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This document summarizes interim analysis results from a randomized phase 3 study of abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. The study showed a statistically significant improvement in radiographic progression-free survival with a median of not reached for abiraterone acetate versus 8.3 months for placebo. There was also a strong trend towards improved overall survival with a median of not reached for abiraterone acetate versus 27.2 months for placebo and a 25% reduction in risk of death. Benefits were seen across patient subgroups.

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Interim Analysis (IA) Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients (pts) With Metastatic Castration-Resistant Prostate Cancer (mCRPC) 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA; 2Massachusetts General Hospital Cancer Center, Boston, MA; 3Royal Marsden Hospital, Sutton, UK; 4Janssen Research & Development, Los Angeles, CA; 5MD Anderson Cancer Center, Houston, TX; 6St. George Private Hospital, Kogarah, Australia; 7Institut Gustave Roussy, University of Paris Sud, Villejuif, France; 8Haematology and Oncology Clinics of Australia, Brisbane, Australia; 9Institut Català d'Oncologia de l'Hospitalet, Barcelona, Spain; 10St. John of God Hospital, Subiaco, Australia; 11Hospital Universitari Vall d Hebron, Barcelona, Spain; 12Radboud University Medical Centre, Nijmegen, Netherlands; 13Memorial Sloan- Kettering Cancer Center, New York, NY Ryan et al, Proc ASCO 2012, LBA4518 x1 1 PRESENTED AT PRESENTED AT
Disclosures • Charles Ryan, Paul Mainwaring, Jose Piulats Rodriguez, Siobhan Ng, Joan Carles, Peter Mulders, Eric Small, and Dana Rathkopf have no disclosures to report • Matthew Smith has served as a paid consultant and received research funding from Cougar Biotechnology and Johnson & Johnson • Johann de Bono has served as a paid consultant for Johnson & Johnson • Arturo Molina, Thomas Griffin, and Thian Kheoh are employees of Janssen Research & Development, and own stock in Johnson & Johnson • Christopher Logothetis has served as a consultant for Johnson & Johnson and Janssen Pharmaceuticals, Inc., and has received honoraria and research funding from Johnson & Johnson • Paul De Souza has served as a paid consultant for Janssen Pharmaceuticals, Inc. • Karim Fizazi has served as a paid consultant for Janssen Pharmaceuticals, Inc. and Cougar Biotechnology, and has received honoraria from Janssen Pharmaceuticals, Inc. • Howard Scher has owned stock in Johnson & Johnson, has served as an abiraterone consultant/advisory board member, and has received consulting fees/grants/travel support fees from Cougar Biotechnology This study was sponsored by Ortho Biotech Oncology Research & Development (unit of Cougar Biotechnology). Writing assistance was provided by I. Mills, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC. Ryan et al, Proc ASCO 2012, LBA4518 2 2 PRESENTED AT PRESENTED AT 2
Persistent Unmet Need in mCRPC Current Therapies Have Limitations: 1. Restricted to Post-Chemotherapy Setting 2. OS Benefit in Chemo-Naïve Setting Without Objective Response or Impact on How a Patient Feels or Functions 3. Limited Penetrance of Chemotherapy 1. NCCN prostate cancer guidelines Version 3.2012. 2. Kantoff P, N Engl J Med. 2011; 363:411-422. Ryan et al, Proc ASCO 2012, LBA4518 3 3 PRESENTED AT PRESENTED AT 3
Abiraterone Acetate: Androgen Biosynthesis Inhibitor Cholesterol Pregnenolone Aldosterone Abiraterone 17OH- Cortisol Pregnenolone Abiraterone DHEA Androstenedione Testosterone DHT Androgens Ryan et al, Proc ASCO 2012, LBA4518 4 4 PRESENTED AT PRESENTED AT 4
