(1) La terapia con abiraterona prolonga la supervivencia de pacientes con CPRC metastásico resistente a la castración, incluso en aquellos con metástasis viscerales. (2) La supervivencia es mayor en pacientes sin enfermedad visceral. (3) La progresión radiológica se retrasa más con abiraterona que con placebo tanto en pacientes con como sin metástasis viscerales.
1. Un análisis crítico de la situación actual del
tratamiento del CPRCm. Desarrollo futuro
2. Las células de cáncer de próstata:
sensibles a andrógenos
Premio Nobel 1966
Despite regressions of great
magnitude, it is obvious that
there are many failures of
Charles Huggins
endocrine therapy to control
1901-1997 the disease
Nobel lecture
December 13, 1966
3. Evolución en el cáncer de próstata
Cuidados paliativos
Terapia deprivación
andrógenos
Docetaxel Exitus
Tamaño y actividad del tumor
(medido según nivel de PSA)
Tratamiento
local
Años
10 11,5
Pre metastásico Metastásico
Asintomático Sintomático
No resistente a la castración Resistente a la castración
4. Molecular states framework for androgen receptor
activation in prostate cancer
Nelson P S JCO 2012;30:644-646
5. HISTORIA DEL TRATAMIENTO DEL CPRC
AÑOS 80 QUIMIOTERAPIA INACTIVA
AÑOS 90 MITOXANTRONA: QT PALIATIVA SIN
AUMENTO SUPERVIVENCIA
2004 DOCETAXEL: SUPERVIVENCIA 1ªL
CABAZITAXEL; ABIRATERONA;
2010-12
ENZALUTAMIDA; RAD-223;
ORTERONEL
6. 2010
Metastásico, sin Metastásico, sin
Metastásico,
quimioterapia previa, quimioterapia previa,
Post-docetaxel
asintomático sintomático
Segunda línea hormonal, Docetaxel Mitoxantrone
docetaxel Otros
Ácido zoledrónico
8. Summary of Agents with Survival Benefit in CRPC
RAD-223
Abiraterone Cabazitaxel Sipuleucel-T MDV3100
chloride
Pending;
2011 2010 (US), postdocetaxel
Approval 2010 (US) Approved
(US and EU) 2011 (EU) or docetaxel
ineligible
Following
docetaxel failure
(with prednisone)
Following Asymptomatic or
and asymptomatic
mCRPC docetaxel minimally
or minimally – –
indication failure (with symptomatic
symptomatic
prednisone) mCRPC
mCRPC
predocetaxel
Trial
Placebo Mitoxantrone Placebo Placebo Placebo
comparator
+4.8
+4.6 months; +2.4 months; +4.1 months; +3.6 months;
OS benefit months;
HR = 0.65 HR = 0.70 HR = 0.78 HR = 0.695
HR = 0.63
Efficacy
PSA, PFS, pain, Time to SRE,
endpoints with PSA, PFS – PSA, PFS
time to SRE PSA, ALP
positive results
9. 2013
Metastásico, sin Metastásico, sin
Metastásico,
quimioterapia previa, quimioterapia previa,
Post-docetaxel
asintomático sintomático
2ª línea hormonal Docetaxel Cabazitaxel
Docetaxel Abiraterona
Sipuleucel Enzalutamida
Abiraterona Mitoxantrone
Ácido zoledrónico
Denosumab
RAD 223
10.
11. Comunidad Valenciana
12.07.2012
Abiraterona o cabazitaxel deben ser prescritos
por médico especialista en Oncología Médica
12. Docetaxel >6 meses: retratar siempre con docetaxel
>3 m-<6m: retratar con docetaxel
Cabazitaxel < 3 m: tratar con cabazitaxel siempre que:
- PS 0-1
- No riesgo de neutropenia
- Tiempo de progresión a tratº hormonal previo < 1 año
- No abiraterona previa
Considerar entre 3-6 m de ILD
Abiraterona <3 m: tratar con abiraterona si:
- PS<2; no mets viscerales ni enf rápidamente progresiva
- Puede garantizarse la adherencia
- Tiempo de progresión a tratº hormonal previo >1 año
- No refractariedad a docetaxel
Considerar si ILD 3-6 m y no hay enfermedad rápidamente
progresiva y mets viscerales
14. CAPIO
Pacientes con enfermedad agresiva: rápida progresión
sintomática, afectación visceral, tratº previo con múltiples
maniobras hormonales ineficaces y/o ketoconazol y que cumplan
los siguientes criterios:
– RDT en <40% de la médula ósea
– PS 0-1
– Progresión durante docetaxel o antes de 6 m tras el mismo
– Adecuada función hematológica/cardiaca
Cabazitaxel
15. CAPIO
Pacientes con enfermedad menos agresiva
Abiraterona
Tercera línea y a considerar en 2ª por pacientes no candidatos a
docetaxel
Mitoxantrone
16. Servicio Aragonés de Salud
• Progresión precoz a docetaxel en < 3 meses:
cabazitaxel
• Progresión >6 m después: docetaxel
• Entre 3-6 m:
– Docetaxel si respuesta previa
– Abiraterona o cabazitaxel (si baja probabilidad de
respuesta a abiraterona*)
*progresión precoz a primera línea de hormonoterapia (<7 m),
Gleason 8-10; tratº previo con ketoconazol
17. HU 12 de Octubre
Debe contemplarse la administración de
abiraterona con preferencia a la de cabazitaxel
por sus ventajas en forma de administración y
perfil de seguridad
18. SERGAS
• Docetaxel: si se cumplen los 2 criterios
siguientes
– Respuesta bioquímica o radiológica
– Tiempo de progresión a docetaxel > 6 m
Si 3-6 m, deberá considerarse igualmente terapia de elección.
