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Il trattamento del carcinoma della prostata in fase di resistenza alla castrazione

Il trattamento del carcinoma della prostata in fase di resistenza alla castrazione. Giuseppe Procopio, MD, . 2002 2004 . . . . . . . . . . . . . . . . . 2010 2011. Treatment options for patients with CRPC. Zoledronic Acid 1. Sipuleucel-T 3.

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Il trattamento del carcinoma della prostata in fase di resistenza alla castrazione

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  1. Il trattamento del carcinoma dellaprostata in fase di resistenzaallacastrazione Giuseppe Procopio, MD,

  2. 2002 2004 . . . . . . . . . . . . . . . . . 2010 2011 Treatment options for patients with CRPC Zoledronic Acid1 Sipuleucel-T3 Cabazitaxel4 Docetaxel2 Abiraterone6 Denosumab5 The near future MDV3100 7 Alpharadin8 1Saad et al. J Natl Cancer Inst 2002; 94: 1458–1468 2Tannock et al. N Engl J Med 2004;351(15): 1502-1512 3Kantoff et al. N Engl J Med 2010; 363(5): 411-422 4de Bono et al. Lancet. 2010; 376(9747): 1147-1154 5Fizazi et al. Lancet 2011; 377(9768): 813-822 6de Bono et al. N Engl J Med 2011; 346(21): 1995-2005 7Scher HI et al. N Engl J Med. 2012 Aug 15. ]8Parker C. et al. ESMO 2011: Abstract 2, and ASCO GU 2012

  3. Prostate Cancer Clinical States Noncastrate Castration resistant Diagnoses: 217,730 Deaths: 32,050 Clinical Metastases: Noncastrate Clinical Metastases: Castrate Post- Cabazitaxel Abiraterone MDV3011 Radium 223 Clinical Metastases: Castrate 1st-Line Docetaxel Clinical Metastases: Castrate Pre- Provenge Clinically Localized Disease Rising PSA Rising PSA: Castrate With detectable metastases: deaths from cancer exceed those from other causes Modified from Scher and Heller. Urology. 2000.

  4. TAX 327Updated Survival Analysis 1.0 Docetaxel q3wk Docetaxel qwk 0.8 Mitoxantrone q3wk Median survival Hazard (months) ratio P-value Docetaxel q3wk: 19.2 0.79 0.004 Docetaxelqwk: 17.8 0.87 0.086 Mitoxantrone q3wk 16.3 – – 0.6 Probability of Survival 0.4 0.2 0.0 0 1 2 3 4 5 6 7 Years Berthold DR et al. J ClinOncol. 2008;26:242-245. Tannock I. N Engl J Med. 2004;351:1502-1512.

  5. Phase III Trials Docetaxel plus for CRPC • Oblimersensodium1 • OGX-0112 • Bevacizumab • Aflibercept • Lenalidomide6 • Dasatinib3 • Atrasentan4 • Zibotentan5 1. Sternberg CN et al. Ann Oncol. 2009 Jul;20(7):1264-9 2 .Chi KN et al, J ClinOncol. 2010 Sep 20;28(27):4247-54 3. Araujo JC et al, Cancer. 2012 Jan 1;118(1):63-71 4.Quinn DI, J Clin Oncol 30, 2012 (suppl; abstr 4511) 5.Trump DL, Prostate. 2011 Sep;71(12):1264-75 6. Petrylak D et al, ESMO 2012 LBA24.

  6. Overall Survival with 2nd lineChemotherapy for mCRPC Sternberg CN, et al. J ClinOncol 2009;27:5431−8 de Bono J, et al. Lancet. 2010 Oct 2;376(9747):1147-54

  7. TROPIC: Study Design (n=720) n=360 Cabazitaxel 25mg/m2 q3w Prednisone 10mg qd R A N D O M I Z E R A N D O M I Z E mCRPC Progression after docetaxel Mitoxantrone 12mg/m2 q3w Prednisone 10mg qd • Stratification factor : • ECOG PS (0,1 vs 2) • Measurable/non-measurable • Primary Endpoint: • Overall survival (OS) • Secondary Endpoint: • PSA response, PSA progression, PFS, RR, pain progression, safety, PK of cabazitaxel n=360 Reduction of 25% in the risk of death or median OS=10.67 months for cabazitaxelvs 8 months 511 events, duration 36 months de Bono et al. Lancet 2010; 376(9747): 1147-1154

  8. CabazitaxelApproved as Second-Line Chemotherapy 30% reduction in risk of death Combined medianfollow-up: 12.8 months de Bono et al. Lancet 2010; 376(9747): 1147-1154

  9. Androgen biosynthesis inhibitors: Abiraterone, TAK700 2nd generation AR inhibitors: MDV3100, ARN509 Chen Y, et al. Lancet Oncol. 2009;10:981-991.

