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Daniele Santini Università Campus Bio-Medico Roma

Daniele Santini Università Campus Bio-Medico Roma. Patients With Bone Metastases From Pca Are at High Risk for Developing SREs. Any. Pathologic fracture. Radiation therapy. Surgical intervention. Spinal cord compression. Patients With SRE, %. 24 months.

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Daniele Santini Università Campus Bio-Medico Roma

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  1. Daniele Santini Università Campus Bio-Medico Roma

  2. Patients With Bone Metastases From Pca Are at High Risk for Developing SREs Any Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Patients With SRE, % 24 months Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

  3. Skeletal Complications Reduce Quality of Life in Prostate Cancer Patients Total Physical Functional Emotional a Change/Standard Deviation a a a a a Change in FACT-G score for patients with an event vs patients without an event aP < .05. Data from Weinfurt KP, et al. Ann Oncol. 2005;16(4):579-584.

  4. SREs Are Associated With Lower Survival in Prostate Cancer • 360 Days Survival • No SRE: 49.7% • ≥ 1 SRE: 28.2% • P = .02 • Median Survival Times • No SRE: 338 days (95% CI = 189, 460) • ≥ 1 SRE: 248 days (95% CI = 181, 296) No SRE (n = 355) ≥ 1 SRE (n = 116) 1 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 360 0 90 180 270 Survival, days Abbreviations: CI, confidence interval; SRE, skeletal-related event. DePuy V, et al. Support Care Cancer. 2007;15:869-876.

  5. IGF1 TGFb-1 IGF1 TGFb-1 Osteocalcina ALP TGF-b1 ET1 uPA PTHrP IL-6 Wnt DDK-1 FISIOPATOLOGIADELLA METASTASI ADDENSANTE >RANKL/<OPG OPG Bertoldo F, Santini D Textbook of Osteoncology 2010

  6. Molecular states and bone targeted therapies Armamentarium Androgen deprivation therapy Bisphosphonates (CITBL, only for BMD) Denosumab (CITBL, also for fracture rate) Nelson PS, J Clin Oncol, feb 2012

  7. Molecular states and bone targeted therapies Armamentarium Castration-resistant patients Docetaxel (only in metastating setting) Cabazitaxel (in docetaxel-progressing patients) AR inhibitors (MDV3100) (in docetaxel-progressing patients, ASCO 2012) Bisphosphonates (zoledronic acid only in bone metastatic setting) Denosumab (both in bone metastasis prevention and in metastatig setting) Abiraterone (only in metastating setting, after docetaxel) Nelson PS, J Clin Oncol, feb 2012

  8. Target therapies and potential applications in prostate cancer CTIBL Bone met prevention in castration resistant prostate cancer patients SREs in castration resistant metastatic disease

  9. RANK is expressed by cancer cells both at primary tumor and at bone metastases (p= .528) (p= .194) PRIMITIVI METASTASI PRIMITIVI METASTASI b. confronto primitivi-metastasi considerando solo le coppie metastasi-tumore d’origine • confronto primitivi-metastasi considerando tutti i campioni Santini D. J Cell Phys, 2010

  10. Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147) N = 1.435 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 Event-driven study:time to bone metastasis or death Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) R A N D O M I Z A T I O N Denosumab 120 mg SC every 4 weeks Placebo Smith MR, et al. Lancet. 2012.

  11. Bone metastasis-free survival Placebo 716 691 569 500 421 375 345 300 259 215 168 137 99 60 36 Denosumab 716 695 605 521 456 400 368 324 279 228 185 153 111 59 35 1.0 HR = 0.85 (95% CI 0.73, 0.98) P = 0.028 0.8 0.6 Proportion of patients 0.4 0.2 Median months Events 25.2 370 Placebo 29.5 Denosumab 335 0.0 0 6 9 15 18 27 30 33 39 42 3 12 21 24 36 Study month Smith MR, et al. Lancet. 2012.

