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PROGRAMA CIENTÍFICO
ID d
el e
vento
:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Dra. Aránzazu González del Alba Servicio de Oncología Médica
Hospital Universitario Son Espases Palma de Mallorca
Barcelona, 18 de marzo de 2014
Manejo del cáncer de próstata metastásico en el 2014
PROGRAMA CIENTÍFICO
ID del evento:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Introducción
• 15% de pacientes diagnosticados de CaP fallecerán a causa de enfermedad avanzada
• La terapia de deprivación androgénica (TDA) es eficaz en la mayoría de casos, aunque la progresión es la norma al cabo de 1-2 años de la respuesta inicial.
• Segundas maniobras hormonales pueden ser una opción en algunos pacientes, aunque las respuestas son transitorias con agentes disponibles hasta la fecha y sin impacto en supervivencia.
PROGRAMA CIENTÍFICO
ID del evento:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Introducción II
• Denominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que progresa a pesar de niveles séricos de castración (<50 ng/ml)
1984-1989
Evolución histórica del tratamiento del cáncer de próstata avanzado
However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy
1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1. 12. Parker C, et al. ASCO GU 2012. Abstract 8.
1996 2002 2004 .... 2010 2011
Mitoxantrone[3] Docetaxel*[5,6]
Sipuleucel-T*[8]
LHRH agonists*[1,2]
Abiraterone*[10]
Reversible AR blockers[1,2]
Cabazitaxel*[7] Denosumab[9] Zoledronic Acid[4]
Enzalutamida[11]
Radium-223[12]
* Approved agent for PCa
Revisar Terminología
• “Cáncer de próstata hormono-refractario”
• “Cáncer de próstata andrógeno-independiente”
• “Cáncer de próstata resistente a castración”
Evidencia clara de que segundas maniobras hormonales (antiandrógenos, ketoconazol, estrógenos y nuevos agentes) consiguen respuesta clínica incluso en pacientes refractarios a TDA
The FDA approved mitoxantrone-prednisone as palliative treatment for patients with
symptomatic HRPC
• Improvement in pain control
• No difference in survival
Median survival
(months) HR P
Docetaxel q3w
18.9 0.76 0.009
Docetaxel q1w
17.3 0.93 0.3
Mitoxantrone q3w
16.4 - -
2004: Docetaxel improves OS vs mitoxantrone
Tannock IF et al. N Engl J Med 2004;351:1502-12. Berthold D et al. J Clin Oncol 2008;26:242-5. * Data 2006 7
Docetaxel q3w (N=335)
Docetaxel q1w (N=334)
Mitoxantrone q3w (N=337)
3-year survival rate* 18.6% 16.8% 13.5%
mCPRC tratamiento de primera línea
Docetaxel 75 mg/m2 cada 3 semanas
estándar en primera línea de CRPC metastático
1Heidenreich A, et al. (2010 update) www.uroweb.org 2Mohler J, et al. (2009 update) www.nccn.org 3Basch EM, et al. J Clin Oncol 2007;25:1–6 4Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76–8
ASINTOMATICO MINIMAMENTE SINTOMATICO
SINTOMATICO
PROGRESION PSA PROGRESION GGO PROGRESION VISCERAL
BAJA CARGA TUMORAL
ALTA CARGA TUMORAL
Distintas situaciones clínicas en CPRC
PROGRAMA CIENTÍFICO
ID del evento:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Scher et al. J Clin Oncol 2008;26:1148-59
Criterios de progresión en CP
•Metástasis hepáticas
•Nº localizaciones m1 (<2 vs >2)
•Dolor al inicio del tto.
•PS (<80 vs >80)
•Tipo de progresión
•Enfermedad medible
•Empeoramiento GGO
•Grado Gleason (<8 vs >8)
•PSA-DT (<55 vs >55 días)
•PSA basal ↑
•F alcalina ↑
•Hb ↓
La vía de señal androgénica
Molecular states framework for androgen
receptor (AR) activation in prostate cancer.
Nelson P S JCO 2012 feb ;30:644-646
Evolución natural del cáncer de próstata
Volumen tumoral
Tiempo
ADT / Castración
Docetaxel
Terapia local*
Metastásico
Síntomas
Resistente a la castración
No metastásico
Asintomático
Sensible a hormonas
Terapias hormonales de 2ª línea
Bicalutamida Flutamida Nilutamida
Muerte
Cabazitaxel
Abiraterona
Rad 223
Enzalutamida
*por ejemplo, cirugía, radioterapia
Kohli & Tindall. Mayo Clin Proc 2010;85:77–86.