Abiraterone Acetate: OS Benefit Shown in Post-Chemotherapy mCRPC Patients Median Survival was 14.8 months Improvement of 3.9 months over Prednisone control arm 1. de Bono J, N Engl J Med. 2011; 364:1995-2005. Ryan et al, Proc ASCO 2012, LBA4518 5 5 PRESENTED AT PRESENTED AT 5
Landmarks of Disease Progression in mCRPC Secondary Endpoints Pain PSA Tumor/Bone ECOG PS Decline Death Baseline Progression Progression Chemotherapy Primary Endpoints: rPFS and OS 24-48 months Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771. ECOG PS= Eastern Cooperative Oncology Group Performance Status. Ryan et al, Proc ASCO 2012, LBA4518 6 6 PRESENTED AT PRESENTED AT 6
Overall Study Design of COU-AA-302 R Efficacy end points Patients A N AA 1000 mg daily Co-Primary: • Progressive chemo- D Prednisone 5 mg BID O • rPFS by central review naïve mCRPC (Actual n = 546) M • OS patients I (Planned N = 1088) Z Secondary: • Asymptomatic or E Placebo daily • Time to opiate use mildly symptomatic D Prednisone 5 mg BID (cancer-related pain) (Actual n = 542) • Time to initiation of 1:1 chemotherapy • Time to ECOG-PS deterioration • TTPP • 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 Ryan et al, Proc ASCO 2012, LBA4518 7 7 PRESENTED AT PRESENTED AT 7
COU-AA-302: rPFS Definition • Progressive disease (PD) by bone scan: Adapted from Consensus Criteria1 – Blinded central radiologist review – < 12 weeks after randomization • ≥ 2 new bone lesions plus 2 additional at confirmation (“2+2”) – ≥ 12 weeks after randomization • ≥ 2 new bone lesions with subsequent confirmation • PD (soft tissue lesions) by CT or MRI by modified RECIST criteria • Death from any cause 1. Scher H, J Clin Oncol. 2008;26:1148-1159. Ryan et al, Proc ASCO 2012, LBA4518 8 8 PRESENTED AT PRESENTED AT 8
COU-AA-302 Statistical Plan Overall Assumption rPFS OS α 0.01 0.04 Power 91% 85% HR 0.67 0.80 Expected events 378 773 Planned OS Analysis 1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12 IA1 IA2 IA3 (~15% OS Events) (40% OS Events) (55% OS events) 116 Events 311 Events 425 Events  < 0.0001  = 0.0005  = 0.0034 IA = interim analysis. Ho, HR=1.0. Ryan et al, Proc ASCO 2012, LBA4518 9 9 PRESENTED AT PRESENTED AT 9
Treatment Arms Evenly Matched AA + P Placebo + P (n = 546) (n = 542) Median age, years (range) 71 (44-95) 70 (44-90) Median time from initial diagnosis to first dose (years) 5.5 5.1 Median PSA (ng/mL) 42.0 37.7 Median testosterone (ng/dL) 4.0 4.0 Median alkaline phosphatase (IU/L) 93.0 90.0 Median hemoglobin (g/dL) 13.0 13.1 Median lactate dehydrogenase (IU/L) 187.0 184.0 Gleason score (≥8) at initial diagnosis 53.9% 50.0% Extent of disease Bone Metastases 83% 80%  >10 bone lesions 48% 47% Soft tissue or node 49.1% 50% Pain (BPI Short Form) 0-1 66% 64% 2-3 32% 33% Ryan et al, Proc ASCO 2012, LBA4518 10 10 PRESENTED AT PRESENTED AT 10
Treatment Duration and Discontinuation *Unequivocal clinical progression is one or more of the following: pain requiring opiates, chemotherapy, palliative radiation therapy, decline in ECOG PS, surgical intervention. Data from safety population. Ryan et al, Proc ASCO 2012, LBA4518 11 PRESENTED AT PRESENTED AT PRESENTED AT 11
Statistically Significant Improvement in rPFS Primary End Point 100 AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 (0.35-0.52) 80 P value: < 0.0001 Progression-Free (%) 60 40 20 AA + P PL + P 0 0 3 6 9 12 15 18 Time to Progression or Death (Months) AA 546 489 340 164 46 12 0 PL 542 400 204 90 30 3 0 Data cutoff 12/20/2010. NR, not reached; PL, placebo. Ryan et al, Proc ASCO 2012, LBA4518 12 12 PRESENTED PRESENTED AT PRESENTED AT 12
