Quimioterapia en cáncer de próstata

PAPEL DE LA QUIMIOTERAPIA EN CPSC
SECUENCIACIÓN EN EL CPRCm
Enrique Gallardo
Lugo, 27 de mayo de 2016

PAPEL DE LA QUIMIOTERAPIA EN CPSC
Enrique Gallardo

Tannock IF. J Clin Oncol 1985;3(7):1013-21

• Tasas de respuesta objetiva del 9% en pacientes con enfermedad
medible en ensayos anteriores al PSA.
• Población no representativa del CPRCm
• Conclusión: “Adenocarcinoma of the prostate still must be considered
a chemotherapeutically resistant tumor”.
Yagoda A, Petrylak D. Cancer 1993;71:1098-109

Clínicamente
Localizado
Hormono-
Refractario
Tratamiento local Deprivación androgénica Tratamiento hormonal
2ª línea
Metastásico
hormonosensible
PARADIGMAS DE TRATAMIENTO 1990s

La FDA aprobó Mitoxantrone-Prednisona como
tratamiento paliativo para pacientes con CPHR
sintomático
Beneficio en el control del dolor a favor de
quimioterapia sin diferencia en supervivencia
Tannock IF, et al. J Clin Oncol 1996;14:1756-64

DOCETAXEL ES ESTÁNDAR EN PRIMERA LÍNEA
DE QUIMIOTERAPIA EN CPRCm
Tannock IF, et al. N Engl J Med 2004;351(15):1502-12
Petrylak D, et al. N Engl J Med 2004;351(15):1513-20

Clínicamente
Localizado
Tratamiento local Deprivación androgénica Quimioterapia
Metastásico
hormonosensible
PARADIGMAS DE TRATAMIENTO 2004
Resistente a la
Castración

EL RECEPTOR ANDROGÉNICO SE HALLA PRESENTE A
LO LARGO DE LA EVOLUCIÓN DEL CPRC
AR IS ALWAYS PRESENT DURING THE
DISEASE EVOLUTION

A
R
A
R
Proliferation
Apoptosis
Differentiation
EMT
A
R
A
RMicrotubule
targeting
chemotherapy
nuclear
Microtubules facilitate AR nuclear translocation and enhance
downstream AR transcriptional activity - Taxanes block this pathway
Zhu ML, et al. Cancer Res 2010;70:7992-8002
TAXANES BLOCK AR NUCLEAR TRANSLOCATION

DOCETAXEL INHIBITS PSA EXPRESSION IN
HUMAN PROSTATE TUMORS
* Significant reduction
in PSA expression
in prostate tumors
of patients treated
with docetaxel
Control Docetaxel treatment
Zhu ML, et al. Cancer Res 2010;70:7992-8002

TAXANES INDUCE EXPRESSION & NUCLEAR
LOCALIZATION OF FOXO1 (POTENT AR REPRESSOR)
Gan L, et al. Cancer Res 2009;69:8386-94

DOCETAXEL SUPPRESSES ANDROGEN RECEPTOR NUCLEAR
TRANSLOCATION IN PCA TUMORS
A
Similar AR levels in controls &
docetaxel-treated prostate cancer pts
A
B
CD
B-C Marked reduction of AR nuclear
translocation with docetaxel
D Higher PSA expression in cells
with AR nuclear localization Zhu ML, et al. Cancer Res 2010;70:7992-8002

NUCLEAR AR TRANSLOCATION WITH
mCRPC THERAPIES
van Soest RJ, et al. Eur J Cancer 2013;49(18):3821-30

TIMING IS EVERYTHING: PRECLINICAL EVIDENCE
SUPPORTING SIMULTANEOUS RATHER THAN SEQUENTIAL
CHEMOHORMONAL THERAPY FOR PROSTATE CANCER
Eigl BJC, et al. Clin Cancer Res 2005;11:4905-11

Clínicamente
Localizado
Tratamiento local Deprivación androgénica Quimioterapia
Metastásico
hormonosensible
Resistente a la
Castración
?

