2. Prostate
carcinoma
Around 10-20% of
patients diagnosed
with prostate cancer
will develop
metastases
and, eventually, will
reach the phase of
castration-resistant
prostate carcinoma
(CRPC)
Jemal et al. Cancer J Clin 2011;61(2):69-90
3. Las células de cáncer de próstata:
sensibles a andrógenos
Premio Nobel 1966
5 años más tarde se desarrollaron los análogos de LHRH
Charles Huggins
1901-1997
Huggins C, Hodges CV. Cancer Research 1941;1(4):293–297.
4. Las células de cáncer de próstata:
sensibles a andrógenos
Premio Nobel 1966
5 años más tarde se desarrollaron los análogos de LHRH
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
5. 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
6. ¿Qué significa Resistencia a la Castración?
Progresión de la enfermedad a pesar de niveles de
castración (testosterona < 50ng/dl)
500
ng/dl
Testosterona
Resistencia a la castración
50
ng/dl
PSA
TDA
7. Molecular states framework for androgen receptor
activation in prostate cancer
Nelson P S JCO 2012;30:644-646
8. HISTORIA DEL TRATAMIENTO DEL CPRC
AÑOS 80 QUIMIOTERAPIA INACTIVA
AÑOS 90 MITOXANTRONA: QT PALIATIVA SIN
AUMENTO SUPERVIVENCIA1,2
2004 DOCETAXEL3,4: SUPERVIVENCIA 1ªL
2010 CABAZITAXEL5: SUPERVIVENCIA 2ªL
1. Tannock IF. JCO 1996 2. Kantoff PW. JCO 1999
3. Petrylak D. NEJM 2004 4. Tannock IF. NEJM 2004
5. De Bono JS. Lancet 2010
9. AÑOS 90: MITOXANTRONA
ESTUDIO CANADIENSE1 MITROXANTRONA PREDNISONA
(Tannock) PREDNISONA (n=80) (n=81)
% % P
Respuesta al dolor 29 9 0,01
Consumo de analgésicos 9 9
Beneficio paliativo 38 21 0,025
MITROXANTRONA
CALGB 91822 HIDROCORTISONA
HIDROCORTISONA
P
Descenso de PSA ≥ 50% 38% 22% 0,008
TTP 3,7 m 2,3 m 0,025
Respuesta en dolor ++++ ++ NS
Supervivencia 12,6 m 12,3 m NS
1. Tannock IF. J Clin Oncol 1996
2. Kantoff PW,J Clin Oncol 1999
11. 2004: SWOG 99161
Docetaxel 60 mg/m2 IV cada 21 d
Estramustina 280 mg po TID D1-5
R Mitoxantrone 12 mg/m2 IV cada 21 d
N=770
Prednisona 5 mg BID continuamente
Petrylak DP, et al. NEJM 2004;351:1513-1520
13. 2004: TAX 3271
Docetaxel 75 mg/m2 q3w
Patients with Prednisone 5 mg bid
R
metastatic A
HRPC N
D Docetaxel 30 mg/m2 weekly
• Disease progression,
(biochemical: increasing O (5 of 6 weeks)
PSA) M Prednisone 5 mg bid
• Karnofsky performance I
status ≥60% S
E Mitoxantrone 12 mg/m2 q3w
• Pain assessed at
baseline Prednisone 5 mg bid
(n=1006)
Tannock IF. N Engl J Med 2004;351:1502-12
14. TAX327: SUPERVIVENCIA GLOBAL¹
OS (m) HR P
Combined 18.2 0.83 0.03
D 3 weeks 18.9 0.76 0.009
D weekly 17.3 0.91 0.3
Mitoxantrone 16.4 - -
19.2 m
16.3 m
15.