rPFS Benefit Demonstrated Across Full Spectrum of Patient Subgroups Favors Favors AA Placebo Median (months) Variable Subgroup AA Placebo HR 95% CI All subjects ALL NE 8.3 0.43 (0.35-0.52) Baseline ECOG 0 13.7 8.3 0.45 (0.36-0.57) 1 NE 7.4 0.35 (0.23-0.54) Baseline BPI 0-1 NE 8.4 0.42 (0.32-0.54) 2-3 11.1 8.2 0.51 (0.35-0.75) Bone metastasis only at entry YES NE 13.7 0.48 (0.34-0.69) NO 11.3 5.6 0.38 (0.30-0.49) Age < 65 13.7 5.6 0.36 (0.25-0.53) ≥ 65 NE 9.7 0.45 (0.35-0.58) ≥ 75 NE 11.0 0.57 0.39-0.83) Baseline PSA above median YES 11.9 8.0 0.44 (0.33-0.58) NO NE 8.5 0.40 (0.29-0.54) Baseline LDH above median YES NE 5.6 0.37 (0.28-0.49) NO NE 9.0 0.48 (0.36-0.65) Baseline ALK-P above median YES 11.5 8.2 0.50 (0.38-0.66) NO NE 8.3 0.34 (0.25-0.47) Region N.A. NE 8.2 0.36 (0.27-0.48) Other 11.5 8.4 0.52 (0.39-0.69) 0.2 0.75 1 1.5 Ryan et al, Proc ASCO 2012, LBA4518 13 13 PRESENTED PRESENTED AT PRESENTED AT 13
Strong Trend in OS Primary End Point 100 80 Survival (%) 60 40 AA + P (median, mos): NR PL + P (median, mos): 27.2 20 HR (95% CI): 0.75 (0.61-0.93) AA + P P value: 0.0097 PL + P 0 0 3 6 9 12 15 18 21 24 27 30 33 Time to Death (Months) AA 546 538 524 503 482 452 412 258 120 27 0 0 PL 542 534 509 493 465 437 387 237 106 25 2 0 Data cutoff 12/20/2011. Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008. Ryan et al, Proc ASCO 2012, LBA4518 14 PRESENTED AT PRESENTED AT 14
Point Estimates for OS Favor AA in All Patient Subgroups Favors Favors AA Placebo Median (months) Variable Subgroup AA Placebo HR 95% CI All subjects ALL NE 27.2 0.75 (0.60-0.93) Baseline ECOG 0 NE 27.2 0.71 (0.55-0.92) 1 NE 26.4 0.86 (0.58-1.28) Baseline BPI 0-1 NE 27.2 0.71 (0.54-0.94) 2-3 25.5 NE 0.87 (0.59-1.29) Bone metastasis only at entry YES NE 27.2 0.68 (0.48-0.96) NO NE 27.5 0.81 (0.61-1.06) Age < 65 NE NE 0.80 (0.51-1.24) ≥ 65 NE 26.4 0.73 (0.57-0.94) ≥ 75 NE 23.8 0.71 (0.51-1.00) Baseline PSA above median YES 26.9 23.8 0.72 (0.55-0.94) NO NE NE 0.77 (0.54-1.09) Baseline LDH above median YES NE 23.6 0.69 (0.53-0.91) NO NE 27.5 0.79 (0.55-1.12) Baseline ALK-P above median YES NE 23.6 0.79 (0.60-1.04) NO NE 27.5 0.66 (0.46-0.94) Region N.A. NE 27.2 0.66 (0.49-0.88) Other NE NE 0.89 (0.65-1.22) 0.2 0.75 1 1.5 Ryan et al, Proc ASCO 2012, LBA4518 15 15 PRESENTED PRESENTED AT PRESENTED AT 15
Subsequent Therapy Was Common AA + P Placebo + P (n = 546) (n = 542) n (%) n (%) No. with selected subsequent 242 (44.3) 327 (60.3) therapy for mCRPC Docetaxel 207 (37.9) 287 (53.0) Cabazitaxel 45 (8.2) 52 (9.6) Ketoconazole 39 (7.1) 63 (11.6) Sipuleucel-T 27 (4.9) 24 (4.4) Abiraterone acetate* 26 (4.8) 54 (10.0) *Prior to unblinding (e.g. not per protocol) Ryan et al, Proc ASCO 2012, LBA4518 16 16 PRESENTED AT PRESENTED AT 16
Serologic and Clinical Responses AA + P Placebo + P RR (95% CI) P Value (n = 546) (n = 542) PSA decline ≥50% 62% 24% NA <0.0001 N=220 N=218 RECIST: Defined 36% 16% 2.273 <0.0001 objective response (1.591, 3.247) Complete response 11% 4% Partial response 25% 12% Stable disease 61% 69% Progressive disease 2% 15% Ryan et al, Proc ASCO 2012, LBA4518 17 17 PRESENTED AT PRESENTED AT 17
Statistically Significant Improvement in All Secondary End Points AA + P Placebo + P Median Median HR (95% CI) P Value (months) (months) Time to opiate use NR 23.7 0.69 (0.57, 0.83) 0.0001 (cancer related pain) Time to chemotherapy 25.2 16.8 0.58 (0.49, 0.69) <0.0001 initiation Time to ECOG PS 12.3 10.9 0.82 (0.71, 0.94) 0.0053 deterioration Time to PSA 11.1 5.6 0.49 (0.42, 0.57) <0.0001 progression Note: All secondary end points remain significant after adjusting for multiplicity testing Patient Reported Outcomes favored AA +P vs Placebo +P Full data to be reported Data cut off 12/20/2011. Ryan et al, Proc ASCO 2012, LBA4518 18 18 PRESENTED AT PRESENTED AT 18
