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Transcript of Actualización de la evidencia científica de Abiraterona en Prequimioterapia Joan Carles Jefe de...
Actualización de la evidencia científica de Abiraterona en
Prequimioterapia
Joan CarlesJefe de Sección
Director del Programa de GU, SNC y SarcomasHospital Universitario Vall d’Hebron
Barcelona
Resistente a la castraciónSensible a la castración
HISTORIA NATURAL DEL CÁNCER DE PRÓSTATA
SintomáticoASINTOMÁTICO
No metástasis
Terapia local
Deprivación de andrógenos
Quimioterapia
Postquimioterapia
Death
Desde el punto de vista del tratamiento hormonal existen dos tipos de pacientes:1. Cáncer de próstata sensible a terapia hormonal2. Cáncer de próstata resistente a la castración
Metástasis
GUIAS CLÍNICAS EUA 2010
• La abstención terapéutica
• La supresión de Antiandrógeno
• La adición de otro Antiandrógeno
• Los compuestos con actividad Estrogénica
• Corticoides
• Los agentes Adrenolíticos ó inhibidores de CYP 17
OPCIONES TERAPÉUTICAS DE SEGUNDA LÍNEA
RETIRADA DEL ANTIANDRÓGENO
• Ensayo Prospectivo de 210 enfermos• 21% RO por PSA• 0% RO radiológicas• SLP 3 meses• mSLP a 12 meses del 19%
Sartor et al Cancer 2008;112:2393-2400
BJU Inter. 2012;110:E826-29
CONCLUSIÓNEn pacientes CPRC sintomáticos el tratamiento con prednisona es similar aflutamida per con mejor calidad de vida
Fosså S D et al. JCO 2001;19:62-71
CYP17 y síntesis de andrógenos
CYP 17: codificado en cromosoma 10 (q24.3)
Retículo Endoplasmáticotestículo-células de Leydig teca interna del ovariosuprarrenal (zona fascicular y reticular)
Cataliza dos reacciones Esteroideas17α- Hidroxilasa17-20 Liasa
Haider SM et al. Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy. J Mol Biol 2010;400(5):1078-98.
PERSISTENCIA DE ANDRÓGENOS A PESAR DE LA DEPRIVACIÓN ANDROGÉNICA
Mostaghel et al. Urol Oncol 2009;27(3):251-7
Expresión enzimática de las principales enzimas esteroidogénicas en CPRC frente a tumor primario
¿Cómo se consigue el aumento de síntesis de andrógenos Intratumoral?
Fuente de andrógenos Intratumoral
RAA vs RAA + Ketoconazol
• 260 pacientes, Cáncer de próstata en progresión a BAC:
Retirada de antiandrógeno
Retirada de antiandrógeno + Ketoconazol
-Prednisona
Ketoconazol -Prednisona
Small et al. JCO 2004, 22: 1025-33 Cortesía Dr Cassinello
Supervivencia libre de enfermedad
Supervivencia global
Small et al. JCO 2004
PSA RR TTP PSA OR mOS
RAA 11% 5.9 2% 15.3
RAA + KETO 27% 8.6 20% 16.7
TRATAMIENTO HORMONAL DE SEGUNDA LÍNEA
• Retirada de antiandrógeno 20-35% 3-5 meses• Flutamida 34-54%• Bicalutamida altas dosis 20-24%• Nilutamida 29-50% 11 meses• Acetato de megestrol 8-12%• Corticoides a bajas dosis 18-22%• Aminoglutetimida 37%• Ketoconazol 27-63%• Estrogenos (DES) 26-66%
% Respuestas Duración
NO MEJORIA DE LA
SUPERVIVENCIA
Intensidad dolor SM (meses) 1-año, % 2-años, % 3-años,% Mínimo/ninguno PSA-DT > 45 días PSA-DT < 45 días
21.4 32.4 16.5
75 86 72
43 62 33
29 45 25
Leve 15.0 56 20 11 Moderado/ severo 13.1 52 20 4
Oudard S, et al. BJUI 2009
Supervivencia en el CPRC según la intensidad del dolor
NOMOGRAMA 2014
Halabi S et al. JCO 2014;32:671-677
Survival distribution by the training, testing, and validation data sets.
