Curare l osso per curare il Tumore

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1 Curare l osso per curare il Tumore Daniele Santini University Campus Bio-Medico, Rome

2 Bone Health nel pazienti neoplastico ELEVATO TURNOVER OSSEO CTIBL FRAGILITÀ PROGRESSIONE OSSEA SRE Nuova metastasi Perdita ossea Homing delle cellule tumorali Crescita della metastasi ossea CTX NTX P1NP SDF-1 TGF b PDGF IGF-1 OP CTX NTX P1NP SDF-1 TGF b PDGF OP CTX NTX P1NP SDF-1 TGF b PDGF OP Scheletro non metastatico Nicchia preneoplastica Metastasi ossea Courtesy of Francesco Bertoldo

3 The skeleton is affected throughout the natural history of prostate cancer Death PSA / tumour burden Initial diagnosis and therapy ADT Cancer treatment induced bone loss 1 (Study 138) Prevention of SREs 3 (Study 103) Prevention of bone mets 2 (Study 147) SRE Bone mets Castration-resistant Time 1. Smith, et al. N Engl J Med 2009;361:745 55; 2. NCT ; 3. NCT

4 CANCER TREATMENT INDUCED BONE LOSS Rate of BMD Loss Normal men Late menop. women 0.5% 1% Early menop women Aromatase Inhibitor Bone Marrow transpl 2 % 2.6% 3.3% Androgen deprivation 4.6% AI + GNrh agonist 7.0% Ovarian failure due chemiother % Lumbar spine BMD (% /year Bone Loss)

5 FRACTUR-FREE SURVIVAL AMONG PATIENTS WITH PROSTATE CANCER ACCORDING TO ANDROGEN-DEPRIVATION THERAPY Shahinian VB et al

6 Survival in Prostate Cancer Patients with and without fractures Cumulative Propor rtion of Survival NO FX Oefelein MG, J Urol 2002 Mesi

7 Bone target agents: effects on BMD in Men with ADT Induced Bone Loss 7 7% Risedronate 35mg % 4.2% 4% 4.6% 5.3% 4.1% 4.8%. Alendronate 70 mg) Zoledronate 4 mg once y Zoledronate 4mg/ 3 mo DNB 60 mg/6 mo ) % from baseline % 2% 2% 1.1% 1.1% 3.2% 0 Spine Ishizako K 2007 Smith NEJM 2009 Michaelson MD 2007; Satoh T 2009 Hip Smith MR 2003; Campbell 2010 Bhoopalam 2009

8 Study Schema Design: Randomised, double-blind, placebo-controlled, multicentre Study protocol amended from 2 to 3 years to extend period for safety and fracture evaluation Men with nonmetastatic prostate cancer receiving continuous ADT (n=1468) Stratified by End points Primary Secondary Age (<70 y vs 70 y) Prior ADT duration ( 6 mo vs >6 mo) R A N D O M I S E Baseline Denosumab 60 mg SC Q6M ( 6 doses) (n=734) Placebo SC Q6M ( 6 doses) (n=734) Supplemental calcium and vitamin D Percentage change from baseline at month 24 in lumbar spine BMD Incidence of new vertebral fractures over 36 months Percentage change from baseline at month 36 in lumbar spine BMD Percentage change from baseline at 24 and 36 months in total hip and femoral neck BMD Fracture at any site (morphometric/clinical vertebral or nonvertebral) Time to first clinical fracture Safety events Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361: months

9 RR 0.15 RR 0.31 RR 0.38

10 G.U. 20/5/15 n 115 PREVENZIONE PRIMARIA IN DONNE IN MENOPAUSA MASCHI > 50 ANNI CON RISCHIO FRATTURA ELEVATO Previsione di trattamento > 3 mesi PN >5 mg (o equiv.) Bocco ormonale adiuvante ( per la durata del trattamento) BMD T-score<-3 + Familiarità fx vertebre e/o femore BMD T-score<-4 1 scelta:. Alendronato Risedronato Ac zoledronico 2 scelta: denosumab Courtesy of Francesco Bertoldo 1Scelta: Denosumab Alendronato Risedronato Ac zoledronico Sclerosi mult. Parkinson Grave disabilità motoria Diabete mellito M. infiamm cron. Intest. AR+ connettiviti BPCO AIDS 1. alendronato/risedronato 2. Denosumab,ac zoledronico,ibandronato 3. raloxifene