No New Safety Concerns Identified with Longer AA Treatment than in 301 Study AA + P Placebo + P (n = 542) (n = 540) % % All Grades Grades 3/4 All Grades Grades 3/4 Fatigue 39 2 34 2 Fluid retention 28 0.7 24 1.7 Hypokalemia 17 2 13 2 Hypertension 22 4 13 3 Cardiac disorders 19 6 16 3 Atrial fibrillation 4 1.3 5 0.9 ALT increased 12 5.4 5 0.8 AST increased 11 3.0 5 0.9 Most ALT and AST increases occurred during the first 3 months of treatment Ryan et al, Proc ASCO 2012, LBA4518 19 19 PRESENTED AT PRESENTED AT 19
IDMC Unblinds Study at 2nd Interim Analysis • February 2012 – Investigators and sponsors remained blinded – Concluded that OS, rPFS, and secondary end points all favored AA – Recommended unblinding study and that patients in placebo arm be offered treatment with AA Ryan et al, Proc ASCO 2012, LBA4518 20 20 PRESENTED AT PRESENTED AT 20
Time to All Landmarks Favored Abiraterone Secondary Endpoints p < 0.0001 p < 0.0001 p = 0.001 p = 0.0053 Pain PSA Tumor/Bone ECOG PS Decline Death Baseline Progression Progression Chemotherapy p < 0.0001 p = 0.0097 Primary Endpoints: rPFS and OS 24-48 months Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771. ECOG PS = Eastern Cooperative Oncology Group Performance Status. Ryan et al, Proc ASCO 2012, LBA4518 21 21 PRESENTED AT PRESENTED AT 21
Summary • In patients with asymptomatic and mildly symptomatic, chemotherapy-naïve mCRPC, treatment with abiraterone acetate plus prednisone: – Delays disease progression – Increases survival – Extends time with minimal or no symptoms – No new important safety signals Ryan et al, Proc ASCO 2012, LBA4518 22 22 PRESENTED AT PRESENTED AT 22
Acknowledgments The Patients, Their Caregivers and Families Australia Canada Germany Netherlands T. Elliott C. Formaker J. Pinski A. Boyce T. Cheng P. Albers C. Bangma S. Harland E. Frenkel A. Pantuck A. Costello J. Chin M. Boegemann T. de Reijke H. Innes N. Gabrail B. Polesz I. Davis S. Ellard J. Gleissner W. Gerritsen N. James J. Garcia J. Polikoff P. de Souza Y. Fradet J. Gschwend P. Mulders R. Jones D. Georgel D. Rathkopf V. Ganju M. Gleave P. Hammerer D. Mazhar L. Gomella D. Quinn L. Horvath A. Joshua A. Heidenreich Spain E. Paez O. Goodman C. Redfern R. Lynch L. Klotz M. Kuczyk J. Arranz Arija A. Protheroe I. Gore S. Riggs P. Mainwaring H. Martins K. Miller J. Bellmunt J. Staffurth J. Gullo C. Ryan G. Marx S. Mukherjee R. Oetzel J. Carles J. Hainsworth T. Rodvelt S. Ng S. North J. Roigas R. Lopez United States O. Hamid M. Saleh F. Parnis S. Pautler T. Steuber M. Lopez-Brea F. Ahmann A. Harzstark A. Sartor J. Shapiro F. Saad M. Stöckle J. Piulats- G. Andriole T. Hutson M. Scholz N. Singhal E. Winquist H. Suttmann Rodriguez E. Arrowsmith D. King N. Shore M. Slancar M. Wirth V. Assikis H. Koh E. Small G. Van Hazel Sweden A. Baron A. Koletsky M. Smith S. Wong France A. Bjartell W. Berry F. Kudrik S. Srinivas Greece S. D. Yip S. Abdel-Hamid J. Damber G. Bubley A. Lin M. Taplin E. Efstathiou M. Colombel M. Haggman J. Carney P. Lara U.Vaishampaya C. Papandreou Belgium K. Fizazi M. Hellstrom L. Chu C. Logothetis J. Vieweg P. Carpentier A. Fléchon M. Seke T. Cosgriff R. Lyons M. Vira D. Luyten O. Haillot Italy S. Denmeade J. Maranchie N. Vogelzang S. Rottey F. Joly S. Bracarda United Kingdom H. Deshpande M. Modiano G. Wilding D. Schrijvers S. Oudard T. Marcello J. Brown D. Duchene J. Nieva Y. Wong F. Van Aelst F. Priou C. Sternberg S. Chowdhury A. Ferrari L. Nordquist E. Yu H. Van Poppel E. Raymond J. de-Bono T. Flaig L. Fong Ryan et al, Proc ASCO 2012, LBA4518 23 23 PRESENTED AT PRESENTED AT 23

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asdads

  • 1.