RA, receptor de
andrógenos
Señalización AR continuada
Sipuleucel T Abiraterona Enzalutamida
3/22/2014 SOGUG, Madrid
Oblimersen
AT-101
Custirsen
Sunitinib
Sorafenib
Bevacizumab
Aflibercept
Talidomida
Lenalidomida Atrasentan
Zibotentan
Dasatinib
Negative studies
Docetaxel-HD-Calcitriol1
Docetaxel-Bevacizumab2
Docetaxel-GVAX3
Docetaxel-Oblimersen4
Docetaxel-Lenalidomide
Docetaxel-Atrasentan5
Docetaxel-Aflibercept6
Docetaxel-Zibotentan7
Since 2004, many attempts to further improve docetaxel efficacy have failed
1. Scher HI et al. J Clin Oncol 2010;28:15s (Abstract 4509). 2. Kelly WK et al. J Clin Oncol 2010;28:18s (Abstract
LBA4511). 3. Small E et al. ASCO GU symposium 2009 (Abstract 7). 4. Sternberg C et al. Annals Oncol 2009;20:1264-69.
5. University of Michigan press release (April 2011). 6. Press release Sanofi-Regeneron 2012. 7. Nelson JB et al. J Clin Oncol 2011;29 (suppl 7):Abst 117.
Hasta la fecha ningún estudio fase III de combinación en primera línea ha conseguido mejorar la supervivencia global del CPRC comparado con el tratamiento estándar de docetaxel-Prednisona
Agents with overall survival benefit in mCRPC
Cortesia Dr J.Carles
Sipuleucel T
Sipuleucel-T
Coste = $93,000
No aprobado en Europa
Pacientes asintomáticos o mínimamente sintomáticos
Cabazitaxel: selected to overcome taxane resistance
• Cabazitaxel: Poor affinity for the PgP efflux pump
Greater penetration of the blood brain barrier compared with docetaxel and paclitaxel
Active in vitro and in vivo on tumors resistant to Docetaxel
Mita AC et al, Clin Cancer Res. 2009, 15, 723-730
Taxane
H
R
• Docetaxel and paclitaxel
have a strong affinity for
the PgP pump
• If the PgP pump is
overexpressed, it drives
drug out of tumor cell
Second-line Cabazitaxel in mCRPC patients: TROPIC – Study design
de Bono JS et al. Lancet 2010;376:1147-54 * or prednisolone, when prednisone was
unavailable 24
146 Sites in 26 Countries (North America, Europe, India, Latin America, Asia, South Africa)
mCRPC patients who progressed during or after treatment
with a docetaxel-based regimen (N=755)
Stratification factors ECOG PS (0, 1) vs ECOG PS (2)
Measurable vs non-measurable disease
Cabazitaxel 25 mg/m2 q3w + 10 mg oral prednisone* daily
10 cycles
Mitoxantrone 12 mg/m2 q3w + 10 mg oral prednisone* daily
10 cycles
Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety
Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression
N=378 N=377
TROPIC trial: Pre-protocol treatments
MP (n=377) CBZP (n=378)
Total prior docetaxel dose (mg/m²)
Median 529.2 576.6
Months from last docetaxel dose to progression
Median 0.70 0.80
Number of patients progressed (%)
During last docetaxel treatment 27.6 30.4
<3 months since last docetaxel dose 48.0 41.8
≥3 months since last docetaxel dose 24.0 27.0
Chemotherapy (%)
1 regimen 71.1 68.8
2 regimens 21.0 24.9
3 regimens 8.0 6.3
De Bono J et al. Lancet, 2010, 376:1147-54
A heavily pretreated population who progressed
rapidly after first line docetaxel
Beneficio SG en todos los subgrupos
De Bono et al. The lancet 2010; 376: 1147-54
*El protocolo se enmendó tras los primeros 59 pacientes incluídos, para asegurar que los pacientes incluídos hubiesen recibido >225 mg/m² de docetaxel
Factor Subgroup Hazard ratio
(95% CI)
Población ITT Todos los pacientes 0.70 (0.59–0.83)
ECOG status 0, 1 0.68 (0.57–0.82)
2 0.81 (0.48–1.38)
Enfermedad medible
No 0.72 (0.55–0.93)
Si 0.68 (0.54–0.85)
No. tratamientos previos
1 0.67 (0.55–0.83)
≥2 0.75 (0.55–1.02)
Edad <65 0.81 (0.61–1.08)
≥65 0.62 (0.50–0.78)
Dolor basal No 0.57 (0.43–0.77)
Si 0.76 (0.59–0.98)
Aumento PSA No 0.88 (0.61–1.26)
Si 0.65 (0.53–0.80)
Dosis total docetaxel
<225 mg/m² 0.96 (0.49–1.86)
≥225 to 450 mg/m² 0.60 (0.43–0.84)
≥450 to 675 mg/m² 0.83 (0.60–1.16)
≥675 to 900 mg/m² 0.73 (0.48–1.10)
≥900 mg/m² 0.51 (0.33–0.79)
Progresión Durante tto con docetaxel 0.65 (0.47–0.90)
<3 meses desde la última dosis de DTX 0.70 (0.55–0.91)
≥3 meses desde la última dosis de DTX
0.75 (0.51–1.11)
0.25 1 2 0.5 1.5 A Favor CBZP A Favor MP
28
TROPIC Trial: Progression-free survival
Pro
po
rtio
n o
f P
FS
(%
)
377
378
55
92
12
18
6
1
4
1
100
80
60
40
20
0
Time (months) 0 6 12 18 21 3 9 15
117
168
30
55
9
6
MP CBZP
Median PFS (months) 1.4 2.8
Hazard ratio 0.75
95% CI 0.65–0.87
P-value 0.0002
Number
at Risk
MP
CBZP
Censored MP CBZP
Combined median follow-up: 13.7 months
PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death.