16. 2010
Metastásico, sin Metastásico, sin
Metastásico,
quimioterapia previa, quimioterapia previa,
Post-docetaxel
asintomático sintomático
Segunda línea hormonal, Docetaxel Mitoxantrone
docetaxel Otros
Ácido zoledrónico
17. Summary of Agents with Survival
Benefit in CRPC
Radium-223
Docetaxel Abiraterone Cabazitaxel Sipuleucel-T MDV3100
chloride
2004 2011 2010 (US), Not
Approval 2010 (US) Not approved
(US and EU) (US and EU) 2011 (EU) approved
Following Following Asymptomatic
Treatment of
mCRPC docetaxel docetaxel or minimally
CRPC (with – –
indication failure (with failure (with symptomatic
prednisone)
prednisone) prednisone) mCRPC
Trial
Mitoxantrone Placebo Mitoxantrone Placebo Placebo Placebo
comparator
+2.5 months; +4.6 months; +2.4 months; +4.1 months; +4.8 months; +2.8 months;
OS benefit
HR = 0.76 HR = 0.65 HR = 0.70 HR = 0.78 HR = 0.63 HR = 0.695
Efficacy
PSA, pain PSA, PFS,
endpoints Time to SRE,
response, pain, time PSA, PFS – PSA, PFS
with positive PSA, ALP
QOL to SRE
results
22. Intratumoral androgens and AR function persist in
CRPC
Montgomery R B et al. Cancer Res 2008;68:4447-4454
23. Los bajos niveles de andrógenos tras la castración
tienen relevancia clínica
Impacto en supervivencia.
A menor niveles de testosterona sérica mayor supervivencia
24. Fase III
COU-AA-301
Fase III, multicéntrico, aleatorizado, doble ciego, para estudiar los beneficios
clínicos de abiraterona junto a prednisona, en pacientes con cáncer de
próstata metastásico que han progresado tras uno o dos regímenes de
quimioterapia
Objetivo principal
Pacientes Abiraterona 1000 mg día
•OS
ALEATORIZACIÓN
Prednisona 10 mg
•N=1195 N=797
2:1
Objetivos sec
•1 o 2 regímenes de QT
• TTPP previa, uno de ellos Placebo
• rPFS docetaxel Prednisona 10 mg
• Respuesta PSA n=398
de Bono, J.S. et al. NEJM: 2011;364(21):1995-2005.
25. COU-AA-301:
Variables secundarias (análisis intermedio)
Variable Tiempo de SLP Tasa de Tasa de
progresión del radiológica respuesta del respuestas (%)
PSA (meses) (meses) PSA (%)
Abiraterona 10.2 5.8 38 15
(n=797)
Placebo 6.6 3.6 10 2.8
(n=398)
HR 0.48 0.67
P value <0.001 <0.001 <0.001 <0.001
26. COU-AA-301:
Supervivencia global (análisis final)
Mediana de seguimiento: 20.2 meses
Mediana de duración de tratamiento: 8 meses (Abiraterona) vs. 4 meses (control)
100
HR (95% CI): 0.74 (0.64-0.86)
P<0.0001
80
AA median oS
60 15.8 months
Survival (%)
40 Placebo median OS
11.2 months
20
0
0 6 12 18 24 30
Time to death (months)
Fizazi et al. ECCO 2011. Abstract 7000.
28. 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
(Actual n = 546)
naïve mCRPC M • OS
patients I
Z Secondary:
(Planned N = 1088)
E Placebo daily • Time to opiate use
• Asymptomatic or D Prednisone 5 mg BID (cancer-related pain)
mildly symptomatic (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. ASCO 2012; Abstract LBA4518 (Oral Presentation)
29. Statistically Significant Improvement in rPFS Primary End Point
AA + P (median, mos): NR
PL + P (median, mos): 8.3
HR (95% CI): 0.43 (0.35-0.52)
100
P value: < 0.0001
Progression-Free (%)
60
40
6 12 18
Time to progression (months)
Data cutoff 20/12/2010
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
30. 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
Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008
Data cutoff 20/12/2011
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
31. Mejoría en objetivos secundarios
AA + P Placebo + P
Median Median HR (95% CI) P Value
(months) (months)
Time to opiate use 0.69
NR 23.7 0.0001
(cancer related pain) (0.57, 0.83)
Time to chemotherapy 0.58
25.2 16.8 <0.0001
initiation (0.49, 0.69)
Time to ECOG PS 0.82
12.3 10.9 0.0053
deterioration (0.71, 0.94)
Time to PSA 0.49
11.1 5.6 <0.0001
progression (0.42, 0.57)
32. MDV3100
T
T Enzalutamida
Inhibe la unión del
andrógeno al AR AR
No efectos
agonistas en
modelos Inhibe la translocación nuclear del AR
preclínicos
AR
Muerte
Inhibe la asociación del AR con DNA celular
Tran et al; Science 2009
324:787-90
33. Overexpression of AR in CRPC Tumors
Increased AR protein
AR mRNA overexpression
Increased AR DNA copy number
Increased Androgen synthesis
Scher et al. Endocrine-Related. Cancer 11:2004;459 > Intratumoral androgen levels
34. AFFIRM: Phase III trial of MDV3100 vs placebo
in post-chemotherapy treated CPRC
R
A
MDV3100
Población N
160 mg/d
D Objetivo primario
N=800
1199 pacientes con O
CPRC en progresión M Supervivencia
tras tratº con I Placebo global
docetaxel Z N=399
E
2.