  12. Bone Metastasis-Free Survival in Patients with PSADT ≤ 6 Months Denosumab 147 Trial HR = 0.77 (95% CI 0.64, 0.93) P = 0.006 23% Risk Reduction Median Months Delay (Months) Events 18.7 242 Placebo 7.2 25.9 197 Denosumab Smith MR, et al. ASCO GU, 2012.

  13. Sopravvivenza libera da metastasi ossee in pazienti con PSADT ≤4 mesi F. Saad, ASCO 2012

  14. ZEUS: Zoledronic Acid for Preventionof Bone Metastases in Prostate Cancer Primary endpoint: Time to bone metastases Secondary endpoints: Overall survival, PSA doubling time, substudies on bone markers, adverse events • N = 1,433 • Prostate cancer, M0 • ± previous local curative treatment, ± ADT • High-risk PC with ≥ 1 of the following criteria: • Gleason Score 8-10 • pN+ • PSA  20 at diagnosis R Zoledronic acid 4 mg q 3 months No zoledronic acid Treatment duration: 4 years Accrual complete Abbreviations: ADT, androgen-deprivation therapy; PC, prostate cancer; PSA, prostate-specific antigen.

  15. Target therapies and potential applications in prostate cancer CTIBL Bone met prevention in castration resistant prostate cancer patients SREs in castration resistant metastatic disease

  16. Randomized Trial of Zoledronic Acid Versus Placebo in Patients With Prostate Cancer R A N DO M I Z E D Zoledronic acid 4 mg q 3 wk + daily oral vitamin D 400 IU and calcium 500 mg n = 214 n = 208 Placebo q 3 wk + daily oral vitamin D 400 IU and calcium 500 mg 0 15 monthsCore analysis1 24 months Final analysis2 1. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.

  17. Zoledronic Acid Reduced the Risk of SREs Regardless of Prior SRE History RiskReduction P Value Before Study Entry 0.670 33% .027 No Prior SRE 0.603 40% .028 Prior SRE 0.640 Overall TrialPopulation .002 36% 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 Risk Ratio (ZOL 4 mg vs Placebo) In favor of placebo In favor of ZOL Abbreviations: SRE, skeletal-related event; ZOL, zoledronic acid. Adapted from Saad F, et al. Clin Genitourin Cancer. 2007;5(6):390-396.

  18. Study Design: International, Randomised, Double-Blind, Active-Controlled Study Fizazi K, et al. Lancet. 2011;377:813–822. • Key Inclusion Criteria • Castration-resistant prostate cancer and 1 bone metastases • Key Exclusion Criteria • Current or prior IV bisphosphonate treatment N = 950 denosumab 120 mg SC and placebo IV Q4W Supplemental calcium and vitamin D strongly recommended N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W

  19. Baseline Characteristics Fizazi K, et al. Lancet. 2011;377:813–822.

  20. Primary Endpoint: Time to First On-Study SRE Fizazi K, et al. Lancet. 2011;377:813–822. HR = 0.82 (95% CI, 0.71–0.95)P 0.001 (noninferiority) P = 0.008 (superiority) 1.00 0.75 0.50 Proportion of Subjects Without SRE Kaplan-Meier Estimate of Median Months 0.25 20.7 Denosumab Zoledronic acid 17.1 0.00 15 18 21 24 0 3 6 9 12 27 Study Month Patients at Risk:

  21. Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) (Multiple-Event Analysis) Fizazi K, et al. Lancet. 2011;377:813–822. 2.0 Rate ratio = 0.82 (95% CI, 0.71–0.94) P = 0.009 (superiority) 1.8 1.6 1.4 1.2 1.0 Cumulative Mean Number of SREs per Patient 0.8 0.6 Events 0.4 Denosumab 494 0.2 584 Zoledronic acid 0.0 0 3 15 27 30 6 9 12 18 21 24 33 36 Study Month

  22. Exploratory Endpoint: Overall Survival Fizazi K, et al. Lancet. 2011;377:813–822. HR = 1.03 (95% CI, 0.91–1.17) P = 0.65 1.00 0.75 Proportion of Patients Survived 0.50 0.25 Denosumab Zoledronic acid 0.00 21 24 3 6 9 12 15 18 27 30 0 Study Month Patients at Risk:

