IL TRATTAMENTO DEL MICROAMBIENTE OSSEO Alfredo Berruti Università degli Studi di Brescia Azienda Ospedaliera Spedali Civili Brescia THE VICIOUS CIRCLE Kingsley LA et al Mol Cancer Ther 2007;6(10):2609–2617 Skeletal-Related Events Are Prevalent in the Absence of Therapy Placebo arm* 90 Patients with SRE, % 80 79% 70 60 50 50% 49% 51% 46% 40 30 20 10 0 Breas RC NSCLC Prostat Multiple t C5 and myelom e cance OST4 a3 cancer 2 1 r 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. Bisphosphonates and SRE and Bone Pain in Advanced Postate Cancer SREs Bone Pain Yuen KK et al Cochrane Database Syst Rev 2006 Quesiti aperti Possono gli inibitori del riassorbimento osseo migliorare la prognosi dei pazienti? Sono efficaci anche nel paziente metastatico ormono sensibile? Quale il loro ruolo in adiuvante? 27 Prostate Cancer Survival 100 Median, days Percent surviving ZOMETA® 80 4 mg Placebo P value 546 469 .103 60 40 20 0 0 120 240 360 480 600 720 840 960 Days* Zol 4 mg Placebo 214 208 162 148 *Time after start of study drug. 113 94 56 40 10 5 SURVIVAL POOLED ANALYSIS Hazard Ratio Study or Subgroup log[Hazard Ratio] SE Weight IV, Fixed, 95% CI Year Dearnaley -0.223 0.129 46.4% 0.80 [0.62, 1.03] 2003 Smith 2014 -0.128 0.88 [0.70, 1.11] 2014 Total (95% CI) 0.12 53.6% Hazard Ratio IV, Fixed, 95% CI 100.0% 0.84 [0.71, 1.00] Heterogeneity: Chi² = 0.29, df = 1 (P = 0.59); I² = 0% Test for overall effect: Z = 1.96 (P = 0.05) 0.5 0.7 1 1.5 2 Favours BP Favours no BP Valcamonico F Petrelli F, Barni S, et al, J Clin Oncol 2014 in press Key Inclusion Criteria •Adults with prostate, •and ≥ 1 bone metastasis / lesion Key Exclusion Criteria Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 951) 1:1 •No current or prior IV bisphosphonate administration for treatment of bone metastases Daily Supplements of Calcium and Vitamin D Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 953) Lancet 2011; 377: 813–22 Lancet 2011; 377: 813–22 Targeting Tumor cell Tumor (bone) microenvironment J Natl Cancer Inst 2011;103:1665–1675 … e in adiuvante? Parasitism of the bone microenvironment by prostate cancer Yu C et al, Critical ReviewsTM in Eukaryotic Gene Expression, 22: 131–148 (2012) Brian Ell and Yibin Kang Cell 151, October 26, 2012 GNRH AGONISTI Aromatasi Inhibitors CHEMIOTERAPIA Menopause Age Low vitamin D leves High Bone Turnover Cancer cell Homing New Bone Metastasis Osteoporosis Fragility Fractures SRE Fractures Hypercalcemia Radiotherapy Othopedic Surg. Pain Bone Metastasis Gowth BP Brian Ell and Yibin Kang Cell 151, October 26, 2012 Eur Urol 2014, in press Non metastatic 508 pts Metastatic 311 pts Lancet Oncol. 2009 September 9; 10(9): 872–876. Lessons From 60 Years of Practice: PSA Era Radical prostatectomy 90 First M+ event Radiotherapy PSA (ng/ml) 80 70 60 Hormonal therapy 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time post diagnosis (years) Courtesy Abrahamsson PA Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) N = 1.435 Prostate cancer (non metastatic) Hormone-refractory disease High risk of bone metastases Adequate organ function R A N D O M I Z A T I O N Denosumab 120 mg SC every 4 weeks Placebo Daily supplementation with calcium (≥500 mg) and vitamin D (≥400 IU) strongly recommended Lancet 2012; 379: 39–46 Time to bone metastases or death Lancet 2012; 379: 39–46 PSA DT <10 <6 <4