Points This was an international, randomized, double-blind, active-controlled trial comparing denosumab with zoledronic acid for the treatment of bone metastases in patients with castration-resistant prostate cancer The primary endpoint was time to first on-study SRE comparing denosumab with zoledronic acid for noninferiority Secondary efficacy endpoints, evaluated only if noninferiority was demonstrated, were superiority tests comparing denosumab and zoledronic acid for time to first on-study SRE and time to first and subsequent SRE(s) (multiple-event analysis) Background Eligible patients were men  18 years old with histologically confirmed prostate cancer and current or prior radiographic evidence of at least one bone metastasis and documented failure of at least 1 hormonal therapy Patients were randomized 1:1 to receive either SC injections of denosumab 120 mg and an IV placebo Q4W, or an IV infusion (lasting no less than 15 minutes) of zoledronic acid 4 mg and an SC injection of placebo Q4W Daily supplementation with calcium and vitamin D was strongly recommended Key exclusion criteria included current or prior IV bisphosphonate or oral bisphosphonate administration to treat bone metastasis References XGEVA™ (denosumab) prescribing information, Amgen. 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: 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) Fizazi K, et al. Lancet 2011;377: 815,A,2 XGEVA™ PI 2010: 9,14 Fizazi K, et al. Lancet 2011;377: 814,A,2;B,1 *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. Fizazi K, et al. Lancet 2011;377: 814,B,5; 815,A,1 XGEVA™ PI 2010: 2,2.1 Fizazi K, et al. Lancet 2011;377: 815,A,1 XGEVA™ PI 2010: 3,6.1 Fizazi K, et al. Lancet 2011;377: 814,B,1-2 16

17 Baseline Characteristics
Fizazi K, et al. Lancet 2011;377: 815,Table 1 Characteristic Denosumab (N = 950) Zoledronic Acid (N = 951) Median age, years (IQR) 71 (64–77) 71 (66–77) ECOG performance status of 0 or 1, n (%) 882 (93) 886 (93) Stratification Factors PSA at randomisation  10 g/L, n (%) 805 (85) 806 (85) Recent chemotherapy ( 6 weeks before randomisation), n (%) 132 (14) Previous SRE, n (%) 232 (24) 231 (24) Median time from diagnosis of bone metastasis to randomisation, months (IQR) 3.94 (1.22–15.67) 5.19 (1.31–16.10) Key Points A total of 1901 patients were randomized to receive denosumab (n = 950) or zoledronic acid (n = 951) Baseline age, race, and ECOG performance status variables were balanced between groups Background Randomization was stratified by previous SRE, PSA level ( 10 g/L vs  10 g/L), and chemotherapy for prostate cancer within 6 weeks before randomization Patients in the zoledronic acid arm had a slightly longer median time from bone metastases diagnosis to study randomization (denosumab, 3.94 months; zoledronic acid, 5.19 months) although the quartiles were similar Reference 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: Fizazi K, et al. Lancet 2011;377: 815,Table 1 IQR = interquartile range. ECOG = Eastern Cooperative Oncology Group. PSA = prostate-specific antigen. Fizazi K, et al. Lancet. 2011;377:813–822. 17

18 Adjustments for Renal Function
Fizazi K, et al. Lancet 2011;377: 817,B,1; 818,B,1 Adjustments for Renal Function Denosumab (N = 942) Zoledronic Acid (N = 946) Subjects with dose adjustments for creatinine clearance at baseline, n (%) NA 213 (22) Subjects with doses withheld for serum creatinine increases on study, n (%) 143 (15) Fizazi K, et al. Lancet 2011;377: 817,B,1; 818,B,1 Key Points Protocol-mandated dose adjustments of IV zoledronic acid for baseline creatinine clearance occurred in 213 (22%) patients per the Zometa prescribing information. One hundred forty-three (15%) patients required zoledronic acid doses to be withheld on study for serum creatinine increases per the Zometa prescribing information Reference 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: NA = not applicable per protocol. Fizazi K, et al. Lancet. 2011;377:813–822. 18

