Kanıt: Klinik çalışmalarda ZYTIGA

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1 mkdpk de Sonunda Gerçek İlerleme! Kanıt: Klinik çalışmalarda ZYTIGA Dr. Sevil Bavbek 5. Türk Tıbbi Onkoloji Kongresi Mart 214, Antalya

2 Endocrine therapies Adrenals Testis Abiraterone Orteronel Androgen Receptor inhibitors: -Bicalutamide -MDV 31 -ODM-21 -ARN 59 Castration (alhrh or Surg.) Testosterone Autocrine secretion Abiraterone Orteronel DNA Cell division

3 b Abiraterone: CYP17 blockade inhibits androgen synthesis

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6 COU-AA-31: Abiraterone acetate Phase III post-chemotherapy 1195 patients with progressive mcrpc Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel R A N D O M I Z E D 2:1 Abiraterone 1mg daily Prednisone 5mg BID n=797 Placebo daily Prednisone 5mg BID n=398 Efficacy end points (ITT) Primary end point: OS (25% improvement; HR.8) Secondary end points: TTPP rpfs PSA response FACT-P questionnaire Prospective data collection: Day 1 of Cycles 1, 4, 7, 1, and every 6 cycles thereafter until the end of study treatment Stratification by: ECOG performance status -1 vs 2 Worst pain over previous 24 hours BPI short form; -3 (absent) vs 4-1 (present) Prior chemotherapy 1 vs 2 Type of progression PSA only vs radiographic with or without PSA BPI, Brief Pain Inventory; HR, hazard ratio; ITT, intent to treat; TTPP, time to PSA progression; rpfs, radiographic progression-free survival; PSA, prostate-specific antigen Fizazi et al. Lancet Oncology 212 3(1): Harland et al. Eur J Cancer 213 Aug 22. pii: S (13)72-X. doi: 1.116/j.ejca [Epub ahead of print]

7 COU-AA-31 Baseline Demographics Abiraterone (n=797) Placebo (n=398) Total (n=1195) Median age, years (range) 69. (42-95) 69. (39-9) 69. (39-95) Race, % White Black Asian ECOG PS 2, % Significant pain present, % Prior chemotherapies, %

8 Extent of disease Baseline Disease Characteristics Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) Bone 89% 9% Node 45% 41% Liver 11% 8% Lung 13% 11% Other Visceral 6% 5% Prostate mass 8% 6% Other tissue 5% 5% Viscera, NOS.1% PSA (median, ng/ml) ( ) ( ) Hemoglobin (median, g/dl) LDH (median, IU/L) de Bono et al. N Engl J Med 211; 346(21): de Bono et al. N Engl J Med 211; 346(21): (Supplementary Data)

9 Baseline Disease Characteristics Gleason score at initial diagnosis Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) % 46.% % 54.% PSA at initial diagnosis (ng/ml) Median (range) 27 ( ) 35.5 ( ) Previous cancer therapy Surgery 54% 49% Radiotherapy 72% 72% Hormonal 1% 1% Other* 1% 1% * Includes chemotherapy de Bono et al. N Engl J Med 211; 346(21): de Bono et al. N Engl J Med 211; 346(21): (Supplementary Data)

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11 Survival Benefit Observed With AA Is Consistent For Majority of Subgroups Fizazi et al, abstr #7, ECCO 211

12 Survival (%) Survival (%) Survival by Baseline ECOG Status Favors AA for ECOG -1, but not for ECOG 2; May be Attributed by the Small Sample Size ECOG -1 ECOG 2 (1% of patients) Abiraterone + prednisone: 17 months 8 Abiraterone + prednisone: 7.3 months Placebo + Prednisone: 12.3 months 4 2 Placebo + prednisone: 7 months Time to Death (Months) Time to Death (Months) Median OS Abiraterone + prednisone vs. Placebo + prednisone ECOG -1: 17 vs months (HR=.74; 95% CI: ; p=.2) ECOG 2: 7.3 vs. 7 months (HR=.77; 95% CI: ; p=.2166) Fizazi et al. Lancet Oncol 212; 13(1): (Supplementary Appendix)

13 Survival (%) Survival (%) Survival (%) Survival Benefit Observed With AA Across All Age Groups < 65 Years 65 Years 75 Years Abiraterone + prednisone : 15. months 8 6 Abiraterone + prednisone : 16.2 months 8 6 Abiraterone + prednisone : 15.6 months 4 2 Placebo + prednisone : 11.2 months 4 2 Placebo + prednisone : 11.1 months 4 2 Placebo + prednisone : 9.3 months Time to Death (Months) Time to Death (Months) Median 22 OS Abiraterone prednisone vs. Placebo 6 + prednisone: < 65 years: 15. vs months (HR=.69; 95% CI: ) 65 years: 16.2 vs months (HR=.76; 95% CI:.63-.9) 75 years: 15.6 vs. 9.3 months (HR=.64; 95% CI: ) Time to Death (Months) Fizazi et al. ECCO 211: Abstract 7 (oral presentation)