De Bono J et al. Lancet, 2010, 376:1147-54
25% reduction in risk of progression
29
TROPIC Trial: Response rate and time to progression
(174) (168) (N patients)
Pain response rate
0.001 0.75
(0.63–0.90) 6.4 3.1 Median TTP (months)
0.63 0.91
(0.69-1.19)
9.2 7.7 Response rate (%)
MP (n=377)
CBZP (n=378)
Hazard ratio (95% CI)
P-value
Tumor assessment
Response rate* (%) 4.4 14.4 – 0.0005
Median TTP (months) 5.4 8.8 0.61
(0.49–0.76) <0.0001
PSA assessment
Response rate* (%) 17.8 39.2 – 0.0002
TTP: time to progression ; *50% decrease or more in PSA
De Bono J et al. Lancet, 2010, 376:1147-54
30
Most Frequent Treatment-Emergent Adverse Events*
*Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.
Low rate of grade 3-4 peripheral neuropathy (1% in each group)
De Bono J et al. Lancet, 2010, 376:1147-54
MP (n=371) CBZP (n=371)
All grades (%) Grade 3/4
(%) All grades (%) Grade 3/4
(%)
Any adverse event 88 39 96 57
Febrile neutropenia 1 1 8 8
Neutropenia* 88 58 94 82
Diarrhea 11 <1 47 6
Fatigue 27 3 37 5
Back pain 12 3 16 4
Nausea 23 <1 34 2
Vomiting 10 0 23 2
Hematuria 4 1 17 2
Abdominal pain 4 0 12 2
Síntesis de andrógenos
Abiraterona
Nacusi et al Nature Publishing Group 2011;8:378–384
COU-AA-301 Study Design
Abiraterone acetate
1000 mg daily
Placebo daily
Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study
(147 sites in 13 countries; USA, Europe, Australia, Canada)
OS (25% improvement; HR 0.8) Primary endpoint:
• 1195 patients with progressive,
mCRPC
• Failed 1 or 2 chemotherapy
regimens, one of which
contained docetaxel
• Randomised 2:1
T
R
E
A
T
U
N
T
I
L
P
R
O
G
R
E
S
S
I
O
N
Prednisone 5mg twice daily
Prednisone 5mg twice daily
de Bono et al. N Engl J Med 2011; 346(21): 1995-2005
Stratification by:
• ECOG performance
status (0-1 vs. 2)
• Worst pain over
previous 24 hours (BPI
short form; 0-3 [absent]
vs. 4-10 [present])
• Prior chemotherapy (1
vs. 2)
• Type of progression
(PSA only vs.
radiographic progression
with or without PSA
progression)
Updated Analysis (775 Events): OS Benefit of
AA Increased From 3.9 to 4.6 Months
Median duration of follow-up: 20.2 months
Median duration of treatment: 8 months with AA vs. 4 months with placebo
HR (95% CI): 0.74 (0.64-0.86)
p < 0.0001
AA median OS (95% CI):
15.8 months (14.8-17.0)
Placebo median OS (95% CI):
11.2 months (10.4-13.1)
100
80
60
40
20
0
0
Su
rviv
al (%
)
6 12 18 24
797
398
657
306
473
183
273
100
15
6
Time to Death (Months)
30
0
0
AA
Placebo
AA
Placebo
Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)
Survival Benefit Observed With AA Is
Consistent for Majority of Subgroups
0.5 0.75 1 1.5
Region
Baseline ALK-P above median
Baseline LDH above median
Baseline PSA above median
Visceral disease at entry
Age, years
Type of progression
No. prior chemo regimens
Baseline BPI
Baseline ECOG
All subjects
Other
N.A.