    Interim Analysis (IA)Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients (pts) With Metastatic Castration-Resistant Prostate Cancer (mCRPC) 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA; 2Massachusetts General Hospital Cancer Center, Boston, MA; 3Royal Marsden Hospital, Sutton, UK; 4Janssen Research & Development, Los Angeles, CA; 5MD Anderson Cancer Center, Houston, TX; 6St. George Private Hospital, Kogarah, Australia; 7Institut Gustave Roussy, University of Paris Sud, Villejuif, France; 8Haematology and Oncology Clinics of Australia, Brisbane, Australia; 9Institut Català d'Oncologia de l'Hospitalet, Barcelona, Spain; 10St. John of God Hospital, Subiaco, Australia; 11Hospital Universitari Vall d Hebron, Barcelona, Spain; 12Radboud University Medical Centre, Nijmegen, Netherlands; 13Memorial Sloan- Kettering Cancer Center, New York, NY Ryan et al, Proc ASCO 2012, LBA4518 x1 1 PRESENTED AT PRESENTED AT
  • 2.
    Disclosures • Charles Ryan, Paul Mainwaring, Jose Piulats Rodriguez, Siobhan Ng, Joan Carles, Peter Mulders, Eric Small, and Dana Rathkopf have no disclosures to report • Matthew Smith has served as a paid consultant and received research funding from Cougar Biotechnology and Johnson & Johnson • Johann de Bono has served as a paid consultant for Johnson & Johnson • Arturo Molina, Thomas Griffin, and Thian Kheoh are employees of Janssen Research & Development, and own stock in Johnson & Johnson • Christopher Logothetis has served as a consultant for Johnson & Johnson and Janssen Pharmaceuticals, Inc., and has received honoraria and research funding from Johnson & Johnson • Paul De Souza has served as a paid consultant for Janssen Pharmaceuticals, Inc. • Karim Fizazi has served as a paid consultant for Janssen Pharmaceuticals, Inc. and Cougar Biotechnology, and has received honoraria from Janssen Pharmaceuticals, Inc. • Howard Scher has owned stock in Johnson & Johnson, has served as an abiraterone consultant/advisory board member, and has received consulting fees/grants/travel support fees from Cougar Biotechnology This study was sponsored by Ortho Biotech Oncology Research & Development (unit of Cougar Biotechnology). Writing assistance was provided by I. Mills, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC. Ryan et al, Proc ASCO 2012, LBA4518 2 2 PRESENTED AT PRESENTED AT 2
  • 3.
    Persistent Unmet Needin mCRPC Current Therapies Have Limitations: 1. Restricted to Post-Chemotherapy Setting 2. OS Benefit in Chemo-Naïve Setting Without Objective Response or Impact on How a Patient Feels or Functions 3. Limited Penetrance of Chemotherapy 1. NCCN prostate cancer guidelines Version 3.2012. 2. Kantoff P, N Engl J Med. 2011; 363:411-422. Ryan et al, Proc ASCO 2012, LBA4518 3 3 PRESENTED AT PRESENTED AT 3
  • 4.
    Abiraterone Acetate: Androgen Biosynthesis Inhibitor Cholesterol Pregnenolone Aldosterone Abiraterone 17OH- Cortisol Pregnenolone Abiraterone DHEA Androstenedione Testosterone DHT Androgens Ryan et al, Proc ASCO 2012, LBA4518 4 4 PRESENTED AT PRESENTED AT 4
  • 5.
    Abiraterone Acetate: OS Benefit Shown in Post-Chemotherapy mCRPC Patients Median Survival was 14.8 months Improvement of 3.9 months over Prednisone control arm 1. de Bono J, N Engl J Med. 2011; 364:1995-2005. Ryan et al, Proc ASCO 2012, LBA4518 5 5 PRESENTED AT PRESENTED AT 5
  • 6.
    Landmarks of DiseaseProgression in mCRPC Secondary Endpoints Pain PSA Tumor/Bone ECOG PS Decline Death Baseline Progression Progression Chemotherapy Primary Endpoints: rPFS and OS 24-48 months Adapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771. ECOG PS= Eastern Cooperative Oncology Group Performance Status. Ryan et al, Proc ASCO 2012, LBA4518 6 6 PRESENTED AT PRESENTED AT 6
  • 7.
    Overall Study Designof COU-AA-302 R Efficacy end points Patients A N AA 1000 mg daily Co-Primary: • Progressive chemo- D Prednisone 5 mg BID O • rPFS by central review naïve mCRPC (Actual n = 546) M • OS patients I (Planned N = 1088) Z Secondary: • Asymptomatic or E Placebo daily • Time to opiate use mildly symptomatic D Prednisone 5 mg BID (cancer-related pain) (Actual n = 542) • Time to initiation of 1:1 chemotherapy • Time to ECOG-PS deterioration • TTPP • 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 Ryan et al, Proc ASCO 2012, LBA4518 7 7 PRESENTED AT PRESENTED AT 7
  • 8.