1
Scher et al; NEJM 2012;367:1187-97
39. CABAZITAXEL
• Nuevo taxano semisintético5:
• Tan potente como docetaxel en la
estabilización de los microtúbulos.
• Datos Preclínicos1,2:
• Tan potente como docetaxel en
líneas celulares sensibles y en
modelos tumorales sensibles.
• Activo en células tumorales y Estabilización
modelos tumorales resistentes a microtúbulos
taxanos.
• Cabazitaxel es capaz de cruzar la
barrera hematoencefálica. Docetaxel
no6,7. Cabazitaxel Inhibe la mitosis
Muerte
1.Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84.
celular
2. Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552.
3. Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.
4 .Kavallaris M. Nat Rev Cancer. 2010;10:1-11.
5. M.C. Bissery, H. Bouchard, J.F. Riou, P. Vrignaud, C. Combeau, J.D. Bourzat, A. Commercon, F. Lavelle. AACR, #1364, 41, 2000
6. Dykes DJ, Sarsat JP, Bissery MC. AACR, #1916, 41, 2000.
7.Cisternino S, Bourasset F, Archimbaud Y, Sémiond D, Sanderink G, Scherrmann JM. British Journal of Pharmacology, 138, 1367-75, 2003.
39
40. TROPIC
146 centros en 26 países
Pacientes con CPRCm que hayan progresado durante o
después de tratamiento con un régimen basado en
docetaxel
(N=755)
Factores estratificación:
ECOG PS (0, 1 vs 2) / enf. medible vs enf. no medible
Cabazitaxel 25 mg/m² c/3 sem Mitoxantrona 12 mg/m²
IV + prednisona* por 10 ciclos c/3sem IV + prednisona* por
(n=378) 10 ciclos (n=377)
*Dosis oral de prednisona/prednisolona: 10 mg/día
OP: SG
De Bono JS et al. Lancet. 2010;376:1147-1154
De Bono JS et al. J Clin Oncol. 2010:28 (suppl 15s): abstract 4508.
41. Mitoxantrone Cabazitaxel
Mediana OS 12.7 m 15.1 m
HR 0.72
p-value <.0001
OS
SLP
42.
43. Cabazitaxel Mitoxantrona
(n=371) (n=371)
Todos los Grado 3 Todos los Grado 3
grados n (%) grados n (%)
n (%) n (%)
Neutropenia 347 (94) 303 (82) 325 (88) 215 (58)
Neutropenia febril – 28 (8) – 5 (1)
Leucopenia 355 (96) 253 (68) 34 (92) 157 (42)
Anemia 361 (97) 39 (11) 30 (281) 18 (5)
Trombocitopenia 176 (47) 15 (4) 160 (43) 6 (2)
Diarrea 46.6 6.2 10.5 0.3
Fatiga 36.7 4.9 27.5 3
Náuseas 34.2 1.9 22.9 0.3
46. Sipuleucel: estudio IMPACT
R
Patients A
N Sipuleucel cada 2 semanas
• Progressive mCRPC D
O 3 infusiones Efficacy end points
patients M
(N = 512) I Primary:
• Asymptomatic Z • OS
E
D
Placebo
2:1
15-19 % de los pacientes habían recibido docetaxel
47. Sipuleucel PLacebo
Mediana OS 25.8 m 21.7 m
HR 0.78 (CI 95%: 0.61-0.98)
p-value 0.02
51. Estudios negativos
Antiangiogénicos: bevacizumab; lenalidomida
Antagonistas de los receptores de endotelina:
atrasentán, zibotentán
Aflibercept: en combinación con docetaxel (VENICE)
Estudios pendientes
Dasatinib: en combinación con docetaxel
Cabozantinib: RR del 84% en un fase II
55. Denosumab: Pacientes con mets óseas
R
A Denosumab 120 mg q4w
N Primary endpoint
Metastatic CRPC D •Tiempo hasta 1º
O
(n = 1904) M
evento
I relacionado con
Z mets óseas
A
T
I Secundarios:
Key Inclusion Criteria
O •SLP, SG
• No prior bisphosphonate
N
use Ácido zoledrónico
1:1
Clinicaltrials.gov identifier # NCT00286091
Fizazi et al. Lancet 2011;377:813--22
59. Denosumab: Phase III 147 Trial in Non-
Metastatic CRPC Study Design
R
A Denosumab 120 mg q4w
N Primary endpoint
Non-metastatic D •Bone metastasis-
O
CRPC M
free survival
(n = 1432) I
Z
Secondary
A endpoints
T •Time to
I
Key Inclusion Criteria symptomatic
O
• High risk for development bone metastasis
N
of bone metastases (PSA Placebo •Overall survival
≥ 8 ng/ml or PSA doubling 1:1
time ≤ 10 months)
• No prior bisphosphonate
use
Clinicaltrials.gov identifier # NCT00286091
Smith et al. Lancet 2012;379:39-46
60. Intervalo Tiempo
libre de mts hasta
óseas aparición
de mts
óseas
Tiempo a mts OS
óseas
sintomáticas
61. Radium-223 Targets Bone Metastases
Range of alpha-particle
Radium-223
Bone surface
Alpha-particles induce double-strand DNA breaks in adjacent
tumour cells1
– Short penetration of alpha emitters (2-10 cell diameters) =
highly localised tumour cell killing and minimal damage to
surrounding normal tissue
1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams &
Wilkins; 2007:103.