NO
YES
NO
YES
NO
YES
NO
YES
≥ 75
≥ 65
< 65
Radiographic
PSA only
2
1
≥ 4
< 4
2
0-1
ALL
15.1
16.4
19.5
12.4
20.8
10.4
18.2
13.6
17.1
12.9
15.6
16.2
15
14.8
18.3
14.2
17.1
13.3
18.4
7.3
17
15.8
11.5
11.1
18
8.1
18
8
15.3
8.8
12.3
8.3
9.3
11.1
11.2
10.5
13.6
10.4
11.7
9.3
13.9
7
12.3
11.2
0.80
0.68
0.88
0.60
0.75
0.77
0.79
0.65
0.69
0.79
0.64
0.76
0.69
0.78
0.63
0.80
0.71
0.78
0.69
0.77
0.74
0.74
(0.64-1.00)
(0.56-0.83)
(0.69-1.12)
(0.50-0.74)
(0.59-0.96)
(0.63-0.93)
(0.63-0.99)
(0.53-0.79)
(0.58-0.82)
(0.59-1.05)
(0.48-0.85)
(0.63-0.90)
(0.53-0.91)
(0.65-0.93)
(0.47-0.84)
(0.61-1.03)
(0.59-0.85)
(0.63-0.96)
(0.56-0.85)
(0.50-1.17)
(0.63-0.86)
(0.64-0.86)
Variable Subgroup
Median (months)
AA Placebo HR 95% CI
Favors
AA
Favors
Placebo
Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)
AEs of Special Interest
de Bono et al. N Engl J Med 2011; 346(21): 1995-2005
AA (n = 791)
Placebo (n = 394)
All Grades Grade 3 Grade 4 All
Grades Grade 3 Grade 4
Fluid retention and
edema 31% 2% <1% 22% 1% 0
Hypokalemia 17% 3% <1% 8% 1% 0
Cardiac disorders 13% 3% 1% 11% 2% <1%
LFT abnormalities 10% 3% <1% 8% 3% <1%
Hypertension 10% 1% 0 8% <1% 0
PROGRAMA CIENTÍFICO
ID del evento:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Radionúclidos y tratamiento paliativo
• Hasta la fecha actual 3 radionúclidos habían sido aprobados para el tratamiento del dolor óseo:
• Radionúclidos de primera generación: Fósforo 32
• Radionúclidos de segunda generación: Stroncio 89
• Radionúclidos de tercera generación: Samario 153
• Sr 89 demostró aumento del tiempo a recurrencia del dolor
• Sm 153: Alivio del dolor y disminución del consumo de analgésicos con menor toxicidad hematológica
Climent MA, 2012 Crit Rev and Hematology
Radium Ra 223 Dichloride (Alpharadin)
• Metal alcalino
térreo
• Afinidad ósea por
su “parecido” al
Calcio
• Emisor alfa
Ra 88
56
Ba
Sr 38
20
Ca
1. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.
Características Físicas
Rotura simple Reparables Baja letalidad
Rotura doble Apoptosis Alt. Mitótica Fase G0
Cortesía Dr Vallejo
Bone Targeted Localized Mechanism
of Action – α-Pharmaceuticals
Henriksen G, et al. Cancer Res. 2002;62:3120–25 42
Bone marrow
Tumor Range of α-particle (small volume)
Range of β-particle (large volume)
Bone Bone surface
Radionuclide
ALSYMPCA Trial Design (Alpharadin in symptomatic PC)
M36 M16 M24 M12 M0
R 2:1
Radium Ra 223 dichloridea 50 kBq/kg
Saline* (placebo)
FOLLOW-UP PHASE TREATMENT PHASE 6 injections at
4-week intervals
M28 M6 M20 M32 M8 M10
Stratification factors •Total ALP < 220 U/L vs ≥ 220 U/L •Bisphosphonate use (yes vs no) •Prior docetaxel (yes vs no)
Monthe
Assessments
ALP, alkalinphosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; R, randomization
aPlus best standard of care.
Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512. Clinical Trials.gov identifier # NCT00699751.
Key inclusion criteria •Confirmed symptomatic CRPC •≥ 2 bone metastases •No known visceral metastases •Post-docetaxel or unfit for docetaxel
Primary endpoints: overall survival Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total ALP normalization, time to PSA progression, safety, PS and HRQoL
Month
Radium 223 614 578 504 369 274 178 105 60 41 18 7 1 0 0
Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0
ALSYMPCA: Radium Ra 223 Dichloride Significantly Prolonged Overall Survival Compared With Placebo
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Surv
ival
(%
)
Radium 223 Placebo
Median OS (months) 14.9 11.3
Hazard ratio 0.695
95% CI 0.581-0.832
P < 0.0001
ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; CI, confidence interval; OS, overall survival.
Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512.
