mkdpk de Sonunda Gerçek İlerleme! Kanıt: Klinik çalışmalarda ZYTIGA Dr. Sevil Bavbek 5. Türk Tıbbi Onkoloji Kongresi Mart 214, Antalya
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
b Abiraterone: CYP17 blockade inhibits androgen synthesis
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):983-92 Harland et al. Eur J Cancer 213 Aug 22. pii: S959-849(13)72-X. doi: 1.116/j.ejca.213.7.144. [Epub ahead of print]
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 93.3 92.7 93.1 Black 3.5 3.8 3.6 Asian 1.4 2.3 1.7 ECOG PS 2, % 1.7 11.1 1.8 Significant pain present, % 44.3 44. 44.2 2 Prior chemotherapies, % 28.2 28.4 28.3
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) 128.8 (.4-9253) 137.7 (.6-1114) Hemoglobin (median, g/dl) 11.8 11.8 LDH (median, IU/L) 223. 237.5 de Bono et al. N Engl J Med 211; 346(21): 1995-25 de Bono et al. N Engl J Med 211; 346(21): 1995-25 (Supplementary Data)
Baseline Disease Characteristics Gleason score at initial diagnosis Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) 7 48.9% 46.% 8 51.1% 54.% PSA at initial diagnosis (ng/ml) Median (range) 27 (.1-1665.9) 35.5 (1.1-7378.) 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): 1995-25 de Bono et al. N Engl J Med 211; 346(21): 1995-25 (Supplementary Data)
Survival Benefit Observed With AA Is Consistent For Majority of Subgroups Fizazi et al, abstr #7, ECCO 211
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) 1 1 8 Abiraterone + prednisone: 17 months 8 Abiraterone + prednisone: 7.3 months 6 6 4 2 Placebo + Prednisone: 12.3 months 4 2 Placebo + prednisone: 7 months 6 12 18 24 3 6 12 18 24 3 Time to Death (Months) Time to Death (Months) 715 353 68 281 452 174 263 97 14 6 82 45 49 25 21 9 1 3 1 Median OS Abiraterone + prednisone vs. Placebo + prednisone ECOG -1: 17 vs. 12.3 months (HR=.74; 95% CI:.63-.87; p=.2) ECOG 2: 7.3 vs. 7 months (HR=.77; 95% CI:.5-1.17; p=.2166) Fizazi et al. Lancet Oncol 212; 13(1): 983-992 (Supplementary Appendix)
Survival (%) Survival (%) Survival (%) Survival Benefit Observed With AA Across All Age Groups < 65 Years 65 Years 75 Years 1 1 1 8 6 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 6 12 18 24 3 6 12 18 24 3 6 12 18 24 3 232 119 Time to Death (Months) 183 88 137 55 75 2 565 Time to Death (Months) 474 336 Median 22 OS Abiraterone 278 218 + prednisone 128 78 vs. Placebo 6 + prednisone: 111 82 < 65 years: 15. vs. 11.2 months (HR=.69; 95% CI:.53-.91) 65 years: 16.2 vs. 11.1 months (HR=.76; 95% CI:.63-.9) 75 years: 15.6 vs. 9.3 months (HR=.64; 95% CI:.48-.85) 198 13 22 Time to Death (Months) 18 131 44 76 27 6 4 Fizazi et al. ECCO 211: Abstract 7 (oral presentation)
Survival (%) Survival (%) Survival Benefit Observed With AA for Subgroups With and Without Visceral Disease at Study Entry Without Visceral Disease With Visceral Disease 1 1 8 Abiraterone + prednisone : 17.1 months 8 Abiraterone + prednisone : 12.9 months 6 6 4 2 Placebo + prednisone : 12.3 months 4 2 Placebo + prednisone : 8.3 months 6 12 18 24 544 299 466 242 Time to Death (Months) 345 146 22 78 15 5 3 Median OS Abiraterone + prednisone vs. Placebo + prednisone: Without visceral disease: 17.1 vs. 12.3 months (HR =.69; 95% CI:.58-.82) With visceral disease: 12.9 vs. 8.3 months (HR =.79; 95% CI:.59-1.5) 6 12 18 24 253 99 191 64 Time to Death (Months) 128 37 Fizazi et al. ECCO 211: Abstract 7 (oral presentation) 71 22 1 3
All Secondary End Points Achieved Statistical Significance Abiraterone + Prednisone (n = 797) Placebo + Prednisone (n = 398) HR 95% CI TTPP (months) 1.2 6.6.58 (.46,.73) rpfs (months) 5.6 3.6.67 (.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): 1995-25
PSA Response Rate (%) Fizazi et al. ECCO 211: Abstract 7 (oral presentation) Fizazi et al. Lancet Oncol 212; 13(1): 983-992 Total and Confirmed PSA Response Rates Were Significantly Higher With AA 45 4 35 3 38.5 29.5 p <.1 p <.1 Total Confirmed 25 2 15 1 5 1.1 5.5 Abiraterone + prednisone Placebo + prednisone
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):983-92 de Bono et al. New Eng J Med 211; 364: 1995-25
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):983-92 de Bono et al. New Eng J Med 211; 364: 1995-25
Gleason skoru prediktif değil Abiraterone ile klinik yararlanım Gleason skorundan bağımsız
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.18 7.4 months 4.7 months.88 1.675 (1.119 2.341).717 (.557-.922) Duration of palliation (median) 4.2 months 2.1 months.56 - Logothetis et al. Lancet Oncol 212: 212; 13: 121 17
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 (.92-1.91) 3.71 (2.69-4.44).9 Time to progression (months) 25 th percentile (95% CI) 9.27 (7.39-12.88) 4.57 (2.79-6.47).19
Overall survival Outcomes AA (n = 797) Placebo (n = 398) P Value Median, months 14.8 1.9 <.1 PSA response rate Total 38.% 1.1% <.1 Confirmed 29.1% 5.5% <.1 Radiographic PFS Median, months 5.6 3.6 <.1 Time to first SRE (pathologic fracture/spinal cord compression/ palliative radiation/bone surgery) 25 th percentile, days 31. 15. <.1 Logothetis et al Lancet Oncol 211
Patients With Improvement (%) 7 6 5 4 3 2 1 AA Was Associated With Higher FACT-P Responses Abiraterone + prednisone (n = 797) * * p =.284 Placebo + prednisone (n = 398) * * * * p <.1 p <.5 48 32 46 28 54 48 54 39 44 33 41 28 58 4 46 25 Harland et al. ECCO 211: Abstract 71 (oral presentation)
Median time to decline (days) AA Delayed Time to Deterioration of QoL Abiraterone + prednisone (n=797) Placebo + prednisone (n=398) 45 4 35 * * * * * * p<.1 * 3 25 2 P=.325 * 15 1 5 363 253 339 24 168 89 424 226 337 169 424 274 262 142 395 253 Harland et al. ECCO 211: Abstract 71 (oral presentation)
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
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