1 / 53

Daniele Santini Università Campus Bio-Medico Roma

Daniele Santini Università Campus Bio-Medico Roma. Baseline (n = 376). 0.8. 0.7. > 3. 0.6. P < .0001. 0.5. 0.4. 0.3. < 3. 0.2. 0.1. Proportion died. 0.0. 0. 3. 6. 9. 12. 15. 18. 21. 24. Time since randomization, months. > 3 Bone Lesions associated With Shorter Survival.

clarimonde-jonathan
Download Presentation

Daniele Santini Università Campus Bio-Medico Roma

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Daniele Santini Università Campus Bio-Medico Roma

  2. Baseline (n = 376) 0.8 0.7 > 3 0.6 P < .0001 0.5 0.4 0.3 < 3 0.2 0.1 Proportion died 0.0 0 3 6 9 12 15 18 21 24 Time since randomization, months > 3 Bone Lesions associated With Shorter Survival Shirina N, et al. Presented at ASCO 2006. Poster 8529.

  3. > 3 Bone Lesions Associated with Shorter Time to SRE Baseline (n = 376) 0.8 > 3 0.7 P < .0001 0.6 0.5 0.4 < 3 0.3 0.2 0.1 Proportion with SRE 0.0 0 3 6 9 12 15 18 21 24 Time since randomization, months Shirina N, et al. Presented at ASCO 2006. Poster 8529.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Skeletal complications according to types and number of bone lesions p=n.s. % of patients undergoing SRE p=0.01

  9. Skeletal Related Event (SRE) free survival according to types and number of bone lesions < 3 bone lesions 4-6 bone lesions > 6 bone lesions Mixed bone lesions Blastic bone lesions Cumulative proportion SRE free surviving Cumulative proportion SRE free surviving Months Months

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

  11. 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.

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

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

  14. ZOL Reduced All Types of SREs vs Placebo at 2 Years in Patients With Bone Metastases From PC P = .028 60 49 50 38 40 33 Patients With SRE, % 30 26 25 17 20 8 7 10 6 4 4 2 1 0 0 Any SRE Radiationto Bone Fractures Spinal CordCompression Change inAntineoplasticTherapy Surgeryto Bone HCM Zoledronic acid 4 mg (n = 214) Placebo (n = 208) 14 Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event. Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

  15. 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

  16. 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:

  17. 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

  18. 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:

  19. J Brown EAU, 2011

  20. 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

  21. Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone metastases

  22. Abiraterone post-docetaxel does improve Overall Survival Fizazi K et al. Lancet Oncology, 2012

  23. Abiraterone pre-docetaxel does improve Overall Survival 100 80 60 Survival (%) 40 20 Abiraterone Prednisone 0 3 6 9 12 15 18 21 24 27 30 33 0 Time to Death (Months) 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 Abiraterone Prednisone Ryan et al. NEJM, 2013

  24. Enzalutamide post-docetaxel does improve Overall Survival Scher HI et al, NEJM, 2012

  25. Radium-223 does improve Overall Survival S Nilsson et al, Clinical Genitourinary Cancer, 2013

  26. Cabazitaxel does improve Overall Survival De Bono JS et al. Lancet 2010

  27. Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone progression

  28. Abiraterone post-docetaxel improve quality of life Logothetis et al. Lancet Oncology, 2012

  29. Abiraterone pre-docetaxel improve quality of life Ryan et al. NEJM, 2013

  30. Enzalutamide post-docetaxel improve quality of life JS De Bono, ASCO, 2012

  31. Radium-223 improve quality of life Parker CC et al. Eur Urology, 2012

  32. Cabazitaxel improve quality of life Tombal B, EAU, 2011

  33. Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone progression

  34. Abiraterone post-docetaxel does delay SREs 4.7 months of difference Logothetis et al. Lancet Oncology, 2012

  35. Abiraterone post-docetaxel does delay SREs Logothetis et al. Lancet Oncology, 2012

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

  37. Enzalutamide post-docetaxel does reduce SREs

  38. Radium-223 does delay SREs 5.5 months of difference Pre-planned analysis C Parker et al, ASCO, 2012

  39. Cabazitaxel No data on SREs

  40. Why should we use CT/HT to delay skeletal related events? To improve overal survival To improve quality of life To delay SRE To delay bone progression

  41. Abiraterone post-docetaxel does delay bone progression Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)

  42. Abiraterone pre-docetaxel does delay bone progression 100 80 60 Progression-Free (%) 40 20 Abiraterone Prednisone 0 3 6 9 12 15 18 0 Time to Progression or Death (Months) Abiraterone Prednisone 546 542 489 400 340 204 164 90 46 30 12 3 0 0 Ryan et al. NEJM, 2013

  43. Enzalutamide post-docetaxel does delay bone progression Scher HI et al, NEJM, 2012

  44. Cabazitaxel does delay disease progression De Bono JS et al., Lancet, 2010

  45. 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 Abstract 4513Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).

  46. Risposta sulle lesioni ossee (revisione indipendente)

  47. What about bisphosphonate and denosumab? To improve overal survival NO To improve quality of life YES To delay SRE YES To delay bone progression NO

  48. What about new HT/CT agents in CRPC? To improve overal survival YES To improve quality of life YES To delay SRE YES To delay bone progression YES

  49. Open Issues 1 Nello studio AA post-docetaxel il 42% circa dei pazienti avevano ricevuto bisfosfonati in ciascun braccio di trattamento: come sono andati i pazienti non trattati con BPs? Nello studio MDV-3100 post-docetaxel il 30% circa dei pazienti avevano ricevuto bisfosfonati in ciascun braccio di trattamento: come sono andati i pazienti non trattati con BPs? Necessità di studi mirati a valutare l’effetto di AA e MDV-3100 sui marker di riassorbimento osseo (CTX, NTX, BALP): cosa succederebbe se scoprissimo una modulazione degli stessi?

More Related