Radium 223 Placebo
Median OS Δ: 3.6 months
Prior docetaxel use NO prior docetaxel use
ALSYMPCA Updated Analysis
OS by Stratification Variables:
Prior Docetaxel Use
Radium-223 352 327 238 155 88 45 27 5 1 0 0
Placebo 174 152 104 61 35 15 5 4 1 1 0
Radium-223, n = 352
Median: 14.4 months
Placebo, n = 174
Median: 11.3 months
HR = 0.710
95% CI, 0.565, 0.891
P = 0.00307
Radium-223, n = 262
Median: 16.1 months
Placebo, n = 133
Median: 11.5 months
HR = 0.745
95% CI, 0.562, 0.987
P = 0.03932
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36 40 Month
%
Radium-223 262 236 168 119 70 31 14 7 1 0
Placebo 133 113 74 42 24 14 9 3 1 0
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36
%
Month
Current bisphosphonate use NO current bisphosphonate use
Radium-223, n = 250
Median: 15.3 months
Placebo, n = 124
Median: 11.5 months
HR = 0.699
95% CI, 0.525, 0.931
P = 0.01378
Radium-223, n = 364
Median: 14.5 months
Placebo, n = 183
Median: 11.0 months
HR = 0.736
95% CI, 0.587, 0.923
P = 0.00775
ALSYMPCA Updated Analysis
OS by Stratification Variables:
Bisphosphonate Use
Radium-223 364 331 235 159 97 50 27 6 0 0 0
Placebo 183 155 102 58 33 16 10 6 2 1 0
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36 40
Radium-223 250 232 171 115 61 26 14 6 2 0
Placebo 124 110 76 45 26 13 4 1 0 0
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36
% %
Month Month
ALSYMPCA Updated Analysis
OS by Stratification Variables:
Baseline ALP
Total ALP < 220 U/L Total ALP ≥ 220 U/L
Radium-223, n = 348
Median: 17.0 months
Placebo, n = 169
Median: 15.8 months
HR = 0.825
95% CI, 0.635, 1.072
P = 0.14945
Radium-223, n = 266
Median: 11.4 months
Placebo, n = 138
Median: 8.1 months
HR = 0.619
95% CI, 0.486, 0.788
P = 0.00009
Radium-223 266 238 160 95 51 24 10 3 0 0 0
Placebo 138 114 63 28 15 9 3 2 1 1 0
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36 40
Radium-223 348 325 246 179 107 52 31 9 2 0
Placebo 169 151 115 75 44 20 11 5 1 0
100
90
80
70
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36
% %
Month Month
ALSYMPCA: Adverse Events of Interest
All Grades Grades 3 or 4
n (%) Radium 223
(n = 600) Placebo (n = 301)
Radium 223 (n = 600)
Placebo (n = 301)
Hematologic
Anemia 187 (31.2) 92 (31) 77 (13) 40 (13)
Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)
Thrombocytopenia 69 (11.5) 17 (5.6) 38 (6.3) 6 (2)
Nonhematologic
Bone pain 300 (50) 187 (62) 125 (21) 77 (26)
Diarrhea 151 (25) 45 (15) 9 (1.5) 5 (1.7)
Nausea 213 (35.5) 104 (35) 10 (2) 5 (2)
Vomiting 111 (18.5) 41 (14) 10 (2) 7 (2)
Constipation 108 (18) 64 (21) 6 (1) 4 (1)
ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer.
Parker C, et al. J Clin Oncol. 2012;30(suppl.). Abstract LBA4512.
Data on file. Wayne, NJ: Bayer HealthCare Pharmaceuticals. ClinicaTrials.gov identifier # NCT00699751.
Enzalutamide (MDV3100): Mechanism of action
• AR signalling inhibition at three levels:
– Blocks binding of testosterone to the AR
– Inhibits nuclear translocation of AR
– Inhibits binding of the AR to DNA
Enzalutamide
T
Cell nucleus
Inhibits binding of androgens to AR
Inhibits nuclear translocation of AR
Inhibits association of AR with DNA
AR
Cell cytoplasm
T, testosterone
1
2
3
Tran C et al. Science 2009;324:787–790; Baskin-Bey ES et al. ASCO GU 2011 abstr 177;
Watson PA et al. Proc Natl Acad Sci USA 2010;107:16759–65
T
AR
Phase III: AFFIRM trial of enzalutamide in mCRPC patients post-chemotherapy
Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).
n = 1199 mCRPC
1–2 prior chemotherapy
regimens*
R 2:1
Enzalutamide 160 mg qd (n = 800)
Placebo per qd (n = 399)
*≥ 1 docetaxel (glucocorticoids were allowed but not required)
• AFFIRM is a phase III randomised, double-blind, placebo-controlled trial
mCRPC, metastatic castrate-resistant prostate cancer; qd, once per day; R, randomisation
Recruitment in 156 centres from 15 countries across 5 continents between September 2009 and November 2010
• Stratification variables:
• ECOG performance status (0–1 vs 2)
• Mean Brief Pain Inventory Q#3 score (<4, ≥ 4)
Primary endpoint: Overall survival
AFFIRM: Overall survival
Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).
3 6 9 18 21 24 15
100
80
60
40
20
0 0
Surv
ival
(%
)
Duration of overall survival (months) 12
775 701 627 72 7 0 211 800 400 Enzalutamide, n =
376 317 263 33 3 0 81 399 167 Placebo, n =
Placebo: 13.6 months (95% CI: 11.3–15.8)
Enzalutamide: 18.4 months (95% CI: 17.3–NYR)
HR = 0.63 (95%CI: 0.53–0.75); p<0.001 37% reduction in risk of death
4.8 month difference in
median overall survival
CI, confidence interval; HR, hazard ratio; NYR, not yet reached
No at risk:
AFFIRM: Secondary endpoints
Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).
