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



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(Post-chemo-301)

CabazitaxelSipuleucel-T

Docetaxel



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.


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


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


6 15 18 27 33 42 51 57

01

11884

218176

504493

483466

394363

330292

273227

235201


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



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



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


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


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


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


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


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



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

actualización de la evidencia científica de abiraterona en prequimioterapia joan carles jefe de...

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