14 Survival (%) Survival (%) Survival Benefit Observed With AA for Subgroups With and Without Visceral Disease at Study Entry Without Visceral Disease With Visceral Disease Abiraterone + prednisone : 17.1 months 8 Abiraterone + prednisone : 12.9 months Placebo + prednisone : 12.3 months 4 2 Placebo + prednisone : 8.3 months Time to Death (Months) Median OS Abiraterone + prednisone vs. Placebo + prednisone: Without visceral disease: 17.1 vs months (HR =.69; 95% CI: ) With visceral disease: 12.9 vs. 8.3 months (HR =.79; 95% CI: ) Time to Death (Months) Fizazi et al. ECCO 211: Abstract 7 (oral presentation)

15 All Secondary End Points Achieved Statistical Significance Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) HR 95% CI TTPP (months) (.46,.73) rpfs (months) (.58,.78) P Value <.1 <.1 PSA response rate Total 38.% 1.1% - <.1 Confirmed 29.1% 5.5% - <.1 Objective response (RECIST) 14.% 2.8% - <.1 de Bono et al. N Engl J Med 211; 346(21):

16 PSA Response Rate (%) Fizazi et al. ECCO 211: Abstract 7 (oral presentation) Fizazi et al. Lancet Oncol 212; 13(1): Total and Confirmed PSA Response Rates Were Significantly Higher With AA p <.1 p <.1 Total Confirmed Abiraterone + prednisone Placebo + prednisone

17 COU-AA-31: Similar AE incidence rates were observed in both groups* Abiraterone + Prednisone (n=791) All Grades Grades 3/4 Placebo + Prednisone (n=394) All Grades Grades 3/4 All AEs 99% 6% 99% 61% Serious AEs 42% 36% 44% 38% AEs leading to discontinuation 21% 11% 24% 14% AEs leading to death 13% 16% *Grade 1 or 2 urinary tract infections were higher with abiraterone compared with placebo: 12% vs 7%, p=.2 AE, adverse event. Fizazi et al. Lancet Oncology 212 3(1): de Bono et al. New Eng J Med 211; 364:

18 COU-AA-31: AEs of special interest Fluid retention and edema Abiraterone + Prednisone (n=791) All Grades Grade 3 Grade 4 Placebo + Prednisone (n=394) All Grades Grade 3 Grade 4 31% 2% <1% 22% 1% Hypokalemia 17% 3% <1% 8% 1% Cardiac disorders 13% 3% 1% 11% 2% <1% LFT abnormalities 1% 3% <1% 8% 3% <1% Hypertension 1% 1% 8% <1% Fizazi et al. Lancet Oncology 212 3(1): de Bono et al. New Eng J Med 211; 364:

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22 Gleason skoru prediktif değil Abiraterone ile klinik yararlanım Gleason skorundan bağımsız

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24 Pain Intensity Abiraterone + Prednisone (n=797) Placebo + Prednisone (n=398) P Value HR (95% CI) Palliation rate 45% (157/349) 28.8% (47/163).5 - Time to palliation (median) Time to progression (25 th percentile) 5.6 months 13.7 months months 4.7 months ( ).717 ( ) Duration of palliation (median) 4.2 months 2.1 months.56 - Logothetis et al. Lancet Oncol 212: 212; 13:

25 Symptomatic Improvement Pain Interference AA (n = 797) Placebo (n = 398) P Value Palliation, n (%) 132/223 (59.2) 38/1 (38.).4 Time to palliation (months) Median (95% CI) 1.2 ( ) 3.71 ( ).9 Time to progression (months) 25 th percentile (95% CI) 9.27 ( ) 4.57 ( ).19

26 Overall survival Outcomes AA (n = 797) Placebo (n = 398) P Value Median, months <.1 PSA response rate Total 38.% 1.1% <.1 Confirmed 29.1% 5.5% <.1 Radiographic PFS Median, months <.1 Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery) 25 th percentile, days <.1 Logothetis et al Lancet Oncol 211

27 Patients With Improvement (%) AA Was Associated With Higher FACT-P Responses Abiraterone + prednisone (n = 797) * * p =.284 Placebo + prednisone (n = 398) * * * * p <.1 p < Harland et al. ECCO 211: Abstract 71 (oral presentation)

28 Median time to decline (days) AA Delayed Time to Deterioration of QoL Abiraterone + prednisone (n=797) Placebo + prednisone (n=398) * * * * * * p<.1 * P=.325 * Harland et al. ECCO 211: Abstract 71 (oral presentation)

29 COU-AA-31 Conclusions Abiraterone acetate prolonged OS in patients with mcrpc who have progressed after docetaxel-based chemotherapy Median OS improvement of approximately 5 months 36% improvement in median survival 35% risk reduction of death (HR =.65) Improved TTPP, PFS, and PSA response rate 38% of patients had a >5% reduction in PSA Clinical benefit for treatment of bone metastases: Improved pain palliation Delayed pain progression and time to SRE Effect sustained over treatment cycles Favorable Safety Profile

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31 Tumor volume & activity Prostate cancer drug development Chemotherapy NOTE: This diagram represents typical disease progression. Some patients are metastatic at diagnosis and are thus still castrate Castration sensitive. Abiraterone Acetate Sipeuleucel-T Docetaxel Abiraterone Acetate Cabazitaxel Alpharadin Enzalutamide