Enzalutamide (n = 800)
Placebo (n = 399)
Hazard ratio p-value
Confirmed PSA response rates
≥50% reduction from baseline (%) 54 2 – p<0.001
≥90% reduction from baseline (%) 25 1 – p<0.001
PSA progression
Median time to PSA progression (months) 8.3 3.0 0.25 p<0.001
Soft tissue response*
Soft tissue response rate (%) 29 4 – p<0.001
Progression-free survival
Radiographic progression-free survival (months) 8.3 2.9 0.40 p<0.001
Skeletal-related events
Time to first skeletal-related event (months) 16.7 13.3 0.69 p<0.001
Health-related quality of life
Functional Assessment of Cancer Therapy - Prostate (FACT-P) quality of life response rate (%)
43 18 – p<0.001
PSA, prostate-specific antigen
Percentages relate to patients with baseline and postbaseline assessments *n=446 and n=208 for enzalutamide and placebo arms respectively
AFFIRM: Overall survival
Subgroup Hazard ratio for death (95% CI)
Median overall survival (months)
Enzalutamide/placebo
All subjects 0.63 (0.53–0.75) 18.4/13.6
Age < 65 ≥ 65
0.63 (0.46–0.87) 0.63 (0.51–0.78)
–/12.4
18.4/13.9
Baseline ECOG performance status 0–1 2
0.62 (0.52–0.75) 0.65 (0.39–1.07)
–/14.2
10.5/7.2
Baseline mean pain score on BPI-SF (question #3) < 4 ≥ 4
0.59 (0.47–0.74) 0.71 (0.54–0.94)
–/16.2
12.4/9.1
Geographical region North America Other
0.63 (0.47–0.83) 0.64 (0.51–0.80)
17.4/12.3
–/14.4
Number of prior chemotherapy regimens 1 ≥ 2
0.59 (0.48–0.73) 0.74 (0.54–1.03)
–/14.2
15.9/12.3
Type of progression at study entry PSA progression only Radiographic progression PSA progression
0.62 (0.46–0.83) 0.64 (0.52–0.80)
–/19.5
17.3/13.0
Baseline value > median PSA LDH
0.62 (0.50–0.78) 0.61 (0.50–0.76)
15.3/10.3 12.4/8.5
Scher et al. NEJM Aug 15. [Epub ahead of print] (2012).
0 0.5 1.0 1.5 2.0
Favours Enzalutamide Favours placebo
The size of the circles is proportional to the size of the subgroup
BPI-SF, Brief Pain Inventory - short form; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PSA, prostate-specific antigen
AFFIRM: resumen de AA
AA, acontecimiento adverso; LFT, pruebas de función hepática
*las anomalías en las LFT eran hiperbilirrubinemia y aumento de los niveles de aspartato aminotransferasa o alanina aminotransferasa
El periodo de notificación de acontecimientos adversos para el grupo de enzalutamida fue más del doble que el correspondiente al grupo placebo
Acontecimientos adversos, n (%)
Acontecimientos totales (todos los grados)
Acontecimientos de grado ≥ 3
Enzalutamida (n = 800)
Placebo (n = 399)
Enzalutamida (n = 800)
Placebo (n = 399)
≥ 1 acontecimientos adversos 785 (98) 390 (98) 362 (45) 212 (53)
Cualquier acontecimiento adverso grave
268 (34) 154 (39) 227 (28) 134 (34)
Interrupciones debidas a acontecimientos adversos
61 (8) 39 (10) 37 (5) 28 (7)
Acontecimientos causantes de muerte
23 (3) 14 (4) 23 (3) 14 (4)
Acontecimientos adversos de interés, n (%)
Cansancio 269 (34) 116 (29) 50 (6) 29 (7)
Trastornos cardíacos (cualquiera) 49 (6) 30 (8) 7 (1) 8 (2)
Infarto de miocardio 2 (<1) 2 (<1) 2 (<1) 2 (<1)
Alteración transaminasas* 8 (1) 6 (2) 3 (<1) 3 (<1)
Convulsiones 7 (<1) 0 5 (<1) 0
N Engl J Med 2012; 367: 1187–1197
Zoledronic Acid in Castration-Resistant Prostate Cancer
• Patients in 8-mg arm reduced to 4 mg owing to renal toxicity
• Primary outcome: proportion of patients having ≥ 1 SRE
• Secondary outcomes: time to first on-study SRE, proportion of patients with SREs, and time to disease progression
Patients with prostate cancer
Castration resistant Bone metastases
(N = 643)
Zoledronic acid 4 mg q3 wks
(n = 214)
Placebo q3 wks
(n = 208)
R
A
N
D
O
M
I
Z
E
D
Eligibility Criteria
Zoledronic acid 4 mg q3 wks
(initially 8 mg)
(n = 221)
Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.