Halabi S et al. JCO 2014;32:671-677
Five New Agents with OS Benefits Approved Since Study Initiation
Radium-223
Abiraterone acetate(Chemo-naïve-302)
Enzalutamide (Post-chemo)
Abiraterone acetate(Post-chemo-301)
CabazitaxelSipuleucel-T
Docetaxel
Abiraterone acetate(Chemo-naïve-302)
Enzalutamide (Post-chemo)
Sipuleucel-T
Abiraterone acetatea
(Post-chemo-301)
CabazitaxelDocetaxel
US approvals
EU approvals
Radium-223
20052004 2006 2007 2008 2009 2010 2011 2012 2014 20152013
FPI, first patient in; LPI, last patient in.
Enzalutamide (Chemo-naive)
aHereafter referred to as abiraterone
GUIAS CLÍNICAS EUA 2014
N .Eng J Med. 2013;368:138-48
Colesterol
Pregnenolona Progesterona Corticosterona
17α-OH-pregnenolona
DHEA Androstenediona Testosterona
17α –OH-progesterona Cortisol
AldosteronaDeoxy-corticosterona
DHT5α-reductasa
11-Deoxy-cortisol
CYP19: aromatasa
Estradiol
Desmolasa
Renina
11β-Hydroxylase
17α-hydroxylasa
C17,20-lyasa
ACTH
Feedback positivoHipopotasemia
HipertensiónRetención de líquidos
Ang JE, et al. Br J Cancer. 2009;100:671-675. Attard G, et al. J Clin Oncol. 2008;26:4563-4571.
Abiraterona: Mecanismo de acción
Colesterol
Pregnenolona Progesterona Corticosterona
17α-OH-pregnenolona
DHEA Androstenediona Testosterona
17α –OH-progesterona Cortisol
Aldosterona
Deoxy-corticosterona
DHT5α-reductasa
11-Deoxy-cortisol
CYP19: aromatasa
Estradiol
Desmolasa
Renina
11β-Hydroxylase17α-
hydroxylasa
C17,20-lyasa
ACTH
Prednisona
Ang JE, et al. Br J Cancer. 2009;100:671-675. Attard G, et al. J Clin Oncol. 2008;26:4563-4571.
Abiraterona: Mecanismo de acción
Final Overall Survival Analysis of COU-AA-302,a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer
Patients Without Prior Chemotherapy
CJ Ryan,1 MR Smith,2 K Fizazi,3 K Miller,4 PFA Mulders,5 CN Sternberg,6 F Saad,7 T Griffin,8 EJ Small1, P De Porre,9 YC Park,10 J Li,10 T Kheoh,8 V Naini,8
A Molina,11 and DE Rathkopf12
1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 2Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA; 3Institut Gustave Roussy, University
of Paris Sud, Villejuif, France; 4Department of Urology, Charité Berlin, Berlin, Germany; 5Radboud University Medical Centre, Nijmegen, The Netherlands; 6San Camillo and Forlanini Hospitals, Rome, Italy; 7University of Montréal, Montréal, QC, Canada; 8Janssen Research & Development, Los Angeles, CA, USA; 9Janssen
Research & Development, Beerse, Belgium; 10Janssen Research & Development, Raritan, NJ, USA; 11Janssen Research & Development, Menlo Park, CA, USA; 12Memorial Sloan Kettering Cancer Center and
Weill Cornell Medical College, New York, NY, USA
Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]
Purpose of the Current Analysis
To report prespecified final analysis of COU-AA-302
in chemotherapy-naïve mCRPC patients, including:
1. Full evolution of OS
2. Overall clinical benefit
3. Long-term safety data
mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival.
Five New Agents with OS Benefits Approved Since Study Initiation
Radium-223
Abiraterone acetate(Chemo-naïve-302)
Enzalutamide (Post-chemo)
Abiraterone acetate(Post-chemo-301)
CabazitaxelSipuleucel-T
Docetaxel
Abiraterone acetate(Chemo-naïve-302)
Enzalutamide (Post-chemo)
Sipuleucel-T
Abiraterone acetatea
(Post-chemo-301)
CabazitaxelDocetaxel
US approvals
EU approvals
Radium-223
20052004 2006 2007 2008 2009 2010 2011 2012 2014 20152013
FPI LPI COU-AA-302
FPI, first patient in; LPI, last patient in.