11 THE ROLE OF VITAMIN D IN BONE HEALTH In CANCER PATIENT Vit D Supplementation Low vit Mandatory: D >50 yr High BMI BPs + Fabbisogno 1000 UI/die Utilizzare Prognosis/ solo Colecalciferolo (DIBASE) PTH Survival 15 gg PRIMA DI INZIARE + BPs _ UI per Calcium 2 giorni consecutivi Bisphosphonates DOPO UI 1fl/1-2 mesi Courtesy of Francesco Bertoldo + Cancer Bone High bone turnover Bone Metastases SRE

12 The skeleton is affected throughout the natural history of prostate cancer Death PSA / tumour burden Initial diagnosis and therapy ADT Cancer treatment induced bone loss 1 (Study 138) Prevention of SREs 3 (Study 103) Prevention of bone mets 2 (Study 147) SRE Bone mets Castration-resistant Time 1. Smith, et al. N Engl J Med 2009;361:745 55; 2. NCT ; 3. NCT

13 Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147) Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) N = Prostate cancer (non metastatic) Hormone-refractory disease High risk of bone metastases (PSA at least 8 and/or PSA doubling time less than 10 months Adequate organ function R A N D O M I Z A T I O N Denosumab 120 mg SC every 4 weeks Placebo Event-driven study: time to bone metastasis or death Smith MR, et al. Lancet

14 Bone metastasis-free survival Proportio on of patients Placebo Denosumab HR = 0.85 (95% CI 0.73, 0.98) P = Median months Study month Events Smith MR, et al. Lancet Placebo Denosumab

15 Denosumab 147 Trial Bone Metastasis-Free Survival in Patients with PSADT 6 Months Proportion of Patients With Bone Metastasis- is-free Survival Placebo Denosumab Smith MR, et al. ASCO GU, HR = 0.77 (95% CI 0.64, 0.93) P = % Risk Reduction Placebo Denosumab Median Months Delay (Months) Study Month Events

16 Phase II/III trials in M0 CRPC Study PROSPER NCT STRIVE NCT SPARTAN NCT IMAAGEN NCT ARAMIS NCT Phase 3 (N= ) 2 US (N=400 mix pop) 3 (N=1200) 2 (N=134) 3 (N=1500) Start/ Completion / / / / / Patient M0 CRPC high M0 CRPC and M1 M0 CRPC high risk M0 CRPC M0 CRPC high risk population risk CRPC currently receiving GNRH Treatment Enzalutamide vs placebo Enzalutamide vs bicalutamide ARN 509 vs placebo Abiraterone/pred + GNRH (single arm) 1 o Endpoint MFS PFS MFS Proportion of pts with 50% reduction in PSA Sponsor Astellas/ Medivation ODM-201 vs placebo MFS Medivation/ Astellas Janssen Janssen Bayer/Orion MFS, metastasis-free survival; PFS, progression-free survival; RT, radiotherapy

17 The skeleton is affected throughout the natural history of prostate cancer Death PSA / tumour burden Initial diagnosis and therapy ADT Cancer treatment induced bone loss 1 (Study 138) Prevention of SREs 3 (Study 103) Prevention of bone mets 2 (Study 147) SRE Bone mets Castration-resistant Time 1. Smith, et al. N Engl J Med 2009;361:745 55; 2. NCT ; 3. NCT

18 18 Malattia ormonosensibile

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20 Zoledronic acid: does not work in hormonosensitive PC

21 Docetaxel: bone target therapy?

22 Linee Guida - aggiornamento AIOM 2014 come sono cambiate Carcinoma prostatico con metastasi ossee

23 Malattia resistente alla castrazione 23

24 Denosumab* Phase III SRE prevention trials Three trials of identical design in patients with bone metastases from solid tumours or multiple myeloma Lipton et alasco, 2014 Study Breast cancer (N = 2049) Study Prostate cancer (N = 1904) Study Other solid tumours /MM (N = 1779) R A N D O M I S A T I O N Denosumab 120 mg SC Q4W + Placebo IV Q4W * Supplemental calcium and vitamin D Zoledronic acid 4 mg IV Q4W * + Placebo SC Q4W Primary endpoint: time to first on-study SRE Secondary endpoints: time to first and subsequent SREs, time to disease progression, overall survival, incidence of adverse events 1. Stopeck AT, et al. J Clin Oncol 2010;28:5132 9; 2. Fizazi K, et al. Lancet 2011;377:813 22; 3. Henry DH, et al. J Clin Oncol 2011;29: *IV product dose adjusted as per zoledronic acid product labelling. Excluding breast and prostate. MM, multiple myeloma; Q4W, every 4 weeks; SC, subcutaneously.