Study Design: International, Randomized, Double-Blind, Active-Controlled Study
Key Inclusion
Hormone-refractory (castration-resistant) prostate cancer and bone metastases
Key Exclusion
Current or previous IV bisphosphonate treatment
*Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.
Denosumab 120 mg SC and Placebo IV* q4 wks (n = 950)
Zoledronic acid 4 mg IV* and Placebo SC q4 wks (n = 951)
Calcium and vitamin D supplemented in both treatment groups
Accrual period from May 2006 - December 2008
Analysis cutoff date: October 2009
Fizazi K, et al. Lancet. 2011;377:813-822.
Zoledronic acid 951 733 544 407 299 207 140 93 64 47
Denosumab 950 758 582 472 361 259 168 115 70 39
Pts at Risk, n Study Mo
0
1.00
Pro
po
rtio
n o
f S
ub
jec
ts W
ith
ou
t S
RE
0 3 6 9 12 15 18 21 24 27
0.25
0.50
0.75
KM Estimate of Median Mos
Denosumab
Zoledronic acid
20.7
17.1
HR: 0.82 (95% CI: 0.71-0.95; P = .0002, noninferiority; P = .008, superiority)
18% Risk
reduction
Time to First On-Study SRE
Fizazi K, et al. Lancet. 2011;377:813-822.
Novel Study Design: Co-primary End Points
Abiraterone 1000 mg daily
+
Prednisone 5 mg BID
(actual n = 546)
Co-primary end points:
• rPFS (central review)
• OS
Placebo daily
+
Prednisone 5 mg BID
(actual n = 542)
Progressive mCRPC
without prior
chemotherapy;
Asymptomatic or
mildly symptomatic
Patient
Population
BID, twice daily; rPFS, radiographic progression free survival; OS, overall survival; HR-QoL, Health-related quality of
life; FACT-P, Functional Assessment of Cancer Therapy-Prostate; BPI-SF, Brief Pain Inventory-Short Form; ECOG
PS, Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen.
5
aStratification by ECOG PS 0 vs 1.
R A N D O M I Z E D
1:1a
Secondary end points:
• Time to opiate use
• Time to initiation of
chemotherapy
• Time to ECOG PS
deterioration
• Time to PSA
progression
Exploratory end points:
• HR-QoL (FACT-P, BPI-SF)
Study COU-AA-302
Abiraterone Doubled Time to rPFS
IA3 data. rPFS assessed by investigator review at prespecified IA.
100
80
60
40
20
0
0
Su
bje
cts
Wit
ho
ut
Pro
gre
ss
ion
or
De
ath
(%
)
6 12 18 30 36 24
546
542
389
244
240
133
157
78
20
7
0
0
Abiraterone
Prednisone
117
45
Months From Randomization
Abiraterone
Prednisone
Abiraterone (median, mos): 16.5
Prednisone (median, mos): 8.3
HR (95% CI): 0.53 (0.45-0.62)
p Value: < 0.0001
15 9 3 21 27 33
485
406
311
176
195
99
131
62
66
20
4
0
11
OS Favors Abiraterone
IA3 data. aPrespecified significance level by O’Brien-Fleming Boundary = 0.0035.
100
80
60
40
20
0
0
Su
bje
cts
Wit
ho
ut
De
ath
(%
)
6 12 18 30 36 24
546
542
524
508
482
465
421
400
68
67
0
0
Abiraterone
Prednisone
333
283
Months From Randomization
Abiraterone
Prednisone
Abiraterone (median, mos): 35.3
Prednisone (median, mos): 30.1
HR (95% CI): 0.79 (0.66-0.95)
p Valuea: 0.0151
15 9 3 21 27 33
538
534
503
492
452
437
393
361
175
153
15
9
13
Improvement in All Clinical End Points
IA3 data. Note: All secondary end points remain significant after adjusting for multiplicity testing.
Abiraterone Prednisone
Median (months)
Median (months)
HR (95% CI) p Value
Secondary end points
Time to opiate use
(cancer-related pain) NR 23.7 0.71 (0.59-0.85) 0.0002
Time to chemotherapy
initiation 26.5 16.8 0.61 (0.51-0.72) < 0.0001
Time to ECOG PS
deterioration 12.3 10.9 0.83 (0.72-0.94) 0.0052
Time to PSA progression 11.1 5.6 0.50 (0.43-0.58) < 0.0001
Exploratory end points
Time to BPI-SF pain
interference progression 10.3 7.4 0.80 (0.68-0.93) 0.0049
Time to degradation in
FACT-P (total score) 12.7 8.3 0.79 (0.67-0.93) 0.0046
16
PREVAIL: A Phase 3 trial of enzalutamide after progression on ADT in men with mCRPC
Patient population:
• 1717 men with progressive mCRPC
• Asymptomatic/ mildly symptomatic
• Chemotherapy-naïve
• Steroids allowed but not required
Co-primary endpoints:
• OS
• rPFS
Enzalutamide 160 mg/day (capsules)
n=872
Placebo n=845
R A N D O M I Z E D
1:1
ADT=androgen-deprivation therapy; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; rPFS=radiographic progression-free survival.
