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Daniele Santini Università Campus Bio-Medico Roma.

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Presentation on theme: "Daniele Santini Università Campus Bio-Medico Roma."— Presentation transcript:

1 Daniele Santini Università Campus Bio-Medico Roma

2 Baseline (n = 376) P < Time since randomization, months Proportion died < 3 > 3 > 3 Bone Lesions associated With Shorter Survival Shirina N, et al. Presented at ASCO Poster 8529.

3 > 3 Bone Lesions Associated with Shorter Time to SRE Baseline (n = 376) P <.0001 < Time since randomization, months Proportion with SRE > 3 Shirina N, et al. Presented at ASCO Poster 8529.

4 24 months Patients With SRE, % Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Any Saad F, et al. JNCI. 2002;94(19): ; Saad F, et al. Eur Urol Suppl. 2007;6(11): Patients With Bone Metastases From Pca Are at High Risk for Developing SREs

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

6 SREs Are Associated With Lower Survival in Prostate Cancer Abbreviations: CI, confidence interval; SRE, skeletal-related event. DePuy V, et al. Support Care Cancer. 2007;15: Probability Survival, days No SRE (n = 355) 1 SRE (n = 116) 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)

7 PTHrP IL-6 F ISIOPATOLOGIA DELLA M ETASTASI A DDENSANTE IGF1 TGF IGF1 TGF ET1 uPA Osteocalcina ALP TGF- 1 Bertoldo F, Santini D Textbook of Osteoncology 2010 Wnt DDK-1 OPG >RANKL/

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

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

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 = 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 RANDOMIZATIONRANDOMIZATION Denosumab 120 mg SC every 4 weeks Denosumab 120 mg SC every 4 weeks Placebo 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) Smith MR, et al. Lancet

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 Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event. Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11): P = Any SRERadiation to Bone FracturesSpinal Cord Compression Change in Antineoplastic Therapy Surgery to Bone HCM Zoledronic acid 4 mg (n = 214)Placebo (n = 208) Patients With SRE, % ZOL Reduced All Types of SREs vs Placebo at 2 Years in Patients With Bone Metastases From PC 14

15 N = 951 zoledronic acid 4 mg IV* and placebo SC Q4W N = 950 denosumab 120 mg SC and placebo IV Q4W Study Design: International, Randomised, Double- Blind, Active-Controlled Study Fizazi K, et al. Lancet. 2011;377:813–822. Primary Endpoint Time to first on-study skeletal-related event (SRE) (noninferiority) Secondary Endpoints Time to first on-study SRE (superiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE(s) (superiority) Time to first and subsequent on-study SRE(s) (superiority) Supplemental calcium and vitamin D strongly recommended Key Inclusion Criteria Castration-resistant prostate cancer and 1 bone metastases Key Exclusion Criteria Current or prior IV bisphosphonate treatment

16 Primary Endpoint: Time to First On-Study SRE Fizazi K, et al. Lancet. 2011;377:813– Proportion of Subjects Without SRE Kaplan-Meier Estimate of Median Months Denosumab Zoledronic acid HR = 0.82 (95% CI, 0.71–0.95) P (noninferiority) P = (superiority) Study Month Patients at Risk: Zoledronic acid Denosumab

17 Secondary Endpoint: Time to First and Subsequent On-Study SRE(s) (Multiple-Event Analysis) Fizazi K, et al. Lancet. 2011;377:813–822. Rate ratio = 0.82 (95% CI, 0.71–0.94) Cumulative Mean Number of SREs per Patient Denosumab Zoledronic acid Events P = (superiority) 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 = Proportion of Patients Survived Study Month Denosumab Zoledronic acid Denosumab Patients at Risk:

19 J Brown EAU, 2011

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

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 V3.0 COU-AA-302 Abiraterone pre-docetaxel does improve Overall Survival Survival (%) Time to Death (Months) 33 Abiraterone Prednisone Abiraterone Prednisone Abiraterone (median, mos):NR Prednisone (median, mos):27.2 HR (95% CI):0.75 ( ) P value: Ryan et al. NEJM, 2013

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

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

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 + Prednisone (n = 797) Placebo + Prednisone (n = 398) P Value Palliation, n (%) 132/223 (59.2) 38/100 (38.0) Median Time to palliation (months) (95% CI) 1.02 ( ) 3.71 ( ) Logothetis et al. Lancet Oncology, 2012 Abiraterone post-docetaxel improve quality of life

29 AA + P (months) Placebo + P (months) P Value Hazard Ratio (95% CI) FACT-G ( ) PCS < ( ) Physical well- being ( ) Functional well-being ( ) Emotional well-being ( ) Social/Family well-being ( ) Abiraterone pre-docetaxel improve quality of life Ryan et al. NEJM, 2013

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

31

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

33 Cabazitaxel improve quality of life Tombal B, EAU, 2011

34 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

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

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

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

38 Enzalutamide post-docetaxel does reduce SREs

39 Radium-223 does delay SREs C Parker et al, ASCO, months of difference Pre-planned analysis

40 Cabazitaxel No data on SREs

41 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

42 Abiraterone post-docetaxel does delay bone progression Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) P Value Time to progression (months) 25 th percentile (95% CI) 9.27 ( ) 4.57 ( ) Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)

43 V3.0 COU-AA-302 Abiraterone Prednisone Progression-Free (%) Time to Progression or Death (Months) Abiraterone Prednisone Abiraterone (median, mos):NR Prednisone (median, mos):8.3 HR (95% CI):0.43 ( ) P value:< Abiraterone pre-docetaxel does delay bone progression Ryan et al. NEJM, 2013

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

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

46 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 4513 Cabozantinib (XL184) in chemotherapy- pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).

47 Risposta sulle lesioni ossee (revisione indipendente)

48 What about bisphosphonate and denosumab? To improve overal survivalNO To improve quality of lifeYES To delay SREYES To delay bone progressionNO

49 What about new HT/CT agents in CRPC? To improve overal survivalYES To improve quality of lifeYES To delay SREYES To delay bone progressionYES

50 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 leffetto di AA e MDV sui marker di riassorbimento osseo (CTX, NTX, BALP): cosa succederebbe se scoprissimo una modulazione degli stessi?

51 Open Issues 2 Necessità di studiare le modificazioni del metabolismo osseo in corso di terapia combinata tra bone target therapies e nuovi farmaci ormonali Necessità di comprendere meglio quando e per chi usare le bone target therapies INSIEME ai nuovi farmaci: 1.Al momento della comparsa delle metastasi ossee 2.Al momento dellintroduzione della nuova terapia ormonale 3.Al momento dellincremento dei marker di riassorbimento osseo 4.A tutti i pazienti con metastasi ossee? Esiste un effetto antitumorale sinergico?

52 Skeletal Complication Risk: Incremental Benefits in Prostate Cancer No bisphosphonate 49% risk at 2 yrs Zoledronic ~ 20% risk reduction Denosumab Additional ~ 12% risk reduction Denosumab Additional 18% time to first SRE increase Saad F, JNCI, 2004, Fizazi K, Lancet, Questi dati sono pre-era nuovi farmaci…. ora la storia deve essere riscritta

53 Thank you very much for your attention


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