Alfredo Berruti Università degli Studi di Brescia Azienda Ospedaliera Spedali Civili Brescia IL TRATTAMENTO DEL MICROAMBIENTE OSSEO

THE VICIOUS CIRCLE Kingsley LA et al Mol Cancer Ther 2007;6(10):2609–2617

Placebo arm* 50% 49% 51% 46% 79% Patients with SRE, % Breas t cance r 1 Prostat e cancer 2 Multiple myelom a 3 NSCLC and OST 4 RC C 5 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: ; 2. Saad F, et al. J Natl Cancer Inst. 2004;96: ; 3. Berenson JR, et al. J Clin Oncol. 1998;16: ; 4. Rosen LS, et al. Cancer. 2004;100: ; 5. Mulders PF. Presented at: EAU Skeletal-Related Events Are Prevalent in the Absence of Therapy

SREs Bone Pain Bisphosphonates and SRE and Bone Pain in Advanced Postate Cancer 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?

SURVIVAL POOLED ANALYSIS Valcamonico F Petrelli F, Barni S, et al, J Clin Oncol 2014 in press

Lancet 2011; 377: 813–22 Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 953) Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 951) Daily Supplements of Calcium and Vitamin D Key Inclusion Criteria Adults with prostate, and ≥ 1 bone metastasis / lesion Key Exclusion Criteria No current or prior IV bisphosphonate administration for treatment of bone metastases 1:1

Lancet 2011; 377: 813–22

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

… e in adiuvante?

Yu C et al, Critical ReviewsTM in Eukaryotic Gene Expression, 22: 131–148 (2012) Parasitism of the bone microenvironment by prostate cancer

Brian Ell and Yibin Kang Cell 151, October 26, 2012

Bone Metastasis Gowth Cancer cell Homing New Bone Metastasis Fragility Fractures Osteoporosis  GNRH AGONISTI  Aromatasi Inhibitors CHEMIOTERAPIA  Menopause  Age  Low vitamin D leves High Bone Turnover SRE Fractures Hypercalcemia Radiotherapy Othopedic Surg. Pain

Brian Ell and Yibin Kang Cell 151, October 26, 2012 BP

Eur Urol 2014, in press

Non metastatic 508 pts Metastatic 311 pts Lancet Oncol September 9; 10(9): 872–876.

Lessons From 60 Years of Practice: PSA Era Radiotherapy First M+ eventRadical prostatectomy Hormonal therapy Courtesy Abrahamsson PA

N = Prostate cancer (non metastatic) Hormone-refractory disease High risk of bone metastases Adequate organ function RANDOMIZATIONRANDOMIZATION Denosumab 120 mg SC every 4 weeks Denosumab 120 mg SC every 4 weeks Placebo Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) Daily supplementation with calcium (≥500 mg) and vitamin D (≥400 IU) strongly recommended Lancet 2012; 379: 39–46

Time to bone metastases or death

PSA DT <10 <6<6 <4<4