Comité interno de expertos en otros casos
19. SERGAS
• Cabazitaxel: si cumplen todos los criterios:
– Enfermedad visceral
– PSA DT < 3 meses
– Baja probabilidad de respuesta a tratamiento
hormonal (progresión a primera línea de tratº
hormonal: inferior a 1 año)
22. Canning Town
Westminster
Canary
London Bridge Wharf
River Thames Canada North
Bermondsey Water Greenwich
Waterloo
Southwark
Electoral wards just a few miles apart geographically have life
expectancy spans varying by years. For instance, there
are eight stops between Westminster and Canning Town
London Underground Jubilee Line on the Jubilee Line – so as one travels east, every two stops, on
average, mark over a year of shortened lifespan. 1
1 Source: Analysis by London Health Observatory of ONS and GLA data for 2004-08. Diagram produced by Department of Health
23. Differences in Male Life Expectancy within a small area in London
Travelling east from Westminster, every two tube stops represent over
one year of life expectancy lost
Male Life
Male Life
Expectancy
Expectancy
Canning Town 73.6
78.5
(CI 71.9-75.2)
(CI 75.5-81.6)
Westminster
Canary
London Bridge Wharf
River Thames Canada North
Bermondsey Water Greenwich
Waterloo
Southwark
Electoral wards just a few miles apart geographically have life
expectancy spans varying by years. For instance, there
are eight stops between Westminster and Canning Town
London Underground Jubilee Line on the Jubilee Line – so as one travels east, every two stops, on
average, mark over a year of shortened lifespan. 1
1 Source: Analysis by London Health Observatory of ONS and GLA data for 2004-08. Diagram produced by Department of Health
28. Heck et al
BJU Int 2012;110:635-40
Supervivencia según respuesta de PSA a la primera línea
22 vs 7 m
N=39
La respuesta de PSA> 30% no se correlacionó con una mejor SG
29. Loriot et al
Eur J Cancer 2010;46:1770-2
N=39 que habían respondido a docetaxel
40%: docetaxel + estramustina
Respuesta PSA >50%: 38%
SLP
7
6
5
Meses
4
3
2
1
0
Menos de 3 m 3 m o más
30. di Lorenzo et al
BJU Int 2010;107:234-39
N=45
Pacientes que progresan al menos 5 meses después del último ciclo de docetaxel
Respuesta PSA: 24% de los pacientes
31. di Lorenzo et al
BJU Int 2010;107:234-39
PFS: 5 meses SG: 13 meses
Más respuestas en los pacientes que habían progresado
>7 meses después (75 vs 20%)
32. Caffo et al
Urology 2012;79:644-9
N=46
Slope-log PSA (0.62)
Intervalo sin tratº (23 sem)
Respuesta previa
33. Oudard et al
ECCO 2011 abstract 7049
N=270 pac
Retrospectivo
223 con docetaxel
47: No taxano
34. Oudard et al
ECCO 2011 abstract 7049
N=270 pac
Retrospectivo 18 m
17 m
223 con docetaxel
47: No taxano
Análisis multivariante: asociación de estramustina; ILP > 6 meses
37. Docetaxel Abiraterona Cabazitaxel
Mediana PSA 70 130 144
Mets viscerales 35% 11% hep 25%
(17% hep)
Progresión 0 50% 30%
durante docetaxel (42% < 3 m)
Número de 1 30%: 2 o más 16%: 2 o más
regímenes
previos de
docetaxel
SG en pac que 13 m* 16.1 m 14 m
han progresado HR 0.70
>3 m
41. Pacientes con progresión radiológica
Radiographic
100
80 Abiraterone:
14.8 months
Survival (%)
60
40
Placebo:
20 10.5 months
AA
Placebo
0
0 6 12 18 24 30
Time to Death (Months)
559 452 318 177 10 0
273 206 117 61 3 0
42. Pacientes con metástasis viscerales
With Visceral Disease
100
80 Abiraterone:
12.9 months
Survival (%)
60
40
Placebo:
8.3 months
20
AA
Placebo
0
0 6 12 18 24 30
Time to Death (Months)
253 191 128 71 0 0
99 64 37 22 1 0
43. Goodman et al
ASCO GU 2013 #14
Pacientes con enfermedad visceral Pacientes sin enfermedad visceral
AA P p value AA P p value
(n=253) (n=99) (n=544) (n=299)
OS, meses 12.9 8.3 0.1022 17.1 12.3 <0.0001
HR 0.79 (0.6-1.05) 0.69 (0.58-
0.83)
rPFS, meses 5.6 2.8 0.0002 5.9 5.1 <0.0001
HR 0.6 (0.46-0.78) 0.68 (0.58-
0.80)
PSA resp 28% 7% <0.0001 30% 5% <0.0001
RR 11% 0% NE 19% 5% 3.51 (1.5-8)
EA grado 3-4 62% 65% 60% 60%
58. 90% del gasto farmacéutico en cáncer de
próstata: tratamientos hormonales
155
109
Millones de €
32
14
59.