62. ALSYMPCA (ALpharadin in SYMptomatic
Prostate CAncer) Phase III Study Design
TREATMENT
PATIENTS 6 injections at
R 4-week intervals
STRATIFICATION
• Confirmed A
symptomatic N Radium-223 (50 kBq/kg)
CRPC D + Best standard of care
• Total ALP:
• ≥ 2 bone O
< 220 U/L vs ≥ 220 U/L
metastases • Bisphosphonate use: M
• No known Yes vs No I
visceral • Prior docetaxel: S Placebo (saline)
metastases Yes vs No E + Best standard of care
• Post-docetaxel D
or unfit for
docetaxel 2:1
N = 922
Planned follow-up is 3 years
Parker, ASCO 2012 abstract 8
63. • Primary Endpoint
– Overall survival
• Secondary Endpoints
– Time to first SRE
– Time to total ALP progression
– Total ALP response
– Total ALP normalisation
– Time to PSA progression
– Safety
– Quality of life
67. 2010
Metastásico, sin Metastásico, sin
Metastásico,
quimioterapia previa, quimioterapia previa,
Post-docetaxel
asintomático sintomático
Segunda línea hormonal, Docetaxel Mitoxantrone
docetaxel Otros
Ácido zoledrónico
68. 2012
Metastásico, sin Metastásico, sin
Metastásico,
quimioterapia previa, quimioterapia previa,
Post-docetaxel
asintomático sintomático
Segunda línea hormonal, Docetaxel Cabazitaxel
Docetaxel Abiraterona
Sipuleucel Enzalutamida
Abiraterona Mitoxantrone
Ácido zoledrónico
Denosumab
RAD 223
69.
70. Cabazitaxel
Enzalutamide, custirsen,
(approved June 2010)
ipilimumab, orteronel, radium-
Abiraterone 2nd line 223, cabozantinib
(approves April 2011) therapy
1nd line therapy
Docetaxel Aflibercept, dasatinib,
mCRPC lenalidomide, custirsen
Sipuleucel Ipilimimumab;
(approved April 2010) Non-mets CRPC enzalutamide,
orteronel, PROSTVAC
Oestrogen
Ketoconazole
Combined androgen blockade
Bicalutamide
LHRH ag/ Androgen deprivation therapy
GnRH antag
Surgery and radiation
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.
146 sites in 26 countries. Here are the European countriesBelgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Russia, Slovakia, Spain, Sweden, Turkey, UKBetween Jan 2, 2007, and Oct 23, 2008, 755 mCRPC patients who progressed during and after treatment with a docetaxel-based regimenpatients were randomly assigned to 2 treatment groups:cabazitaxel or mitoxantrone plus prednisone or prednisoloneEach patient was to be treated until disease progression, death, unacceptable toxicity, or for a maximum of 10 cycles (30 weeks)Patients were stratified according to ECOG PS 0,1 vs 2 and non measurable diseasePremedication for cabazitaxel patients was rather simple with just 1 IV infusion ≥30 minutes before cabazitaxel dose. It consisted of antihistamine, steroid, and H2 antagonist. The Antiemetic prophylaxis was administered when necessary.