  10. Abiraterone Inhibits Androgen Biosynthesis Through CYP17 1. Attard G et al. J ClinOncol. 2008;26:4563-4571; 2. Attard G et al. J ClinOncol. 2009;27:3742-3748; 3. Reid AH et al. J ClinOncol. 2010;28:1489-1495; 4. Ryan CJ et al. J ClinOncol. 2010;28:1481-1488; 5. Danila DC et al. J ClinOncol. 2010;28:1496-1501; 6. de Bono JS et al. AnnOncol. 2010;21(suppl 8): Abstract LBA5. • Androgens produced at 3 critical sites • Testes • Adrenal gland • Prostate tumor cells • Abiraterone inhibits biosynthesis of androgens that stimulate tumor cell growth • PSA and radiographicresponses in Phase 2 studies of CRPC • Chemo-naïve and post-chemo patients1-6

  11. Phase 3 multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) Stratification by: Abiraterone Acetate Phase III Post-Chemo Study Design Efficacy endpoints (ITT) • 1195 patients progressive mCRPC • Failed 1 or 2 chemotherapy regimens, 1 with docetaxel RANDOMIZED 2:1 • 1° endpoint: • OS (25% improvement; HR 0.8) • 2nd endpoints: • TTPP • rPFS • PSA response Abiraterone 1000 mg daily Prednisone 5 mg bid n = 797 Placebo daily Prednisone 5 mg bid n = 398 de Bono JS et al. N Engl J Med. 2011;364:1995-2005

  12. Overall Survival: Second Pre-planned Analysis Median benefit 4.6 months HR =0.74 (0.638-0.859) P<0.0001 26% reduction in risk of death 100 80 AA median OS (95% CI):15.8 months (14.82-17.02) 60 Survival (%) 40 Placebo median OS (95% CI): 11.2 months (10.41-13.14) 20 Placebo AA Median follow-up 20.2 months 0 0 6 12 18 24 30 Time to Death (Months) AA 797 657 473 273 15 0 398 306 183 6 0 Placebo 100 ScherHI et al. J ClinOncol 2011; 29 (suppl): LBA4517 Fizazi K et al, Lancet Oncol, in press

  13. Adverse Events of Special Interest aMostfrequently reported cardiac terms were tachycardia and atrial fibrillation. The rate of grade 5 lethal cardiac events was identical in the 2 study arms: 1.3% (10 pts) in AA and 1.3% (5 pts) in placebo.

  14. MDV3100 (Enzalutamide, XTANDI) 1 2 3 T • Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway. • No demonstrated agonist effects in pre-clinical models. T Enzalutamide Inhibits Binding of Androgens to AR AR AR Cell cytoplasm And Uniquely Inhibits Nuclear Translocation of AR Cell nucleus Tumor Death Inhibits Association Of AR with DNA Tran et al. Science 2009;324:787–90. 5

  15. AFFIRM Phase III Trial Design RANDOMIZED 2:1 Patient Population: 1199 patients with progressive CRPC *Failed docetaxel chemotherapy Enzalutamide 160 mg daily n = 800 Primary Endpoint: Overall Survival Placebo n = 399 • 90% power to detect a 24% reduction in mortality • Corticosteroids were not required, but allowed • Stratification: PS and BPI score, PCWG2 criteria used 156 centers from 15 countries and 5 continents September 2009 - November 2010

  16. Enzalutamide Overall SurvivalMedian benefit 4.8 months HR = 0.631 (0.529, 0.752) P <0.0001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3, NYR) Placebo: 13.6 months (95% CI: 11.3, 15.8) ScherHI et al. N Engl J Med. 2012 Aug 15, Sternberg CN et al. Global Can Prost, Brussels June 2012

  17. Survival Benefit Across All Subgroups Hazard Ratio for Death (95% CI) Overall Survival median (mo) Enzalutamide / Placebo Favors Enzalutamide* Favors Placebo* ScherHI et al. N Engl J Med. 2012 Aug 15, Sternberg CN et al. Global Can Prost, Brussels June 2012

  18. Adverse Events of Special Interest *Inchyperbilirubinemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased. c FDA-Approved August 31, 2012

  19. Radium-223 Targets Bone Metastases • Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1 • Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue Range of alpha-particle Radium-223 Bone surface 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

  20. ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design STRATIFICATION PATIENTS TREATMENT 6 injections at 4-week intervals • Confirmed symptomatic CRPC • ≥ 2 bone metastases • No known visceral metastases • Post-docetaxel or unfit for docetaxel R AND OMI S ED Radium-223 (50 kBq/kg) + Best standard of care • Total ALP: < 220 U/L vs ≥ 220 U/L • Bisphosphonate use: Yes vs No • Prior docetaxel: Yes vs No Placebo (saline) + Best standard of care 2:1 N = 921 Planned follow-up is 3 years Parker C, ESMO 2011 and ASCO 2012 Clinicaltrials.gov identifier: NCT00699751

  21. ALSYMPCA Updated Analysis Time To First SRE* 100 HR = 0.636 95% CI, 0.519, 0.780P = 0.0001 90 80 70 60 Radium-223, n = 614 Median: 12.2 months 50 % 40 Placebo, n = 307 Median: 6.7 months 30 20 10 0 Parker C, ASCO 2012 *Provisional data

