Denosumab et cancer de prostate Dr Beuzeboc

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1 Denosumab et cancer de prostate Dr Beuzeboc
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2 A vicious cycle of bone destruction may develop in the presence of tumour cells
Osteoblasts and other bone cells increase expression of RANK Ligand Overexpression of RANK Ligand drives increased formation, function and survival of osteoclasts, leading to excessive bone resorption RANK Ligand Osteoblasts Osteoclast In healthy adult bone, RANK Ligand activity is tightly regulated to balance bone formation and resorption.1 However, in the presence of tumour cells, a vicious cycle of bone destruction and tumour growth may develop.2,3 Tumour cells that have invaded bone secrete factors that increase the expression of RANK Ligand by osteoblasts. Increased expression of RANK Ligand upregulates osteoclast activity. Excessive osteoclast activity drives increased bone resorption; this in turn releases growth factors from the bone matrix that may perpetuate tumour activity. This sequence of events drives a vicious cycle of bone destruction and tumour activity. The discovery of the RANK/RANK Ligand pathway and its role in the regulation of bone turnover provides a molecular target for new therapies to interrupt bone destruction and potentially tumour growth in patients with advanced cancer. References Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655– 64. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–93. Tumour cells produce factors that stimulate osteoblasts to secrete RANK Ligand Bone resorption releases growth factors from the bone matrix that may perpetuate tumour activity Tumour Adapted from Roodman GD. N Engl J Med 2004;350:1655–64; Mundy GR. Nat Rev Cancer 2002;2:58493. 2

3 Mécanisme d’action du dénosumab
D’après ASCO® GU 2012 – Mac Vicar GR D’après Roodman GD. N Engl J Med 2004;350(16): 3 3

4 RANK Ligand est surexprimé dans des modèles précliniques de métastases osseuses
Expression d’OPG et RANKL dans les co-cultures d’osteoblastes et de lignées cellulaires de cancer de prostate OSB + 2b OSB + 2a OSB + LNCaP OSB + PC3 Control Control OPG RANK Ligand [OPTIONAL SLIDE] The presence of prostate cancer cells increases RANK Ligand expression and reduces OPG expression from primary mouse osteoblasts. Reference Fizazi K, Yang J, Peleg S et al. Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts. Clin Cancer Res 2003;9:2587–97. Fizazi K et al. Clin Cancer Res 2003;9:2587–97. OSB, primary mouse osteoblast; Prostate cancer cell lines MDA PCa 2a, MDA PCa 2b, LNCaP and PC3; OPG, osteoprotegerin 4

5 (†versus uNTx < 50 ou ‡versus uNTx < 100 nmol/mmol creatinine)
Un uNTx élevé est associé avec un mauvais pronostic dans les cancers de prostate avancés uNTx 50100 nmol/mmol créatinine uNTx ≥ 100 nmol/mmol créatinine P 3.82† < 0.001 SRE 3.25‡ < 0.001 2.65† 0.003 Décès 4.59‡ < 0.001 Elevated uNTx levels have been associated with increased risk of SREs and death in patients with prostate cancer and bone metastases.1 In this study including 203 bisphosphonate-naive prostate cancer patients with bone metastases, risk of SREs and death were compared in patients with high (uNTx cutoffs  100 and  50 nmol/mmol creatinine) or low (uNTx cut-offs < 100 and < 50 nmol/mmol creatinine) uNTx levels. High uNTx assessed on-study was associated with more than 3-fold increased risk of experiencing an SRE for both uNTX cutoffs and more than 2- and 4-fold increased risk of death for the 50 and 100 nmol/mmol creatinine cut-offs, respectively.1 Healthy men have been shown to have a mean uNTx level of 35.7 nmol/mmol creatinine.2 References Brown JE, Cook RJ, Major P et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumours. J Natl Cancer Inst 2005;97:59–69. Orwoll ES, Bell NH, Nanes MS et al. Collagen N-telopeptide excretion in men: the effects of age and intrasubject variability. J Clin Endocrinol Metab 1998;83:3930–5. Risque relatif (†versus uNTx < 50 ou ‡versus uNTx < 100 nmol/mmol creatinine) 1 10 Brown JE et al. J Natl Cancer Inst 2005;97:59–69. 5