Enzalutamide (Chemo-naive)
aHereafter referred to as abiraterone
Challenges in Demonstrating OS Benefit in mCRPC Trials
• Multiple new treatments available with proven OS benefit
• Sequential use of 2 or more of these treatments common
• Chronicity and heterogeneity of mCRPC treatment sequencing
may confound ability to measure OS benefit
• Requires larger and longer clinical studies
COU-AA-302: Study Design
• Final analysis: 96% of expected deaths, 741 actual deaths
Progressive mCRPC
without priorchemotherapy;
Asymptomatic or mildly symptomatic
Patient Population
RANDOMIZED
1:1a
Abiraterone 1000 mg daily+
Prednisone 5 mg BID(actual n = 546)
Placebo daily+
Prednisone 5 mg BID(actual n = 542)
Co-primary end points:• rPFS (central review)• OS
Secondary end points:• Time to opiate use• Time to initiation of
chemotherapy• Time to ECOG PS
deterioration• Time to PSA progression
aStratification by ECOG PS 0 vs 1.
IA3
FA
Unblinding
IA2IA1
2008 2009 2010 2011 2012 20142013
FPI LPI
BID, twice daily; rPFS, radiographic progression-free survival; ECOG PS, Eastern Cooperative Oncology Group performance status; FA, final analysis; IA, interim analysis; PSA, prostate-specific antigen.
Treatment Arms Were Well Balanced at Baseline
Abiraterone (n = 546)
Prednisone(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
Gleason score (≥ 8) at initial diagnosis 54% 50%
Extent of disease
Bone metastases 83% 80%
> 10 bone metastases 49% 47%
Soft tissuea 49% 50%
Pain (BPI-SF)
0-1 66% 64%
2-3 32% 33%
aExcludes visceral metastases.
BPI-SF, Brief Pain Inventory-Short Form (scale 0-10).
Time to All Landmarks SignificantlyImproved With Abiraterone
Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771.
Median Follow-Up of > 4 Years
Primary Endpoints: rPFS and OS
Secondary Endpoints
PSAProgression
DeathECOG PS Decline
ChemotherapyBaseline Tumor/Bone
Progression
Pain
ECOG PS = Eastern Cooperative Oncology Group Performance Status.
Abiraterone Doubled Time to rPFS1
Third interim analysis data. rPFS assessed by investigator review at prespecified IA.
100
80
60
40
20
00
Prog
ress
ion-
Free
Sur
viva
l (%
)
6 12 18 30 3624
546542
389244
240133
15778
207
00
AbirateronePrednisone
11745
Time to Progression or Death (Months)1593 21 27 33
485406
311176
19599
13162
6620
40
HR (95% CI): 0.52 (0.45-0.61)p Value: < 0.0001
Prednisone, 8.2 mos
Abiraterone, 16.5 mos
Rathkopf DE, et al. Eur Urol. 2014 March 6 [Epub ahead of print].
Most Patients Discontinued Due to Progression
Abiraterone (n = 542)
Prednisone(n = 540)
Median duration of follow-up 49.2 months
Median no. of cycles of therapy, range 15.0 (1-62) 9.0 (1-54)
Treatment discontinued 92.3% 100%
Reasons for discontinuation
Progression 68% 69%
Radiographic only 30% 32%
Unequivocal clinical onlya 26% 26%
Radiographic and clinical 13% 10%
Adverse event 9% 6%
Withdrew consent 8% 10%
Other 8% 6%
aUnequivocal clinical progression is 1 or more of the following: pain requiring opiates, chemotherapy, palliative radiation therapy, decline in ECOG PS, surgical intervention.
Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]
Final OS Analysis
• Median follow-up of 49.2 mos• Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients
who received subsequent abiraterone (HR = 0.74)
100
80
60
40
20
00
Ove
rall
Surv
ival
(%)
9 21 30 48 6039
546542
525509
422401
296261
5942
00
AbirateronePrednisone
202148
Time to Death (Months)24123 36 45 54
538534
453438
359322
189132
1510
HR (95% CI): 0.81 (0.70-0.93)p Value: 0.0033
Prednisone, 30.3 mos
Abiraterone, 34.7 mos
6 15 18 27 33 42 51 57
01
11884
218176
504493
483466
394363
330292
273227
235201
Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]
546542
524508
421400
6867
538534
452437
333283
503492
482465
393361
175153
159
00
HR (95% CI): 0.79 (0.66-0.95)p Value: 0.0151
Prednisone, 30.1 mos
Abiraterone, 35.3 mos
546542
525509
422401
296261
5942
00
202148
538534
453438
359322
189132
1510
HR (95% CI): 0.81 (0.70-0.93)p Value: 0.0033
Prednisone, 30.3 mos
Abiraterone, 34.7 mos
01
11884
218176
504493
483466
394363
330292
273227
235201
Statistical Significance of OS Benefit Emerged Over Time
100
80
60
40
20
00
Ove
rall
Surv
ival
(%)
9 21 30 48 6039
AbirateronePrednisone
Time to Death (Months)24123 36 45 546 15 18 27 33 42 51 57
546542
524509
412387
02
538534
452437
120106
503493
482465
258237
2725
00
HR (95% CI): 0.75 (0.61-0.93)p Value: 0.0097
Prednisone, 27.2 mos
Abiraterone, not reached
IA3FAIA2
FA0.0033
IA10.6926
Required p Value for Significance
Actual p Value Observed
Evolution of Statistical Significance
IA20.0097
IA30.0151
FA0.0384
IA20.0008
IA30.0035
IA1<0.0001
2009 2010 2011 2012 2014 20152013
OS Benefit Observed AcrossAll Patient Subgroups
Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]
Subsequent Therapy WasCommon in Both Groups
Abirateronen (%)
Prednisonen (%)
No. with selected subsequent therapy for mCRPC 365 (67) 435 (80)
Abiraterone 69 (13) 238 (44)a
Cabazitaxel 100 (18) 105 (19)
Docetaxel 311 (57) 331 (61)
Enzalutamide 87 (16) 54 (10)
Ketoconazole 42 (8) 68 (13)
Radium-223 20 (4) 7 (1)
Sipuleucel-T 45 (8) 32 (6)
aIncludes 93 patients who received abiraterone per protocol amendments.
Subsequent Therapy WasCommon in Both Groups
Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]
Significant Improvement in Time to Opiate Use for Cancer-Related Pain in the Final Analysis
• At the time of IA3, the median time to opiate use had not been reached for abiraterone• All secondary end points showed significant improvement with abiraterone
100
80
60
40
20
00
Patie
nts
With
out O
piat
e U
se (%
)
9 21 30 48 6039
546542
495442
328273
219168
3525
00
AbirateronePrednisone
14397
Time to Opiate Use (Months)24123 36 45 54
519500
364317
263208
12885
96
6 15 18 27 33 42 51 57
01
7456
162108
454406
407365
297237
244186
192141
169121
HR (95% CI): 0.72 (0.61-0.85)p Value:< 0.0001
Prednisone, 23.4 mos
Abiraterone, 33.4 mos
Pre-Specified AEs of Special Interest:Profile Remains Favorable
Time to All Landmarks SignificantlyImproved With Abiraterone
Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771.
Median Follow-Up of > 4 Years
p = 0.0002p < 0.0001 p = 0.005p < 0.0001
p < 0.0001 p = 0.0033
Primary Endpoints: rPFS and OS
Secondary Endpoints
PSAProgression
DeathECOG PS Decline
ChemotherapyBaseline Tumor/Bone
Progression
Pain
ECOG PS = Eastern Cooperative Oncology Group Performance Status.
Conclusions
• Median follow-up of more than 4 years, Abiraterone improvement in overall survival was statistically significant • 44% in the prednisone arm received Abiraterone
• Abiraterone delayed the need for opiate analgesics
• Tha safety profile of Abiraterona plus prednisona at this final analysis was consistent with that reported at the interim analyses. No new safety signals were observed
• Despite early unblinding, final survival data support continued data collection vs. early trial termination in clinical trial conduct