    COU-AA-302: rPFS Definition • Progressive disease (PD) by bone scan: Adapted from Consensus Criteria1 – Blinded central radiologist review – < 12 weeks after randomization • ≥ 2 new bone lesions plus 2 additional at confirmation (“2+2”) – ≥ 12 weeks after randomization • ≥ 2 new bone lesions with subsequent confirmation • PD (soft tissue lesions) by CT or MRI by modified RECIST criteria • Death from any cause 1. Scher H, J Clin Oncol. 2008;26:1148-1159. Ryan et al, Proc ASCO 2012, LBA4518 8 8 PRESENTED AT PRESENTED AT 8
  • 9.
    COU-AA-302 Statistical Plan Overall Assumption rPFS OS α 0.01 0.04 Power 91% 85% HR 0.67 0.80 Expected events 378 773 Planned OS Analysis 1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12 IA1 IA2 IA3 (~15% OS Events) (40% OS Events) (55% OS events) 116 Events 311 Events 425 Events  < 0.0001  = 0.0005  = 0.0034 IA = interim analysis. Ho, HR=1.0. Ryan et al, Proc ASCO 2012, LBA4518 9 9 PRESENTED AT PRESENTED AT 9
  • 10.
    Treatment Arms EvenlyMatched AA + P Placebo + P (n = 546) (n = 542) Median age, years (range) 71 (44-95) 70 (44-90) Median time from initial diagnosis to first dose (years) 5.5 5.1 Median PSA (ng/mL) 42.0 37.7 Median testosterone (ng/dL) 4.0 4.0 Median alkaline phosphatase (IU/L) 93.0 90.0 Median hemoglobin (g/dL) 13.0 13.1 Median lactate dehydrogenase (IU/L) 187.0 184.0 Gleason score (≥8) at initial diagnosis 53.9% 50.0% Extent of disease Bone Metastases 83% 80%  >10 bone lesions 48% 47% Soft tissue or node 49.1% 50% Pain (BPI Short Form) 0-1 66% 64% 2-3 32% 33% Ryan et al, Proc ASCO 2012, LBA4518 10 10 PRESENTED AT PRESENTED AT 10
  • 11.
    Treatment Duration andDiscontinuation *Unequivocal clinical progression is one or more of the following: pain requiring opiates, chemotherapy, palliative radiation therapy, decline in ECOG PS, surgical intervention. Data from safety population. Ryan et al, Proc ASCO 2012, LBA4518 11 PRESENTED AT PRESENTED AT PRESENTED AT 11
  • 12.
    Statistically Significant Improvementin rPFS Primary End Point 100 AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 (0.35-0.52) 80 P value: < 0.0001 Progression-Free (%) 60 40 20 AA + P PL + P 0 0 3 6 9 12 15 18 Time to Progression or Death (Months) AA 546 489 340 164 46 12 0 PL 542 400 204 90 30 3 0 Data cutoff 12/20/2010. NR, not reached; PL, placebo. Ryan et al, Proc ASCO 2012, LBA4518 12 12 PRESENTED PRESENTED AT PRESENTED AT 12
  • 13.
    rPFS Benefit DemonstratedAcross Full Spectrum of Patient Subgroups Favors Favors AA Placebo Median (months) Variable Subgroup AA Placebo HR 95% CI All subjects ALL NE 8.3 0.43 (0.35-0.52) Baseline ECOG 0 13.7 8.3 0.45 (0.36-0.57) 1 NE 7.4 0.35 (0.23-0.54) Baseline BPI 0-1 NE 8.4 0.42 (0.32-0.54) 2-3 11.1 8.2 0.51 (0.35-0.75) Bone metastasis only at entry YES NE 13.7 0.48 (0.34-0.69) NO 11.3 5.6 0.38 (0.30-0.49) Age < 65 13.7 5.6 0.36 (0.25-0.53) ≥ 65 NE 9.7 0.45 (0.35-0.58) ≥ 75 NE 11.0 0.57 0.39-0.83) Baseline PSA above median YES 11.9 8.0 0.44 (0.33-0.58) NO NE 8.5 0.40 (0.29-0.54) Baseline LDH above median YES NE 5.6 0.37 (0.28-0.49) NO NE 9.0 0.48 (0.36-0.65) Baseline ALK-P above median YES 11.5 8.2 0.50 (0.38-0.66) NO NE 8.3 0.34 (0.25-0.47) Region N.A. NE 8.2 0.36 (0.27-0.48) Other 11.5 8.4 0.52 (0.39-0.69) 0.2 0.75 1 1.5 Ryan et al, Proc ASCO 2012, LBA4518 13 13 PRESENTED PRESENTED AT PRESENTED AT 13
  • 14.