  23. Summary of Adverse Events ‡P = 0.09 Fizazi K, et al. Lancet. 2011;377:813–822.

  24. 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

  25. Bone targeted therapies nella neoplasia prostatica metastatica - Aggiornamento 2012 - L’acido zoledronico si è dimostrato efficace nel ridurre le complicanze scheletriche di pazienti con metastasi ossee da carcinoma prostatico (Livello di evidenza 1++; positiva forte) Il denosumab non è inferiore all’acido zoledronico in termini di tempo al primo SRE (Livello di evidenza 1++; positiva forte) Il denosumab è superiore all’acido zoledronico in termini di tempo al primo SRE e di tempo al primo e ai successivi SRE (Livello di evidenza 1-; positiva debole) Safety: L’incidenza di ONJ durante il trattamento con denosumab è almeno pari a quella riscontratta durante il trattamento con acido zoledronico (Livello di evidenza 1++; positiva forte)

  26. Effect of Abiraterone Acetate on Pain Control and Skeletal-Related Events in Patients With Metastatic Castration-Resistant Prostate Cancer Post Docetaxel: Results From The COU-AA-301 Phase 3 Study C. Logothetis, J. S. de Bono, A. Molina, E. M. Basch, K. Fizazi, S. North, K. N. Chi, R. J. Jones, O. B. Goodman, P. N. Mainwaring, C. N. Sternberg, D. D. Gagnon, R. Dhawan, M. Rothman, Y. Hao, C. S. Liu, T. S. Kheoh, H. I. Scher, and C. M. Haqq Logothetis et al. JCO 2011; 29 (Suppl): Abst4520 (oral)

  27. Meccanismo azione abiraterone • Gli androgeni che stimolano la proliferazione tumorale sono prodotti in tre siti critici: • Testicoli • Ghiandola surrenale • Cellule tumorali prostatiche • Abiraterone inibisce la sintesi degli androgeni in tutti e tre i siti • Testosteronemia < 1ng/dl Cholesterol Desmolase Deoxy- corticosterone Pregnenolone Corticosterone Progesterone Aldosterone CYP17 17α-hydroxylase X 17α-OH- pregnenolone 17α –OH- progesterone 11-Deoxy- cortisol Cortisol ACTH CYP17 C17,20-lyase X 5α-reductase Androstenedione DHT DHEA Testosterone Abiraterone Yang, Drugs. 2011; Attard, JCO 2008

  28. Overall Study Design Efficacy end points RANDOMIZED AA 1000 mg daily Prednisone 5 mg BID n = 797 • Primary end point: • OS • Secondary end points: • PSA response • rPFS • Tertiary end points: • Pain • SREs Patients (N = 1195) Placebo daily Prednisone 5 mg BID n = 398 BPI questionnaire Baseline, Cycle 1 (Day 15), subsequent treatment cycles (Day 1) de Bono et al. NEJM 2011

  29. Symptomatic Improvement -Pain Intensity Palliation P = 0.0002 155/349 (44.4%) 44/163 (27.0%)

  30. Results Logothetis et al. JCO 2011; 29 (Suppl): Abst4520 (oral)

  31. JS De Bono, ASCO, 2012

  32. JS De Bono, ASCO, 2012

  33. JS De Bono, ASCO, 2012

  34. JS De Bono, ASCO, 2012

  35. Molecular states and bone targeted therapies Armamentarium No standard drugs Src inhibitors (dasatinib, saracatinib)? Endothelin RA inhibitors (atresartan, zibotentan)? Anti-HER2/neu? Inhibitor of MET and VEGFR2 (cabozantinib)? AR inhibitors (MDV3100)? Bisphosphonates (problably) Denosumab (strong biological rational – src in a down stream gene of rank- rank is expressed also in prostate cancer cells) Denosumab works also in patients without NTX suppression during zoledronic acid Nelson PS, J Clin Oncol, feb 2012