6 Temps à partir du screening (ans)
Un uNTx élevé est associé à une diminution de la survie dans les cancers de prostate Survie globale des patients avec métastases osseuses de cancer de prostate traités par acide zolédronique (n = 94) uNTx < 20 nmol/mmol créatinine uNTx ≥ 20 nmol/mmol créatinine 100 80 P < 60 Survie (%) 40 Survival time is reduced in men with bone metastases from prostate cancer who have high uNTx levels. In a study of 94 patients with bone metastases from prostate cancer receiving zoledronic acid, elevated uNTx was found to be an independent prognostic factor for overall survival (HR, 2.2; 95% CI, 1.24.0). Median overall was 12 months and 25 months in patients with uNTx  20 nmol/mmol creatinine vs uNTx < 20 nmol/mmol creatinine, respectively. uNTx was characterised as normal (< 20 nmol/mmol creatinine) or elevated (≥ 20 nmol/mmol creatinine), based on the observed median value in this study. Reference Rajpar S, Massard C, Laplance A et al. Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castration-resistant prostate cancer. Ann Oncol 2010;21:1864–9. 20 1 2 3 Temps à partir du screening (ans) Rajpar S et al. Ann Oncol 2010;21:1864–9. 6

7 Bisphosphonates IV / 4 semaines
Etude de phase II du denosumab chez les patients ayant un taux élevé d’uNTx sous biphosphonates R A N D O M I S A T I O N Bisphosphonates IV / 4 semaines (n = 37) Denosumab 180 mg SC / 12 semaines (n = 36) (N = 111) Denosumab 180 mg SC / 4 semaines (n = 38) In a Phase II study, patients with bone metastases from prostate, breast or other cancers and with elevated uNTx while on IV bisphosphonates were randomised to denosumab (one of two treatment regimens: 180 mg SC every 12 weeks or 180 mg SC every 4 weeks) or bisphosphonates IV every 4 weeks). The primary endpoint was the proportion of patients with normalised uNTx at Week 13. Reference Fizazi K, Lipton A, Mariette X et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009;27:1564–71. Critères inclusion Métastases osseuses TTT antérieur Bisphosphonates uNTx > 50 nmol/L* Critère de jugement principal Proportion de patients avec uNTx < 50 nmol/L* à la semaine 13 Fizazi K et al. J Clin Oncol 2009;27:1564–71. *Corrigé en fonction de la créatinine; 7

8 Le denosumab normalise uNTx chez plus de patients que lorsque l’on poursuit les biphosphonates IV
Normalisation uNTx 100 90 78a 80 70 64b 60 Patients avec uNTx < 50 nmol/L* à semaine 13 (%) 50 40 29 30 Denosumab was shown to normalise uNTx in significantly more patients than ongoing bisphosphonate treatment (denosumab SC every 12 weeks, P  0.005; denosumab SC every 4 weeks, P < 0.001). At Week 13, the percentage of patients with uNTx < 50 nmol/L was more than doubled in the two denosumab groups compared with the ongoing bisphosphonate group. Reference Fizazi K, Lipton A, Mariette X et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009;27:1564–71. 20 10 Bisphosphonate IV / 4 sem (n = 35) Denosumab SC / 12 sem (n = 33) Denosumab SC / 4 sem (n = 36) Fizazi K et al. J Clin Oncol 2009;27:1564–71. *Corrigé en fonction de la creatinine. aP < vs IV bisphosphonate; bP ≤ vs IV bisphosphonate. 8