    Strong Trend inOS Primary End Point 100 80 Survival (%) 60 40 AA + P (median, mos): NR PL + P (median, mos): 27.2 20 HR (95% CI): 0.75 (0.61-0.93) AA + P P value: 0.0097 PL + P 0 0 3 6 9 12 15 18 21 24 27 30 33 Time to Death (Months) AA 546 538 524 503 482 452 412 258 120 27 0 0 PL 542 534 509 493 465 437 387 237 106 25 2 0 Data cutoff 12/20/2011. Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008. Ryan et al, Proc ASCO 2012, LBA4518 14 PRESENTED AT PRESENTED AT 14
  • 15.
    Point Estimates forOS Favor AA in All Patient Subgroups Favors Favors AA Placebo Median (months) Variable Subgroup AA Placebo HR 95% CI All subjects ALL NE 27.2 0.75 (0.60-0.93) Baseline ECOG 0 NE 27.2 0.71 (0.55-0.92) 1 NE 26.4 0.86 (0.58-1.28) Baseline BPI 0-1 NE 27.2 0.71 (0.54-0.94) 2-3 25.5 NE 0.87 (0.59-1.29) Bone metastasis only at entry YES NE 27.2 0.68 (0.48-0.96) NO NE 27.5 0.81 (0.61-1.06) Age < 65 NE NE 0.80 (0.51-1.24) ≥ 65 NE 26.4 0.73 (0.57-0.94) ≥ 75 NE 23.8 0.71 (0.51-1.00) Baseline PSA above median YES 26.9 23.8 0.72 (0.55-0.94) NO NE NE 0.77 (0.54-1.09) Baseline LDH above median YES NE 23.6 0.69 (0.53-0.91) NO NE 27.5 0.79 (0.55-1.12) Baseline ALK-P above median YES NE 23.6 0.79 (0.60-1.04) NO NE 27.5 0.66 (0.46-0.94) Region N.A. NE 27.2 0.66 (0.49-0.88) Other NE NE 0.89 (0.65-1.22) 0.2 0.75 1 1.5 Ryan et al, Proc ASCO 2012, LBA4518 15 15 PRESENTED PRESENTED AT PRESENTED AT 15
  • 16.
    Subsequent Therapy WasCommon AA + P Placebo + P (n = 546) (n = 542) n (%) n (%) No. with selected subsequent 242 (44.3) 327 (60.3) therapy for mCRPC Docetaxel 207 (37.9) 287 (53.0) Cabazitaxel 45 (8.2) 52 (9.6) Ketoconazole 39 (7.1) 63 (11.6) Sipuleucel-T 27 (4.9) 24 (4.4) Abiraterone acetate* 26 (4.8) 54 (10.0) *Prior to unblinding (e.g. not per protocol) Ryan et al, Proc ASCO 2012, LBA4518 16 16 PRESENTED AT PRESENTED AT 16
  • 17.
    Serologic and ClinicalResponses AA + P Placebo + P RR (95% CI) P Value (n = 546) (n = 542) PSA decline ≥50% 62% 24% NA <0.0001 N=220 N=218 RECIST: Defined 36% 16% 2.273 <0.0001 objective response (1.591, 3.247) Complete response 11% 4% Partial response 25% 12% Stable disease 61% 69% Progressive disease 2% 15% Ryan et al, Proc ASCO 2012, LBA4518 17 17 PRESENTED AT PRESENTED AT 17
  • 18.
    Statistically Significant Improvementin All Secondary End Points AA + P Placebo + P Median Median HR (95% CI) P Value (months) (months) Time to opiate use NR 23.7 0.69 (0.57, 0.83) 0.0001 (cancer related pain) Time to chemotherapy 25.2 16.8 0.58 (0.49, 0.69) <0.0001 initiation Time to ECOG PS 12.3 10.9 0.82 (0.71, 0.94) 0.0053 deterioration Time to PSA 11.1 5.6 0.49 (0.42, 0.57) <0.0001 progression Note: All secondary end points remain significant after adjusting for multiplicity testing Patient Reported Outcomes favored AA +P vs Placebo +P Full data to be reported Data cut off 12/20/2011. Ryan et al, Proc ASCO 2012, LBA4518 18 18 PRESENTED AT PRESENTED AT 18
  • 19.