60.
61.
62.
63.
64. PEACE-1 Study Design
European Phase III Trial of Abiraterone Acetate in patients with newly
diagnosed (hormone-näive) metastatic prostate cancer
Androgen deprivation therapy
(ADT)
• Patients with newly ADT
diagnosed Abiraterone acetate 1000mg
(hormone näive) Prednisone 5mg BID
metastatic prostate
cancer ADT
• 916 patients Local radiotherapy
planned
ADT
• Randomized Local radiotherapy
Abiraterone acetate 1000mg
Prednisone 5mg BID
Primary endpoint: OS and PFS (HR: 0.75)
Study Sponsor:Unicancer
Courtesy of K Fizazi
65. NCT01088529. Study Design
Phase 2, randomized, double-blind, placebo-controlled study
(1site, MD Anderson Center, Texas; USA)
• 66 pts Localized or
locally advanced
prostate cancer. Neoadyuvant a-LHRH
• ECOG 0-1
• T1c-T2, Gleason 8- Abiraterone acetate
10 1000 mg daily Radical
• T2b-T2c, Gleason
≥7 Prednisone 5mg twice daily
prostatectomy
• Deemed for radical 2-4 weeks after drugs
prostatectomy
• Recruiting.
Neoadyuvant a-LHRH
To find out how treatment with AA changes the tumor (Differences in
Primary endpoint:
pathologic stage)
-Changes in levels of androgens the serum, primary tumor and bone
Secundary endpoint: marrow, biomarkers, difference in rate of positive surgical margins.
- Safety profile of AA + P in a preoperative setting.
66. NCT00924469. Study Design
Phase 2 Open-Label, Randomized, Multi-center Study Interventional, Crossover Assignment,
Open Label, (6 sites; USA)
• 58 pts Localized High
Risk Prostate Cancer
Leuprolide
• ECOG 0-1 22.5mg every 12 weeks
• Gleason 6 (if PSA ≥ 10
ng/ml or PSA velocity ≥ 2 Abiraterone acetate
ng/ml/year) 1000 mg daily / 3 months
• Gleason ≥7 Radical
• Deemed for radical Prednisone 5mg twice daily
prostatectomy prostatectomy
24 weeks after drugs
• Randomized Phase II
Leuprolide
• Ongoing, Not
Recruiting. 22.5mg every 12 weeks
Primary endpoint: Effects of AA + Leuprolide and Prednisone vs. Leuprolide (Hormone levels and prostate biopsy)
Secundary endpoint: Pathologic complete response rate at prostatectomy, PSA response rate, Tumor expression of AR
Sponsor: Cougar Biotechnology, Inc www.clinicaltrials.gov
67. NCT01023061. Study Design
A Phase II trial, Interventional, Open Label, 1 treatment arm.
(2 sites: Washington, USA)
a-LHRH:
Leuprolide /goserelin
• Locally high risk
prostate In weeks 1 and 13
• No randomized phase II
• Intermediate Risk Abiraterone acetate
Disease: T2b/c, or 1000 mg daily / 24 weeks
Gleason 7, or PSA 10-20
• High Risk Disease: Prednisone 5mg twice daily
Gleason 8-10, or PSA >
20, or T3/4 RT
Starting in week 15
• Recruiting For 8.5 weeks
- Incidence of acute and chronic grade 3 or greater toxicity
Primary endpoint: - Levels of DHT and testosterone in prostate biopsy.
- AA effectiveness inducing inhibition of androgen-regulated gene expression and increased apoptotic cell death.
Secundary endpoint: - Time to PSA progression .