9 Etude de phase III du denosumab vs acide zolédronique dans les CPRC avec métastases osseuses
Study 103 R A N D O M I S A T I O N Denosumab 120 mg SC /4 sem + Placebo IV / 4 sem* (n = 950) N = 1904 Supplementation journalière avec calcium (≥ 500 mg) and vitamin D (≥ 400 IU) Zoledronate 4 mg IV / 4 sem* + Placebo SC / 4 sem (n = 951) Critères d’inclusion CRPC Métastases osseuses Critères d’exclusion Bisphosphonates oraux pour le traitement des métastases osseuses Bisphosphonates IV antérieurs Study 103 was a randomised, double-blind, double-dummy, active-controlled Phase III study of denosumab versus zoledronic acid (standard of care) for the treatment of bone metastases in order to prevent or delay SREs in patients with prostate cancer. This international study involved 342 centres in 39 countries worldwide. Eligible patients had histologically confirmed prostate cancer, existing or previous radiographic evidence of at least one bone metastasis, documented failure of at least one hormonal therapy indicated by rising PSA with a final concentration 0.4 ng/mL or higher within 8 weeks of randomisation in the setting of castrate serum testosterone levels, adequate organ function and Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Key exclusion criteria included prior IV bisphosphonate treatment and current or prior oral bisphosphonates for the treatment of bone metastases. Patients were randomised to: Denosumab 120 mg SC and placebo IV every 4 weeks (n = 950). Zoledronic acid 4 mg IV and placebo SC every 4 weeks (n = 951). Per zoledronic acid prescribing information, IV products (zoledronic acid or placebo) were dose-adjusted on the basis of baseline creatinine clearance  60 mL/min and held for renal function deterioration until serum creatinine returned to within 10% of baseline values. There was no requirement for dose adjustment with denosumab. Daily supplementation with calcium (≥ 500 mg) and vitamin D (≥ 400 IU) was strongly recommended. 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;377:813–22. *dose ajustée à la clairance de la créatinine au départ et les suivantes déterminées par la créatininémie Fizazi K et al. Lancet 2011;377:813–22. 9 9

10 Temps jusqu’au premier événement osseux (SRE)
Dénosumab vs Acide Zolédronique Temps jusqu’au premier évènement osseux (SRE) 115 Cancer de la prostate avec métastases osseuses résistant à la castration (2) Temps jusqu’au premier événement osseux (SRE) Patients à risque 1 Sujets sans SRE 3 6 9 12 15 18 21 24 27 0,25 0,5 0,75 Médiane (mois) Dénosumab Acide zolédronique 20,7 17,1 HR = 0,82 (IC95 : 0,71-0,95) p = 0,0002 (non-infériorité) p = 0,008 (supériorité) Mois 951 950 733 758 544 582 407 472 299 361 207 259 140 168 93 115 64 70 47 39 18 % Réduction risque Le dénosumab permet de retarder de façon statistiquement significative le premier événement osseux (HR = 0,82 ; IC95 : 0,71-0,95 [p = 0,008]). Le temps médian jusqu’au premier événement osseux est de 20,7 mois versus 17,1 mois avec le zolédronate, soit une différence de 3,6 mois. - D’après Fizazi K et al, Lancet :813–22 10

11 Dénosumab vs Acide Zolédronique Temps jusqu’au premier événement osseux(SRE) et événements osseux suivants Cancer de la prostate avec métastases osseuses résistant à la castration Temps jusqu’au premier événement osseux et événements osseux suivants (analyse événements multiples) RR = 0,82 (IC95 : 0,71, 0,94) Mois 2 3 6 9 12 15 18 21 24 27 30 33 36 0,4 0,8 1,2 1,6 Dénosumab Acide zolédronique 584 494 Événements p = 0,008 Réduction risque 18 % Nombre cumulé moyen de SRE par patient Le dénosumab réduit également les autres événements osseux (RR = 0,82 ; IC95 : 0,71-0,94 [p = 0,008]) ainsi que les marqueurs de turn over osseux comme le uNTx et le BSAP. Les effets indésirables sont dans les 2 groupes notamment en ce qui concerne les hypocalcémies (12,3 % avec le dénosumab versus 5,4 % avec le zolédronate), mais aussi les ostéonécroses de la mâchoire (2,1 % versus 1,1 % respectivement [p = 0,09]). Le dénosumab vient donc de montrer en présence de métastases osseuses sa supériorité dans la prévention et le retard d’apparition des événements osseux. *Événements survenant au moins 21 jours après le début de l’étude D’après Fizazi K et al, Lancet :813–22 11

