Farmaci per la prevenzione degli eventi scheletrici Alfredo Berruti Università degli Studi di Brescia Azienda Ospedaliera Spedali Civili Brescia

Skeletal-Related Events Are Prevalent in the Absence of Therapy Placebo arm* 79% 50% 51% 49% 46% Patients with SRE, % Breast cancer1 Prostate cancer2 Multiple myeloma3 NSCLC and OST4 RCC5 NSCLC = Non-small cell lung cancer; OST = Other solid tumors; RCC = Renal cell carcinoma. *Placebo arm from zoledronic acid and pamidronate clinical trials. 1. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321; 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882; 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602; 4. Rosen LS, et al. Cancer. 2004;100:2613-2621; 5. Mulders PF. Presented at: EAU 2007.

Patients Experience Multiple Skeletal Complications before Death

Inibitori del riassorbimento osseo Bisfosfonati: apoptosi degli osteoclasti Denosumab: blocco della maturazione degli osteoclasti

Targeting Tumor (bone) Tumor cell microenvironment J Natl Cancer Inst 2011;103:1665–1675

What is the role of bone resorption agents in the management of cancer patients? Role End point Pallative: prevention of skeletal elated events bone pain control Antineoplastic: survival prevention of bone metastases

Le evidenze che hanno portato all’attuale Standard of Care RCT III vs Placebo Pamidronate1,2 Ibandronate3 Zoledronic acid4,5,6 Breast cancer   Multiple myeloma Prostate cancer Lung cancer and other solid tumors 1 Hortobagyi et al. JCO, vol 6, No 6, 1998; 2 Theriault et al. JCO, vol 17, No 3, 1999; 3Body et al. Ann Onc 15: 180. 2004; 4Rosen et al. Cancer Vol 98, No 8, 2003; 5Rosen, Cancer, In press; 6Saad, JNCI, Convenienza di somministrazione PAM 2h infusione ZOL 15 min infusione

Bisphosphonates and SRE in Advanced Breast Cancer Wong MH, et al Cochrane Database Syst Rev. 2012

Bisphosphonates and SRE and Bone Pain in Advanced Postate Cancer SREs Bone Pain Yuen KK et al Cochrane Database Syst Rev 2006

Quando non usare il bisfosfonato

A combined analysis of 3 pivotal, randomised, phase 3 trials Superiority of denosumab to zoledronic acid for prevention of skeletal-related events A combined analysis of 3 pivotal, randomised, phase 3 trials Time To First SRE (test non-inferiority and superiority) -17% Lipton A, et al. European Journal of Cancer (2012) 48, 3082-3092

Other solid tumours/MM3† 1 Efficacia nella prevenzione del primo evento scheletrico e successivi nella maggioranza di istotipi tumorali La riduzione del rischio di sviluppare il primo evento scheletrico è a favore di denosumab in maniera consistente in tutti i tumor type 18% risk reduction 18% risk reduction 16% risk reduction Breast cancer1 Prostate cancer2 Other solid tumours/MM3† 100 HR = 0.82 (95% CI, 0.71–0.95) P = 0.01 (superiority) HR = 0.82 (95% CI, 0.71–0.95) P = 0.008 (superiority) HR = 0.84 (95% CI, 0.71–0.98) P = 0.0007 (non-inferiority) P = 0.06 (NS for superiority) 90 80 Not yet reached 20.7 months 70 20.6 months 60 Patients without SRE (%) 50 40 26.4 months 17.1 months 16.3 months 30 Denosumab consistently reduced risk of first SRE across different tumour types: 18% risk reduction over zoledronic acid in patients with breast cancer (P = 0.01, superiority).1 18% risk reduction over zoledronic acid in patients with prostate cancer (P = 0.008, superiority).2 16% risk reduction over zoledronic acid in patients with solid tumours and multiple myeloma (P = 0.06, superiority).3 17% risk reduction over zoledronic acid in the integrated analysis combining data from all three studies (P < 0.0001, superiority).4 References Stopeck AT, Lipton A, Body J-J, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132–9. 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. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:112532. Lipton A, Siena S, Rader M et al. Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials [Abstract 1249P]. Ann Oncol 2010;21(Suppl 8):viii379. 20 10 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 27 3 6 9 12 15 18 21 24 Denosumab Study month Zoledronic acid 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;29:1125-32. †Excluding breast and prostate. All data from primary analyses. MM, multiple myeloma; NS, non-significant.

Denosumab vs Acido Zoledronico Maggiore efficacia Maggiori costi

Quando preferire Denosumab? Livelli di creatinina elevati

Nuovi scenari Interazioni con i “nuovi” farmaci

Drugs targeting AR and SRE prevention Abiraterone

Enzalutamide: Tempo al primo SRE Il tempo di insorgenza del primo SRE è stato significativamente ritardato da enzalutamide rispetto a placebo: 16.7 versus 13.3 mesi (HR=0.69, 95% CI: 0.57–0.84; p<0.001) 31% riduzione del rischio di SRE 100 80 Enzalutamide: 16.7 mesi (95% CI: 14.6–19.1) 60 SRE libero (%) 40 Placebo: 13.3 mesi (95% CI: 5.5–NYR) 20 3 6 9 12 15 18 21 24 Tempo all’evento (mesi) N. a rischio: Enzalutamide, n= Placebo, n= Text missing after delayed 800 399 676 278 548 196 379 128 209 68 87 33 19 11 2 Tempo al primo SRE definito come il tempo di radioterapia, chirurgia ossea, fratture ossee patologiche, compressione del midollo spinale o il cambiamento di terapia antineoplastica per trattare il dolore osseo. CI= intervallo di confidenza; HR= rapporto di rischio; NYR= non ancora raggiunto; SRE= eventi scheletrici correlati. De Bono J, et al. Presented at ASCO 2012; Oral presentation 4519.

Clin Cancer Res 17: 4854-4861, 2011

Efficacy of bisphosphonates in abiraterone treated patients Efficacy of bisphosphonates in abiraterone treated patients. Explorative analysis (Overall ITT Population) Endpoint BTT Use No BTT Use HR (95% CI) P Value rPFS 13.60 (11.04-16.43) 10.97 (10.68-12.06) 0.855 (0.718-1.018) 0.079 OS NE (30.88, NE) 30.26 (28.58-33.18) 0.754 (0.604-0.940) 0.012 Time to opiate use (27.63, NE) 27.89 (23.62-30.88) 0.801 (0.651-0.985) 0.036 Time to chemotherapy 22.41 (18.46-27.07) 21.06 (19.22-23.26) 0.916 (0.762-1.100) 0.348 Time to ECOG deterioration 14.26 (11.17-15.84) 11.07 (9.95-11.99) 0.750 (0.643-0.874) <0.001 TTPP 8.34 (8.31-11.07) 8.31 (8.21-8.34) 0.878 (0.750-1.028) 0.105 Saad C et al. ASCO 2013; Abstract 5037 (Poster Presentation)

mTOR INHIBITORS AND OSTEOCLAST ACTIVATION Bertoldo F et al. Biochimica and Biophysica Acta : 1845: 248-254, 2014

Supplementazione vitamina D Everolimus + Denosumab or Zoledronic acid Hypophosphatemia Hypocalcemia Supplementazione vitamina D