Sponsor: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium www.clinicatrials.gov
68. Efecto de neoadyuvancia con acetato de abiraterona
(AA) y acetato de leuprolide (LHRHa) en PSA,
respuesta patológica completa (pCR) y casi pCR en
cáncer de próstata localizado de alto riesgo (LHRPC):
Resultados de un estudio aleatorizado fase II
Taplin M-E et al. J Clin Oncol 2012; 30 (suppl ; abstr 4521)
69. AA y LHRHa en CaP de Riesgo Alto/Intermedio recién
diagnosticados con Posterior Prostatectomía Radical
12 weeks LHRHa
12 weeks AA/
LHRHa/pred
Newly Diagnosed
Intermediate and Radical
High Risk CaP Prostatectomy
•Positive biopsies (≥ 3)
•Gleason score ≥ 7 (4 + 3), T3,
PSA ≥ 20 ng/mL or
•PSA velocity > 2 ng/mL/yr
12 weeks Biopsy • Pathologic response
AA/LHRHa/pred • Pathology • Prostate androgen levels
5 mg qd • Prostate androgen • AR signaling
levels (primary
Confirm aim)
pathology • AR signaling
AA, abiraterone acetate; LHRHa, leuprolide acetate; pred, prednisone.
Supported by grants from Janssen R&D (formerly Ortho Biotech Oncology R&D [unit of Cougar Biotechnology])
and from a Prostate Cancer Foundation Challenge Award to Drs Balk and Nelson.
Taplin ME et al. Oral presentation ASCO, Chicago, 2 June 2012
71. Androgen results
Dihydrotestosterone DHEA
5 80
pg/ml
pg/ml
LHRHa AA/ LHRHa/ AA/ LHRHa AA/ LHRHa/ AA/
LHRHa/ AA/ LHRHa/ LHRHa/ AA/ LHRHa/
pred pred pred pred pred pred
12 w 24 w 12 w 24 w
72. Conclusiones
Es factible la administración de 6 meses de terapia neoadyuvante
previas a PR
AA/LHRHa/pred disminuye significativamente los andrógenos de
tejido
El 34% de pacientes tratados 6 meses con AA/LHRHa/pred tuvieron
una pCR (10%) o casi pCR (24%): mayores que los controles
históricos
Tendencia de mejor resultado patológico (0–5 mm de tumor) con
terapias de AA más largas (34% vs 15%)
Taplin ME et al. Oral presentation ASCO, Chicago, 2 June 2012
75. Abiraterona y cabazitaxel: nivel de evidencia I
Docetaxel: parece activo; no comparado
Diferencias entre diferentes Comunidades
Abiraterona: neoadyuvancia; primera línea
Notas del editor
To sum up four drugs which have shown an overall survival advantage have to date been approved for the treatment of metastatic CRPC. Two additional ones have reported results with OS gain. In those trials where an active comparator was used the absolute advantage seems to be a little lower but the hazard ratios are in the same range in all trials.Most of these drugs have in addition shown efficacy by improving clinically relevant secondary endpoints and the side effect profile varies quite a lot between those agents making this a possible argument in treatment decisions in daily clinical practice.
Background: LHRPC is infrequently cured with prostatectomy (RP). To date neoadjuvant androgen deprivation therapy (ADT) has not improved outcomes and residual intra-prostatic androgens remain. AA lowers serum testosterone (T) and DHT to < 1 ng/dL and has improved survival in advanced PC. Methods: We conducted a neoadjuvant, phase 2 trial of AA/LHRHa in LHRPC. The primary aim was to evaluate intra-prostatic T/DHT with LHRHa vs LHRHa/AA. We report secondary endpoints of PSA, pCR and near pCR ([≤ 5mm residual tumor]) and safety. Eligibility: > 3 positive biopsies and either Gleason > 7 (4+3), T3, PSA > 20 ng/mL or PSA velocity > 2 ng/mL/year. For the first 12 wks men were randomized to LHRHa or LHRHa/AA/prednisone (P) 5mg qd. After 12 wks, a prostate biopsy was done to measure T/DHT. Men received 12 more wks of LHRHa/AA/P followed by RP. Results: 58 men enrolled: 28 to initial LHRHa and 30 to initial AA/LHRHa. 2 withdrew prior to RP (1/group). Median age was 58 (50-75). pCR/near pCR was 14/56 (25%). Grade 3 AEs included elevated AST/ALT 5/58 (9%) and hypokalemia 3/58 (5%). No grade 4 mineralocorticoid-related AEs were observed. Conclusions: Neoadjuvant ADT with AA was well tolerated in LHRPC. PSA (<0.2) declines were high and achieved earlier on AA/LHRHa compared to LHRHa. The pCR/near pCR rates were higher for 24 wks AA (34%) than 12 wks AA (15%). No new safety signals were seen with AA used with P 5 mg. These results support further evaluation of aggressive ADT as neoadjuvant/adjuvant therapy for LHRPC.