  36. Overview: bone health and target molecules • Src inhibitors (Saracatinib, Dasatinib)

  37. Evidence for a Role of Src in Bone Metabolism and Metastatic Bone Disease Src kinase is a nonreceptor tyrosine kinase, highly expressed in normal osteoclasts1,2 Src plays an essential role in RANKL-mediatedosteoclast activation3and perhaps survival4 Src knockout mice are osteopetrotic5 Src may be critical for tumor cell survival in bone microenvironment6 1. Horne WC, et al. J Cell Biol. 1992;119(4):1003-1013; 2. Tanaka S, et al. FEBS Lett. 1992;313(1):85-89; 3. Boyce BF, et al. J Clin Invest. 1992;90(4):1622-1627; 4. Wong BR, et al. Mol Cell. 1999;4(6):1041-1049; 5. Lowe C, et al. Proc Natl Acad Sci U S A. 1993;90(10):4485-4489; 6. Zhang XH, et al. Cancer Cell. 2009;16(1):67-78.

  38. Role of Src in Prostate Tumor Cell and Osteoclast Activities Tumor cells Src Systemic factors Local factors Direct bone destruction Osteoclast activity Growth factors Src Osteolysis Activated osteoclast Src Bone Bone complications

  39. Dasatinib in PC: Inhibition of Tumor Cells and Osteoclast Activity Through Src Tumor cells Src Dasatinib Systemic factors Local factors Direct bone destruction Osteoclast activity Src Growth factors Osteolysis Dasatinib Bone

  40. Doc + P vs Doc + P + DASATINIB Preliminary results: 4.8 months OS improvement with the combination Longer PFS with the combination Median time to SRE longer (7.5 vs. 6.0 months) Phase III study: READY (ongoing)(metastatic hormonorefractory prostate cancer patients)

  41. Abstract 4513Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE). Autori, Matthew Raymond Smith, Christopher Sweeney, Dana E. Rathkopf, Howard I. Scher, Christopher Logothetis, Daniel J. George, Celestia S. Higano, Evan Y. Yu, Andrea Lynne Harzstark, Eric Jay Small, A. Oliver Sartor, Michael S. Gordon, Nicholas J. Vogelzang, David C. Smith, Maha Hussain, Johann Sebastian De Bono, Naomi B. Haas, Christian Scheffold, Yihua Lee, Paul G. Corn; ASCO 2012

  42. Risposta sulle lesioni ossee (revisione indipendente)

  43. Molecular states and bone targeted therapies Armamentarium No standard drugs Src inhibitors (dasatinib, saracatinib)? Endothelin RA inhibitors (atresartan, zibotentan)? Anti-HER2/neu? Octreotide? Pasireotide? TKIs? Inhibitor of MET and VEGFR2 (cabozantinib)? Bisphosphonates (problably) Denosumab (strong biological rational – src in a down stream gene of rank- rank is expressed also in prostate cancer cells) Denosumab works also in patients without NTX suppression during zoledronic acid Nelson PS, J Clin Oncol, feb 2012

  44. …. and how to place radium-223 ? Abstract LBA4512Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA). Autori, Chris Parker, StenNilsson, Daniel Heinrich, Joe M. O'Sullivan, Sophie D. Fossa, AlesChodacki, Pawel J. Wiechno, John P. Logue, MihaljSeke, AndersWidmark, DagClementJohannessen, Peter Hoskin, David Bottomley, Robert Edward Coleman, Nicholas J. Vogelzang, C. Gillies O'Bryan-Tear, Jose E. Garcia-Vargas, MinghuaShan, A. Oliver Sartor; TLA C Parker et al, ASCO, 2012

  45. Disegno dello studio A.O. Sartor et al, ASCO GU, 2012

  46. Analisi aggiornata della sopravvivenza globale C Parker et al, ASCO, 2012

  47. Analisi aggiornata del tempo allo sviluppo del primo evento scheletrico C Parker et al, ASCO, 2012

  48. Nuovi farmaci per nuovi e vecchi Target Santini D et al. Cancer Treat Reviews, 2010

  49. Thank you very much for your attention d.santini@unicampus.it

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