  22. ALSYMPCA Updated AnalysisOverall Survival 100 HR = 0.695 95% CI, 0.581, 0.832P = 0.00007 90 80 70 60 50 % Radium-223, n = 614 Median OS: 14.9 months 40 30 20 Placebo, n = 307 Median OS: 11.3 months 10 0 Parker C, ASCO 2012

  23. OS Benefit in Recent CRPC Trials * Only 60% of these patients were post-docetaxel patients

  24. An intervention with little or no toxicity compared with chemotherapy for treatment of asymptomatic or mildly symptomatic CRPC • Aim to prevent or delay the onset of pain related to metastatic disease and disease progression • Prolong survival Clinical Need in CRPC Pre - Chemotherapy

  25. Overall Study Design of COU-AA-302 RANDOMIZED 1:1 Efficacy end points Patients AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) • Co-Primary: • rPFS by central review • OS • Secondary: • Time to opiate use (cancer-related pain) • Time to initiation of chemotherapy • Time to ECOG-PS deterioration • TTPP • Progressive chemo-naïve mCRPC patients(Planned N = 1088) • Asymptomatic or mildly symptomatic Placebo daily Prednisone 5 mg BID (Actual n = 542) Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs 1

  26. Abiraterone Doubled Time to rPFS 100 80 60 Subjects Without Progressionor Death (%) 40 20 Abiraterone Prednisone 0 3 6 9 12 15 18 21 24 27 30 33 36 0 Months From Randomization Abiraterone Prednisone 546 542 485 406 389 244 311 176 240 133 195 99 157 78 131 62 117 45 66 20 20 7 4 0 0 0 IA3 data. rPFS assessed by investigator review at prespecified IA. Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

  27. OS Favors Abiraterone 100 80 60 Subjects Without Death (%) 40 20 Abiraterone Prednisone 0 3 6 9 12 15 18 21 24 27 30 33 36 0 Months From Randomization Abiraterone Prednisone 546 542 538 534 524 508 503 492 482 465 452 437 421 400 393 361 333 283 175 153 68 67 15 9 0 0 IA3 data. aPrespecified significance level by O’Brien-Fleming Boundary = 0.0035. Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

  28. Subsequent Therapy Was Common aFirst patient crossover after unblinding on 7 May 2012. IA3 data clinical cut-of f date on 22 May 2012. bPrior to unblinding (eg. not per protocol). IA3 data. Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

  29. Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone Abiraterone Prednisone 100 75 50 25 Maximal Decline From Baseline (%) 0 -25 -50 -75 -100 • 29% of patients in the prednisone control arm had a decline in PSA of ≥ 50% • 69% of patients in the abiraterone arm had a decline in PSA of ≥ 50% IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA. Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

  30. TAK 700 : Pre-ChemoStudyBone scanflare up in patient with decrease PSA Pre treatment : January 23 2012 PSA 80 mildly symptomatic Week 13: April 14, 2012 PSA 49 asymptomatic

  31. What’s next?

  32. Cabozantinib (XL-184) in mCRPC Baseline 12 weeks CabozantinibDual inhibition MET VEGFR2 74%Soft tissue lesion regression 19%Complete resolution of bone metastases Docetaxel-pretreated patients(similar results obtained in docetaxal-naïve patients) 56%Partial resolution of bone metastases *Partial response or stable disease †Randomization stopped due to cabozantinib efficacy PFS, progression-free survival HussainM, et al. J ClinOncol. 2011;29(15S): Abst 4516

  33. Change in Bone Scan Lesion Area Patients with ≥1 post-baseline bone scan (n = 84) Median change in bone scan lesion area: 60% reduction Smith M et al, ASCO 2012 Abst #4513

  34. New Agents and Trials for CRPC Pre-docetaxel Docetaxel Post-docetaxel • Tasquinimod • Abiraterone • Sipuleucel-T1 • PROSTVAC2 • MDV3100 • Ipilimumab • Alpharadin7 • TAK-700 • OGX-0113 • Dasatinib • Aflibercept • Abiraterone4 • Cabazitaxel5 • MDV31006 • Ipilimumab • TAK-700 • Alpharadin7 • Cabozantinib 1Kantoff PW, NEnglJMed. 2010 Jul 29;363(5):411-22,2Kantoff PW, J ClinOncol 2010; 28:1099–105 3CHi KN, J Clin Oncol; 28:4247-4254, 4 de Bono JS et al. N Engl J Med. 2011;364:1995-2005, 5de Bono et al. Lancet 2010; 376(9747): 1147-1154,6ScherHI et al. N Engl J Med. 2012 Aug 15. 7Parker C et al, ESMO LBA2 and ASCO 2012

  35. Progress and Conclusions in mCRPC • Unequivocal evidence of continued involvement of the AR signaling axis • Non toxic therapies pre-chemotherapy of interest • Need to address prostate cancer heterogeneity to move the field forward • Need to evaluate the best sequence and combination of agents

  36. Conclusioni Prospettive per il paziente mCRPC Miglioramento sopravvivenza Riduzione degli eventi scheletrici Miglioramento della quality of life

  37. Thank you for your attention and your kind invitation

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