19 Denosumab retrasa la aparición del primer evento óseo
XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 2 HR = 0.82 (95% CI, 0.71–0.95) P  (noninferiority) P = (superiority) 1.00 18% Risk reduction 0.75 Proportion of Subjects Without SRE 0.50 Kaplan-Meier Estimate of Median Months 0.25 Key Points Denosumab significantly delayed the time to first on-study SRE by 18% compared with zoledronic acid (HR = 0.82; 95% CI, 0.71–0.95; P  .001 for noninferiority and P = .008 for superiority)1 The median (95% CI) time to first on-study SRE was 20.7 months in the denosumab group and 17.1 months in the zoledronic acid group, a difference of 3.6 months1 Between-group divergence is evident beginning at 3 months after initiation of treatment2 References XGEVA™ (denosumab) prescribing information, Amgen. 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: Denosumab Zoledronic acid 20.7 XGEVA™ PI, 2010: 11,Table 2 17.1 0.00 3 6 9 12 15 18 21 24 27 Fizazi K, et al. Lancet 2011;377: 816,Figure 2 Study Month Patients at Risk: Zoledronic acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 Fizazi K, et al. Lancet. 2011;377:813–822. 19

20 Denosumab reduce la aparición del primero y subsecuentes eventos óseos
XGEVA™ PI, 2010: 11,Table 2 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 2.0 Rate ratio = 0.82 (95% CI, 0.71–0.94) P = (superiority) 1.8 Risk reduction 1.6 18% 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 Key Points Denosumab significantly delayed the time to first and subsequent on-study SREs (rate ratio = 0.82; 95% CI, 0.71–0.94; adjusted P = .009)1 A total of 1078 events occurred, 494 in the denosumab treatment group, and 584 in the zoledronic acid treatment group2 References XGEVA™ (denosumab) prescribing information, Amgen. 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: XGEVA™ PI, 2010: 11,Table 2 Events 0.4 Denosumab 494 Fizazi K, et al. Lancet 2011;377: 816,Figure 3 0.2 Zoledronic acid 584 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Study Month *Events occurring at least 21 days apart. Fizazi K, et al. Lancet. 2011;377:813–822. 20

21 Summary of Adverse Events
Fizazi K, et al. Lancet 2011;377: 818,Table 4 Patient Incidence Denosumab (N = 943) n (%) Zoledronic Acid (N = 945) n (%) Any adverse event (AE) 916 (97) 918 (97) Most Common AEs in Either Arm 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) Fizazi K, et al. Lancet 2011;377: 818,Table 4 Key Points Overall rates of AEs and serious AEs were similar between the two study groups (97% in the denosumab and zoledronic acid groups) The most common AEs were anemia, back pain, decreased appetite, nausea, and fatigue Reference 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: 21

22 Summary of Adverse Events (continued)
Fizazi K, et al. Lancet 2011;377: 818,Table 4 Patient Incidence Denosumab (N = 943) n (%) Zoledronic Acid (N = 945) n (%) Infectious AEs* 402 (43) 375 (40) Acute phase reactions (first 3 days) 79 (8) 168 (18) Renal AEs† 139 (15) 153 (16) Cumulative rate of osteonecrosis of the jaw (ONJ)‡ 22 (2) 12 (1) Year 1 10 (1) 5 (1) Year 2 8 (1) Hypocalcaemia 121 (13) 55 (6) New primary malignancy 18 (2) Fizazi K, et al. Lancet 2011;377: 819,A,3 Fizazi K, et al. Lancet 2011;377: 818,Table 4 Key Point The incidence of AEs of interest was similar between the two study treatment groups Background During the first 3 days of treatment, AEs potentially associated with acute phase reactions occurred in 8% of denosumab and 18% of zoledronic acid patients AEs potentially associated with renal impairment occurred in 15% of the denosumab group and 16% of the zoledronic acid group Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group (P = .09) AEs of hypocalcemia were reported in 121 (13%) patients in the denosumab group and 55 (6%) patients in the zoledronic acid group New primary malignancies were identified in 18 (2%) patients in the denosumab group and 10 (1%) patients in the zoledronic acid group Reference 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: Fizazi K, et al. Lancet 2011;377: 819,A,3 Fizazi K, et al. Lancet 2011;377: 818,Table 4 22