12 Dénosumab vs Acide Zolédronique. Survie globale
117 . Survie globale Survie 3 6 9 12 15 18 21 24 27 30 Patients à risque (n) 1 0,25 0,5 0,75 HR = 1,03 (IC95 : 0,91-1,17) Mois p = 0,65 Dénosumab Acide zolédronique 951 950 864 872 745 746 635 645 519 552 401 427 297 310 207 233 143 156 98 99 55 54 En revanche, le dénosumab, par rapport à l’acide zolédronique, ne modifie pas la survie globale. D’après Fizazi K et al, Lancet :813–22 12

13 Patients avec premier SRE (%)
Moins de SREs avec le denosumab vs acide zolédronique, quel que soit le type de SRE 25 21 Zolédronate (n = 951) Denosumab (n = 950) 20 19 15 14 15 Patients avec premier SRE (%) 10 5 4 The most frequent first on-study SRE was radiation to bone, followed by fracture. Denosumab was associated with fewer SREs vs zoledronic acid across different SREs types. 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;377:813–22. 3 <1 <1 Irradiation Fracture pathologique Compression Chirurgie Osseuse osseuse médullaire Fizazi K et al. Lancet 2011;377:813–22. 13

14 (marqueur ostéolytique) (marqueur ostéoblastique)
Denosumab diminue les marqueurs du turnover osseux comparé à l’acide zolédronique uNTx (marqueur ostéolytique) BSAP (marqueur ostéoblastique) 40 Zoledronate (n = 719) Zoledronate (n = 739) 20 Denosumab (n = 738) Denosumab (n = 755) Médiane changement (Q1, Q3) / baseline (%) -27 -20 -35 -40 -69 -60 In support of the SRE results, denosumab was associated with significantly greater reduction in levels of the bone markers uNTx (P < ) and BSAP (P < ) than zoledronic acid. 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;377:813–22. -84 -80 P < -100 P < Fizazi K et al. Lancet 2011;377:813–22. 14

15 Proportion de patients (%)
Pas de différence significative dans le taux d’ostéonécrose de mâchoire (ONJ) entre denosumab et acide zolédronique Tous les patients (N = 5723) 6 Zolédronate (n = 2836) ONJ potentielle (n = 276) Denosumab (n = 2814) 4 P = 0.13 Proportion de patients (%) ONJ confirmée (n = 89) 1.8 1.8 2 1.3 1.0 0.8 0.5 This was the first prospective evaluation of ONJ utilising data from three large, randomised, Phase III trials, with a rigorous identification and adjudication process. The trials included exclusion criteria specific to ONJ: Prior history or current evidence of ONJ or osteomyelitis of the jaw. Active dental or jaw condition requiring surgery. Planned invasive dental procedures over the course of study. Non-healed oral or dental surgery. Monitoring was conducted by oral examinations every 6 months and spontaneous reports by investigators. Cases of suspected ONJ were adjudicated by a blinded, external panel of independent experts. The flow scheme shows the adjudication process of 5723 patients in the analysis of whom 276 had an oral event suspected to be ONJ. Of these, 89 cases were confirmed by the panel of independent experts: 37 in the zoledronic acid treatment group and 52 in the denosumab treatment group. The cumulative incidence of ONJ was low, with no significant difference between treatment groups (P = 0.13, year 3). Reference Brown J, Henrique Barrios C, Diel IJ et al. Incidence and outcomes of osteonecrosis of the jaw (ONJ) from an integrated analysis of three pivotal randomized double-blind, double-dummy phase 3 trials comparing denosumab and zoledronic acid for treatment of bone metastases in advanced cancer patients or myeloma [Abstract OC-15]. Presented at 10th International Conference on Cancer-Induced Bone Disease (CIBD), 22–25 September 2010; Sheffield, UK. Zoledronate (n = 37) 1.3% Denosumab (n = 52) 1.8% Année 1 Année 2 Année 3 Incidence cumulée ONJ Brown J et al. Presented at CIBD, 2010 [Abstract OC-15]. 15