25 Patients baseline characteristics Baseline characteristic, n (%) or median Zoledronic acid (n = 2861) Denosumab (n = 2862) Women 1349 (47.2) 1316 (46.0) Age, years ECOG status of 0 or (89.0) 2585 (90.3) Tumour type* Breast 1020 (35.7) 1026 (35.8) Prostate 951 (33.2) 950 (33.2) Non-small cell lung 352 (12.3) 350 (12.2) Multiple myeloma 93 (3.3) 87 (3.0) Renal 85 (3.0) 70 (2.4) Small cell lung 48 (1.7) 61 (2.1) Other 312 (10.9) 318 (11.1) Time from first bone metastasis to randomisation, months Previous SRE 1157 (40.4) 1112 (38.9) Lipton et alasco, 2014

26 Subgroup analyses by baseline characteristics. Denosumab significantly delayed patients time to SREs compared to ZA regardless of patient s baseline status. Benefit of denosumabvs ZA on time to first on-study SRE Baseline characteristic HR (95% CI) P-value Axial bone mets only (n=1,422) 0.83 (0.70,1.00) Appendicular bone mets only (n=753) 0.78 (0.61,0.99) Both axial & appendicular bone mets (n=1,695) 0.83 (0.71, 0.97) bone mets (n=2,234) 0.81 (0.71,0.93) <2 bone mets (n=3,489) 0.84 (0.74,0.94) Visceral mets (n=2,341) 0.80 (0.69,0.93) No visceral mets (n=3,382) 0.84 (0.75,0.94) High untx (n=2,553) 0.86 (0.76,0.98) Low untx (n=2,553) 0.75 (0.65, 0.86) <0.001 ECOG 0 (n=2,312) 0.82 (0.71,0.94) ECOG 1 (n=3,398) 0.84 (0.75,0.94) Lipton et alasco, 2014

27 Adro-therapy with alpha emitters 223 Ra: T 1/ gg mean alfa energy: 5.78 Mev (93.5% d) < 4% Beta emission < 2% gamma emission 269Kev (13.6%), 154 Kev (6.04%), 324 Kev (3.9%) U-235 -> Th-231 -> Pa-231 -> Ac-227 -> Th-227 -> Ra-223 -> Rn-219 -> Po-215 -> Pb-211 -> Bi-211 -> Tl > Pb- 207 (stable)

28 ALSYMPCA: Study Design n=921 mcrpc patients 2:1 Randomisation Radium Best standard of care (BSoC) 50 kbq/kg Placebo + BSoC 6 injections at 4 week intervals Key inclusion criteria Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post docetaxel or unfit/unwilling for docetaxel Stratification factors Total ALP: <220 U/L vs 220 U/L Bisphosphonate use: Yes vs no Prior docetaxel: Yes vs no Parker C, et al. N Engl J Med. 2013;369:

29 ALSYMPCA: Overall Survival 3.6 month improvement vs placebo 100 HR=0.70 (95% CI, ) p< % reduction in risk of death 80 Surviva ival (%) (%) Radium-223 (median overall survival, 14.9 mos) 20 0 Radium 223 Placebo Months since Randomization Parker et al. N Engl J Med. 2013; 18;369(3): Placebo (median overall survival, 11.3 mo) No. at Risk Radium Placebo

30 ALSYMPCA: Overall Survival Across Patient Subgroups Subgroup Number of Patients Median Overall Survival (months) Hazard Ratio (95% CI) Radium-223 Placebo Radium-223 Placebo All patients Total ALP <220 U/L 220 U/L Current use of bisphosphonates Yes No Prior use of docetaxel Yes No Baseline ECOG PS 0 or 1 2 Extent of disease <6 metastases 6-20 metastases >20 metastases Superscan Opioid use Yes No NE ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance status; NE, not evaluated Parker C, et al. N Engl J Med. 2013;369: Copyright Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society Favours Radium 223 Favours placebo

31 Phase 3 ALSYMPCA Overall Survival by prior docetaxel Vogelzang NJ, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5068).

32 ALSYMPCA: Median Time to First SSE 100 Patients Wi ithout SSEs (%) HR=0.66; 95% CI: P< Radium BSoC median time to SSE: 15.6 months (n=614) Placebo + BSoC median time to SEE: 9.8 months (n=307) Month Radium Placebo Parker C, et al. N Engl J Med. 2013;369:

33 Radium-223 in combination with denosumab/abiraterone may improve OS Saad et al. J Clin Oncol 2015; 33(s): abstract 5034