23 Osteonecrosis mandibular
Fizazi K, et al. Lancet 2011;377: 818,Table 4 Patient Incidence Denosumab n (%) Zoledronic Acid n (%) Patients with positively adjudicated ONJ 22 (2) 12 (1) Risk Factors Tooth extraction, dental appliance, or poor oral hygiene 17 (77) 10 (83) Chemotherapy 14 (64) 9 (75) Treatment* Limited surgery (eg, debridement) 10 (45) 3 (25) Bone resection 2 (9) 1 (8) Fizazi K, et al. Lancet 2011;377: 818,B,5 Fizazi K, et al. Lancet 2011;377: 818,B,5; 819,A,1 Key Point ONJ occurred infrequently in both treatment groups, and was usually associated with risk factors Background Positively adjudicated ONJ occurred in 22 (2%) patients in the denosumab group and 12 (1%) patients in the zoledronic acid group (P = .09) A history of tooth extraction, poor oral hygiene, and/or dental appliance utilization was present in 17 (77%) of the patients with ONJ in the denosumab group and 10 (83%) of the patients with ONJ in the zoledronic acid group On-study chemotherapy use was reported by 14 (64%) of patients with ONJ in the denosumab group and nine (75%) of the patients with ONJ in the zoledronic acid group As of April 2010, 10 (45%) patients with ONJ in the denosumab group had undergone limited surgeries and two (9%) had bone resections compared with three (25%) patients in the zoledronic acid group who received limited surgical treatment and one (8%) who underwent bone resection Reference 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: Fizazi K, et al. Lancet 2011;377: 818,Table 4 Fizazi K, et al. Lancet 2011;377: 818,B,5 ONJ, osteonecrosis of the jaw *As of April Fizazi K, et al. Lancet. 2011;377:813–822. Fizazi K, et al. Lancet 2011;377: 818,B,5; 819,A,1 23

24 Proportion of Patients
No observaron diferencias en la evolución de PSA, supervivencia libre de progresión o supervivencia global (análisis exploratorio) Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A HR = 1.03 (95% CI, 0.91–1.17) P = 0.65 1.00 0.75 Proportion of Patients Survived 0.50 0.25 Fizazi K, et al. Lancet 2011;377: 817,Figure 4,A Key Points Overall survival (HR = 1.03; 95% CI, 0.91–1.17; P = .65) was similar between study groups1 Overall survival and progression-free survival were similar between arms in all three trials1 Mortality was higher with denosumab in a subgroup analysis of patients with multiple myeloma (HR = 2.26; 95% CI, 1.13–4.50; n = 180)2 References 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: XGEVA™ (denosumab) prescribing information, Amgen. Denosumab Zoledronic acid XGEVA™ PI, 2010: 10-14 0.00 3 6 9 12 15 18 21 24 27 30 Study Month Patients at Risk: Zoledronic acid 951 864 745 635 519 401 297 207 143 98 Denosumab 950 872 746 645 552 427 310 233 156 99 55 54 Fizazi K, et al. Lancet. 2011;377:813–822. 24

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

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

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

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

29

30

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

32 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 Placebo SC 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, Fecha acceso 12 Abril 11 32

33 Baseline characteristics
Characteristic, n (%) or median Placebo (n = 716) Denosumab (n = 716) Age, years 74.0 Time from diagnosis to study entry, years 6.10 PSA, ng/mL 12.5 12.2 PSA ≥8 ng/mL and PSADT ≤10 months 346 (48.3) Prior chemotherapy 55 (7.7) Duration of prior ADT, years 3.9 Local therapy 331 (46.2) 313 (43.7) Gleason score at diagnosis ≤7 432 (60.3) 404 (56.4) 8–10 214 (29.9) 237 (33.1) ECOG performance status ≤1 713 (99.6) 715 (99.9) 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. 33

34 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. 34

35 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 Placebo 25.2 370 Denosumab 29.5 335 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.

36 Time to symptomatic bone metastasis*
1.0 HR = 0.67 (95% CI 0.49, 0.92) P = 0.01 0.8 0.6 Proportion of patients 0.4 0.2 Events Placebo 96 Denosumab 69 0.0 3 6 9 12 15 18 21 24 27 30 33 36 39 Study month Placebo 716 667 565 474 411 368 347 293 242 189 142 130 94 51 *Confirmed bone metastasis reported as symptomatic 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. 36

37 Studies of bone-targeted agents for bone metastases prevention in prostate cancer
Study Patients Treatment arms Selected endpoints Results/ Status MRC PR041,2 M0; T24; WHO PS 02 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 Enthuse M05 Zibotentan 10 mg vs placebo Progression-free survival, OS Smith et al 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 Smith MR, Saad F, Coleman R, et al. Denosumab to prolong bone metastasis-free survival in men with castrate-resistant prostate cancer: results of a global phase 3, randomized, double-blind trial. 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 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 37

38 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