16 Le denosumab peut être utilisé chez les insuffisants rénaux sans adaptation de dose.
- Etude de 16 semaines chez 55 patients présentant une fonction rénale variable, de normale à terminale nécessitant une dialyse, évaluant les effets d’une dose unique de denosumab (60 mg S.C) - Les perturbations de la fonction rénale ne modifient pas significativement les données pharmacocinétiques et pharmacodynamiques du denosumab - Une supplémentation vitamino-calcique n’était pas requise dans le protocole. - L’effet secondaire le plus fréquent a été une hypocalcémie ; 7 ont présenté un nadir de calcémie entre 1.9 et 2 mmol/l et 5 un nadir < 1.9 mmol/l Block GA, J Bone Miner Res Mar 28 16 - Titre de la présentation - nom du département émetteur et/ ou rédacteur - 00/00/2005

17 Dénosumab versus placebo, cancer de la prostate M0 et survenue de métastases osseuses chez les patients à haut risque (1) Critères d’inclusion CRPC M0 Haut risque de métastases osseuses PSA ≥ 8,0 ng/ml et/ou Temps doublement du PSA ≤ 10,0 mois Critères d’exclusion Métastases osseuses Métastases extrasquelettiques (sauf ganglions) Bisphosphonates IV Dénosumab 120 mg s.c. toutes les 4 sem. (n = 716) Supplémentation en calcium et en vitamine D Métastases osseuses ou décès Placebo 120 mg s.c. toutes les 4 sem. (n = 716) Les résultats globaux de cette étude de phase III ont été présentés à l’ESMO 2011 par S. Oudard. Les données présentées à l’ASCO® GU concernent une population spécifique de l’étude : les patients à haut risque de métastases osseuses (PSA supérieur ou égal à 8 et/ou temps de doublement du PSA inférieur ou égal à 10 mois). Objectif I : Survie sans M+ os Objectif II : Temps  1ère M+ os SG ASCO® GU 2012 – D’après Smith et al., abstr. 6 17

18 Baseline Characteristics
Denosumab 147 Trial Characteristic, n (%) or median Placebo (N = 716) Denosumab (N = 716) Age (years) 74.0 Time from diagnosis to study entry (years) 6.1 PSA (ng/mL) 12.5 12.2 PSA dual risk factors1 346 (48) PSA single risk factor2 370 (52) Prior chemotherapy 55 (8) Duration of prior ADT (years) 3.9 Local therapy 331 (46) 313 (44) Gleason score at diagnosis 2 - 7 432 (60) 404 (56) 8 - 10 214 (30) 237 (33) ECOG performance status ≤ 1 713 (~100) 715 (~100) ECOG Performance Status at Study Entry: 0: 514 (72%) Placebo; 505 (70%) Denosumab 1: 199 (28%) Placebo; 210 (29%) Denosumab 2: 3 (0.4%) Placebo; 1 (0.1%) Denosumab 1PSA level ≥ 8.0 ng/mL and PSA doubling time ≤ 10 months 2PSA level < 8.0 ng/mL and PSA doubling time ≤ 10.0 months OR PSA level ≥ 8.0 ng/mL and PSA doubling time > 10.0 months