34 Phase III Randomized Study of Abiraterone *- Radium 223 in Patients with Asymptomatic/Mildly Symptomatic CRPC

35 Why abiraterone and enzalutamide in bone metastatic disease?

36 Abiraterone post-docetaxel does delay SREs 4.7 months of difference Logothetis et al. Lancet Oncology, 2012

37 Abiraterone pre-docetaxel Statistically Significant Improvement in All Secondary End Points Time to opiate use (cancer related pain) AA + P Median (months) Placebo + P Median (months) HR (95% CI) 0.72 (0.61, 0.85) Time to chemotherapy initiation (0.49, 0.69) Time to ECOG PS deterioration Time to PSA progression (0.71, 0.94) 0.49 (0.42, 0.57) P Value < < < Note: All secondary end points remain significant after adjusting for multiplicity testing Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

38 Enzalutamide post-docetaxel does delay SREs 3.4 months of difference Pre-planned analysis JS De Bono, ASCO, 2012

39 Enzalutamide pre-docetaxel does delay SREs Enzalutamide Reduced Risk of First <br />Skeletal-Related Event* Beer TM et al. N EnglJ Med Presented By Andrew Armstrong at 2014 ASCO Annual Meeting

40 Linee Guida - aggiornamento AIOM 2015 Carcinoma prostatico con metastasi ossee Le nuove molecole: abiraterone e enzalutamide L abiraterone e l enzalutamide sono capaci, nei pazienti affetti da tumore della prostata metastatico allo scheletro in fase di resistenza alla castrazione, di ritardare la comparsa degli SRE e la progressione scheletrica Livello di evidenza: 1+

41 Cosa abbiamo scoperto circa l effetto di abiraterone sul microambiente osseo?

42 Il microambiente osseo può fare brutti scherzi durante la terapia con abiraterone Pre-trattamento FCH-PET/CT Metastasi pubica SUVmax= 6 Iperattivazione microambiente osseo + 7 settimane SUVmax= 13 Inibizione del circolo vizioso della metastasi ossea + 15 settimane SUVmax= 4 PSA = 4.5 PSA = 1.8 PSA = 1.1 Courtesy U De Giorgi

43 I targets molecolari di abiraterone sono presenti sia negli osteoclasti che negli osteoblasti REAL TIME PCR HUMAN PRIMARY OSTEOCLAST HUMAN PRIMARY OSTEOBLAST mrna LEVELS vs GUS-β mrna LEVELS vs GUS-β MONOCYTE PRE-OCL OCL MESENCHYMAL CELLS PRE-OBL OBL M. Iuliani, F. Pantano and D. Santini D, Oncotarget, 2015

44 Abiraterone inibisce la differenziazione e la funzione degli osteoclasti CTRL TRAP ASSAY CTRL ABIRATERONE M. Iuliani, F. Pantano and D. Santini D, Oncotarget, 2015

45 Abiraterone promuove la differenziazione e la funzione degli osteoblasti CTRL WITH STEROID CTRL WITHOUT STEROID CTRL ABIRATERONE ABIRATERONE M. Iuliani, F. Pantano and D. Santini D, Oncotarget, 2015

46 Riepilogando.

47 Le potenzialità delle tumortarget theraphies sulla salute dell osso nel paziente oncologico 1 CTIBL FRAGILITÀ Perdita ossea CTX NTX P1NP SDF-1 TGF b PDGF IGF-1 OP CTX NTX P1NP SDF-1 TGF b PDGF OP CTX NTX P1NP SDF-1 TGF b PDGF OP Scheletro non metastatico Nicchia preneoplastica Metastasi ossea Modified from Francesco Bertoldo

48 Percent Incidence of AEs by Duration of Exposure and by Grade (cont) Rathkopf D et al. Eur Urol 2014; [epub]

49 Le potenzialità delle tumortarget theraphies sulla salute dell osso nel paziente oncologico 3 PROGRESSIONE OSSEA 2 Nuova metastasi Homingdelle cellule tumorali Crescita della metastasi ossea CTX NTX P1NP SDF-1 TGF b PDGF IGF-1 OP CTX NTX P1NP SDF-1 TGF b PDGF OP CTX NTX P1NP SDF-1 TGF b PDGF OP Scheletro non metastatico Nicchia preneoplastica Metastasi ossea Courtesy of Francesco Bertoldo

50 Le potenzialità delle tumortarget theraphies sulla salute dell osso nel paziente oncologico 4 SRE/PAIN Crescita della metastasi ossea CTX NTX P1NP SDF-1 TGF b PDGF IGF-1 OP CTX NTX P1NP SDF-1 TGF b PDGF OP CTX NTX P1NP SDF-1 TGF b PDGF OP Scheletro non metastatico Nicchia preneoplastica Metastasi ossea Courtesy of Francesco Bertoldo

51 Posso associare le bone target therapies all abiraterone/enzalutamide?

52 The benefit of abiraterone on clinical outcomes were increased with concomitant use of BTT Saad F, Eur Urol, 2015, in press

53 Grazie per la Vostra Attenzione