GESTIONE DELLE METASTASI OSSEE Quale sarà il ruolo di Denosumab: la 1° linea di trattamento, l’associazione all’ac. zolendronico o la 2° linea ? G. Cartenì Direttore U.O.S.C. di Oncologia Medica A.O.R.N. A. Cardarelli Napoli

+ Skeletal Complication Risk: Incremental Benefits in Prostate Cancer Zoledronic ~ 20% risk reduction No bisphosphonate 49% risk at 2 yrs Denosumab Additional 18% time to first SRE increase Denosumab Additional ~ 12% risk reduction + Saad F, JNCI, 2004, Fizazi K, Lancet, 2011 2

Abiraterone post-docetaxel does delay SREs 4.7 months of difference SRE defined as: pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery Convergence between additional outcomes and Pain/SRE data: AA not only delayed pain progression, but also provided pain palliation, associated with delayed time to SRE, increased overall survival, and greater progression free survival Logothetis et al. Lancet Oncology, 2012

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

Direct Androgen dependent Interactions in Bone disease Stroma > Angiogenesis Osteoblast Tumor Cell Osteoclast Migration proliferation survival > apoptosis ANDROGEN VEGF, vascular endothelial growth factor. Wiren KM, Bone, 2006; Eisermann K, Mol Cancer, 2013 Hypothetic interactions. 5 5

Inhibition of androgen pathway in cancer cells and indirect effects on microenvironment The two-compartment model in bone for novel therapeutics in metastatic castrate-resistant prostate cancer. The “epithelial compartment” contains the prostate cancer epithelial cell (top). The “stromal compartment” contains multiple different cell types including osteoblasts, osteoclasts, T-cells, and endothelial cells (bottom). Multiple autocrine and paracrine signaling pathways that contribute to prostate cancer progression are depicted. The different novel therapeutics that target these pathways are also shown. Please refer to the body of the text for additional details. AR = androgen receptor; ETA-R = endothelin type A receptor; VEGF = vascular endothelial growth factor; DHT = dihydrotestosterone; GF-R = growth factor receptor. Dayyani F et al. JNCI J Natl Cancer Inst 2011;103:1665-1675