19 Dénosumab et prévention des métastases osseuses chez les patients CRPC M0
Médiane (mois) Événements Dénosumab 29,5 + 4,3 335 Placebo 25,2 370 L’effet du dénosumab est d’autant plus marqué que le temps de doublement du PSA est court : ≤ 10 mois : –16 % de risque de métastases osseuses ; p = 0,042 ; ≤ 6 mois : –23 % de risque de métastases osseuses ; p = 0,006 ; ≤ 4 mois : –29 % de risque de métastases osseuses ; p = 0,004. ASCO® GU 2012 – D’après Smith et al., abstr. 6 19

20 Temps jusqu’à métastase symptomatique
Denosumab 147 Trial Temps jusqu’à métastase symptomatique Of 705 bone metastases-free survival events (total # of events from slide 7), 605 were bone metastases and 100 were deaths. Of the 605 patients with bone metastases, 165 were denoted by investigator as symptomatic (27% of bone metastases). Among all patients (716 per arm), 96 (13%) in placebo arm and 69 (10%) in denosumab arm developed symptomatic bone metastases. We therefore see a 33% reduction in risk for symptomatic bone metastasis in patients receiving denosumab compared with placebo.

21 Time to Symptomatic Bone Metastasis By Disease Characteristics
Denosumab 147 Trial Time to Symptomatic Bone Metastasis By Disease Characteristics 1PSA level ≥ 8.0 ng/mL and PSA doubling time ≤ 10 months 2PSA level < 8.0 ng/mL and PSA doubling time ≤ 10.0 months OR PSA level ≥ 8.0 ng/mL and PSA doubling time > 10.0 months

22 Time to Symptomatic Bone Metastasis By Demographic Characteristics
Denosumab 147 Trial Time to Symptomatic Bone Metastasis By Demographic Characteristics

23 Denosumab 147 Trial Overall Survival Note: Overall survival based on both treatment phase and follow-up phase. Median OS less then 4 years in both arms.

24 Summary of Adverse Events
Denosumab 147 Trial Summary of Adverse Events Patient Incidence, n (%) Placebo (N = 705) Denosumab (N = 720) Adverse Events (AEs) 655 (92.9) 676 (93.9) Most Common AEs in Either Arm Back Pain 156 (22.1) 168 (23.3) Constipation 119 (16.9) 127 (17.6) Arthralgia 112 (15.9) 123 (17.1) Diarrhea 102 (14.5) 111 (15.4) Urinary Tract Infection 96 (13.6) 108 (15.0) Serious AEs 323 (45.8) 329 (45.7) Positively Adjudicated Osteonecrosis of Jaw 33 (4.6) Cumulative Incidence Year 1 8 (1.1) Year 2 21 (2.9) Year 3 30 (4.2) Hypocalcemia 2 (0.3) 12 (1.7) ONJ seen in other studies; In this study, exposure was ~20 months compared with only ~12 months in the SRE studies. Hence, it is not unexpected that overall rate here is higher than what was reported in the SRE trials. Yearly ONJ rates are comparable between the current study and SRE studies. Adverse event of hypocalcemia for denosumab in this trial is much lower (1.7%, rounded to 2%) than what was reported in trial 103 of castrate-resistant prostate cancer with bone metastases (13%). N = Number of subjects who received ≥ 1 dose of drug

25 Etude de phase III denosumab vs placebo
- Taux d’effets secondaires et d’AEs similaires dans les 2 groupes - Sauf pour les ONJ et les hypocalcémies - 33 pts (5%) ont présenté une ONJ dans le bras denosumab vs 0 dans le bras placebo - 12 pts (2%) ont présenté une hypocalcémie dans le bras denosumab vs 2 (<1%) dans le bras placebo . Smith MR, Lancet, janvier 2012