    No New SafetyConcerns Identified with Longer AA Treatment than in 301 Study AA + P Placebo + P (n = 542) (n = 540) % % All Grades Grades 3/4 All Grades Grades 3/4 Fatigue 39 2 34 2 Fluid retention 28 0.7 24 1.7 Hypokalemia 17 2 13 2 Hypertension 22 4 13 3 Cardiac disorders 19 6 16 3 Atrial fibrillation 4 1.3 5 0.9 ALT increased 12 5.4 5 0.8 AST increased 11 3.0 5 0.9 Most ALT and AST increases occurred during the first 3 months of treatment Ryan et al, Proc ASCO 2012, LBA4518 19 19 PRESENTED AT PRESENTED AT 19
  • 20.
    IDMC Unblinds Study at 2nd Interim Analysis • February 2012 – Investigators and sponsors remained blinded – Concluded that OS, rPFS, and secondary end points all favored AA – Recommended unblinding study and that patients in placebo arm be offered treatment with AA Ryan et al, Proc ASCO 2012, LBA4518 20 20 PRESENTED AT PRESENTED AT 20
  • 21.
    Time to AllLandmarks Favored Abiraterone Secondary Endpoints p < 0.0001 p < 0.0001 p = 0.001 p = 0.0053 Pain PSA Tumor/Bone ECOG PS Decline Death Baseline Progression Progression Chemotherapy p < 0.0001 p = 0.0097 Primary Endpoints: rPFS and OS 24-48 months Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771. ECOG PS = Eastern Cooperative Oncology Group Performance Status. Ryan et al, Proc ASCO 2012, LBA4518 21 21 PRESENTED AT PRESENTED AT 21
  • 22.
    Summary • In patientswith asymptomatic and mildly symptomatic, chemotherapy-naïve mCRPC, treatment with abiraterone acetate plus prednisone: – Delays disease progression – Increases survival – Extends time with minimal or no symptoms – No new important safety signals Ryan et al, Proc ASCO 2012, LBA4518 22 22 PRESENTED AT PRESENTED AT 22
  • 23.
    Acknowledgments The Patients, Their Caregivers and Families Australia Canada Germany Netherlands T. Elliott C. Formaker J. Pinski A. Boyce T. Cheng P. Albers C. Bangma S. Harland E. Frenkel A. Pantuck A. Costello J. Chin M. Boegemann T. de Reijke H. Innes N. Gabrail B. Polesz I. Davis S. Ellard J. Gleissner W. Gerritsen N. James J. Garcia J. Polikoff P. de Souza Y. Fradet J. Gschwend P. Mulders R. Jones D. Georgel D. Rathkopf V. Ganju M. Gleave P. Hammerer D. Mazhar L. Gomella D. Quinn L. Horvath A. Joshua A. Heidenreich Spain E. Paez O. Goodman C. Redfern R. Lynch L. Klotz M. Kuczyk J. Arranz Arija A. Protheroe I. Gore S. Riggs P. Mainwaring H. Martins K. Miller J. Bellmunt J. Staffurth J. Gullo C. Ryan G. Marx S. Mukherjee R. Oetzel J. Carles J. Hainsworth T. Rodvelt S. Ng S. North J. Roigas R. Lopez United States O. Hamid M. Saleh F. Parnis S. Pautler T. Steuber M. Lopez-Brea F. Ahmann A. Harzstark A. Sartor J. Shapiro F. Saad M. Stöckle J. Piulats- G. Andriole T. Hutson M. Scholz N. Singhal E. Winquist H. Suttmann Rodriguez E. Arrowsmith D. King N. Shore M. Slancar M. Wirth V. Assikis H. Koh E. Small G. Van Hazel Sweden A. Baron A. Koletsky M. Smith S. Wong France A. Bjartell W. Berry F. Kudrik S. Srinivas Greece S. D. Yip S. Abdel-Hamid J. Damber G. Bubley A. Lin M. Taplin E. Efstathiou M. Colombel M. Haggman J. Carney P. Lara U.Vaishampaya C. Papandreou Belgium K. Fizazi M. Hellstrom L. Chu C. Logothetis J. Vieweg P. Carpentier A. Fléchon M. Seke T. Cosgriff R. Lyons M. Vira D. Luyten O. Haillot Italy S. Denmeade J. Maranchie N. Vogelzang S. Rottey F. Joly S. Bracarda United Kingdom H. Deshpande M. Modiano G. Wilding D. Schrijvers S. Oudard T. Marcello J. Brown D. Duchene J. Nieva Y. Wong F. Van Aelst F. Priou C. Sternberg S. Chowdhury A. Ferrari L. Nordquist E. Yu H. Van Poppel E. Raymond J. de-Bono T. Flaig L. Fong Ryan et al, Proc ASCO 2012, LBA4518 23 23 PRESENTED AT PRESENTED AT 23