Beer TM, et al. ASCO-GU 2014; Oral presentation; ClinicalTrials.gov identifier: NCT01212991.
Enzalutamide prolonged radiographic progression-free survival
3 6 15 18 21 12
100
80
60
40
20
0 0
rPFS
(%
)
Months
9
514 256 5 1 0 34 832 128 Enzalutamide, n
305 79 0 0 0 5 801 20 Placebo, n
Placebo
Enzalutamide
HR=0.186 (95% CI: 0.15–0.23); p<0.0001
CI=confidence interval; HR=hazard ratio; rPFS=radiographic progression-free survival.
Beer TM, et al. ASCO-GU 2014; Oral presentation.
Estimated median rPFS, months (95% CI): Enzalutamide: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4) NYR = Not Yet Reached
Enzalutamide reduced the risk of death by 29%
3 6 30 33 36 12
100
80
60
40
20
0 0
Surv
ival
(%
)
Months
9
863 850 33 2 0 797 872 824 Enzalutamide, n
835 781 27 2 0 701 845 744 Placebo, n
Placebo
Enzalutamide
HR=0.706 (95% CI: 0.60–0.84); p<0.0001
15
745
644
18
566
484
21
395
328
24
244
213
27
128
102
CI=confidence interval; HR=hazard ratio.
Beer TM, et al. ASCO-GU 2014; Oral presentation.
Estimated median OS, months (95% CI): Enzalutamide: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR) NYR = Not Yet Reached
Enzalutamide delayed median time to chemotherapy by 17 months
3 6 30 33 36 12
100
80
60
40
20
0 0
Cyt
oto
xic
che
mo
the
rap
y fr
ee
(%
)
Months
9
854 799 21 2 0 665 872 751 Enzalutamide, n
734 518 9 0 0 324 845 415 Placebo, n
HR=0.35 (95% CI: 0.30–0.40); p<0.0001
15
575
257
18
388
165
21
252
103
24
158
64
27
78
25
Placebo: 10.8 months
Enzalutamide: 28.0 months
CI=confidence interval; HR=hazard ratio.
Beer TM, et al. ASCO-GU 2014; Oral presentation.
Metastásico, sin
quimioterapia previa,
asintomático
Metastásico, sin
quimioterapia previa,
sintomático
Metastásico,
Post-docetaxel
Ácido zoledrónico
Segunda línea hormonal Docetaxel
Docetaxel Mitoxantrone Otros (CTX, VNB)
El CPRCm hasta 2010
Metastásico, sin
quimioterapia previa,
asintomático
Metastásico, sin
quimioterapia previa,
sintomático
Metastásico,
Post-docetaxel
Ácido zoledrónico
Denosumab
2ª línea hormonal Docetaxel
Sipuleucel (USA) Abiraterona
Enzalutamida
Docetaxel Rad 223 (EAP)
Cabazitaxel Abiraterona
Mitoxantrone Rad 223 (EAP) Enzalutamida
CPRCm en 2014
PROGRAMA CIENTÍFICO
ID del evento:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Consideraciones finales
• En CPRC la vía de señal de AR continúa activa y promoviendo el crecimiento celular
• La quimioterapia consigue paliación y mejoría en supervivencia en CPRC (primera línea: docetaxel, segunda línea: cabazitaxel) (nivel evidencia 1)
• Abiraterona y Enzalutamida mejoran la supervivencia en pacientes que han progresado a docetaxel (nivel 1) y antes de la QT
PROGRAMA CIENTÍFICO
ID del evento:
Hotel AC Palma Plaça del Pont 3
07014 Palma de Mallorca
15 de mayo de 2013 • 19:00h – 22:00h
Abordaje del paciente con Cáncer de
Próstata Resistente a Castración (CPRCm)
Consideraciones finales
• La inmunoterapia con Sipuleucel-T mejora la supervivencia en pacientes asintomáticos o mínimamente sintomáticos (nivel 1)
• En pacientes con metástasis oseas sintomáticas Rad 223 mejora la supervivencia en pacientes no tratados con docetaxel y tras progresión al mismo
• Queda por definir la mejor secuencia terapéutica en el CPRCm
• La inclusión de pacientes en ensayo clínico sigue siendo primordial: facilita el acceso a fármacos y responde a preguntas relevantes en nuestra práctica clínica.
MUCHAS GRACIAS
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