Pro
• Attack de-novo testosterone
independent clones early
allow ADT to keep PrCa in
remission longer.
• Some patients at the time of
progression are too frail for
chemo.
Con
• ADT will take cells out of
cycle and be less responsive
to cytotoxics.
• Some patients respond for a
long time and never need
chemotherapy.
Androgen Deprivation Therapy
Regression Re-emergence
EARLY CHEMO+ADT: A DEBATE IN ONE SLIDE

CHAARTED GETUG-AFU 15
STAMPEDE
EVIDENCIA CLÍNICA

Sweeney CJ, et al. N Engl J Med 2015;373:737-46
CHAARTED

STRATIFICATION
Extent of Mets
-High vs Low
Age
≥70 vs < 70yo
ECOG PS
- 0-1 vs 2
CAB> 30 days
-Yes vs No
SRE Prevention
-Yes vs No
Prior Adjuvant
ADT
≤12 vs > 12
months
R
A
N
D
O
M
I
Z
E
ARM A:
ADT + Docetaxel
75mg/m2 every 21
days for 6 cycles
ARM B:
ADT (androgen
deprivation therapy
alone)
Evaluate every
3 weeks while
receiving
docetaxel and
at week 24
then every 12
weeks
Evaluate every
12 weeks
Follow for time
to progression
and overall
survival
Chemotherapy at
investigator’s
discretion at
progression
• ADT allowed up to 120 days prior to randomization.
• Intermittent ADT dosing was not allowed
• Standard dexamethasone premedication but no daily prednisone
E3805 – CHAARTED Treatment
Primary endpoint:
Overall survival

CHAARTED
•Objetivo primario: Supervivencia global
•790 pacientes incluidos entre 7/2006 y 11/2012
•Enero 2014  Mediana de seguimiento, 29 meses
–136 muertes en DA sola, 101 muertes en DA+QT
•65% de pacientes con volumen tumoral alto
•Mediana de edad: 63 años (36-91)
•ECOG 0 en 70% pacientes
•No tratamiento local en 73% casos

ADT + Doc (N=397) ADT alone (N=393)
N % N %
Volume of Mets
Low 134 33.8% 142 36.1%
High 263 66.2% 251 63.9%
Gleason Score
4-6 21 5.9% 21 6.1%
7 96 26.9% 82 23.9%
8-10 240 67.2% 240 70.0%
Unknown 40 50
PSA (ng/mL) at time of ADT start
Median 56.0 50.5
Range 0.4-8540.1 0.1-8056.0
CHAARTED – PATIENTS CHARACTERISTICS

CHAARTED – OBJETIVO PRIMARIO:
SUPERVIVENCIA GLOBAL
HR = 0.61 (0.47-0.80), p=0.0003
Mediana de supervivencia global:
ADT + D = 57.6 meses
ADT sola = 44.0 meses

High volume Low volume
Volumen altoVolumen bajo
En el grupo de pacientes con volumen alto de enfermedad metastásica, la
diferencia en la mediana de supervivencia global es de 17 meses
(32.2 vs 49.2 meses)
CHAARTED - SUPERVIVENCIA EN FUNCIÓN DEL
VOLUMEN TUMORAL

E3805 (CHAARTED) – DEFINITION OF HIGH VOLUME
• High volume:
• Visceral metastases
and/or
• 4 or more bone metastases with at least 1 beyond
pelvis and vertebral column

TIME TO CASTRATION RESISTANT PROSTATE
CANCER: PSA, SYMPTOMS OR RADIOGRAPH
P<0.0001
HR: 0.52 (95% CI: 0.40-0.67)
Median time to CRPC:
ADT + D: 16.4 months
ADT alone: 9.1 months

TIME TO CLINICAL PROGRESSION:
SYMPTOMATIC OR RADIOGRAPHIC
P<0.0001
HR=0.43 (95% 0.31-0.59)
Median OS:
ADT + D: 29.5 months
ADT alone: 14 months
Clinical evaluation every 3 months until progression, scans as indicated

CHAARTED - NON-HEMATOLOGIC TOXICITY (%)
ADT + Docetaxel (N=397)
Grade 3 4 5
Allergic reaction 2 <1 -
Fatigue 4 - -
Colitis/Diarrhea 1 - -
Stomatitis 1 - -
Neuropathy-motor 1 - -
Neuropathy-sensory 1 - -
Thrombo-embolism <1 1 -
Sudden death - - 1 patient

ADT + Docetaxel (N=397)
Grade 3 4 5
Anemia 1 <1 -
Thrombocytopenia - <1 -
Neutropenia 3 9 -
Febrile neutropenia 4 2 -
Infection with neutropenia 1 1 -
Worst grade heme and non-heme
toxicity per patient
16% 12% 1 patient
CHAARTED - NON-HEMATOLOGIC TOXICITY (%)

ADT + Docetaxel
(N=397)
Arm A
Number of
cycles
N %
1 11 3.1
2 7 2.0
3 6 1.7
4 8 2.3
5 12 3.4
6 308 87.5
Total 352*
74% with no dose
modifications
*Missing data on 45 pts
due to form change (24
pts), never started Rx (6
pts), data missing (15 pts)
CHAARTED – CHEMOTHERAPY DOSE
ADMINISTERED

CHAARTED

STAMPEDE
James ND, et al. Lancet 2016;387:1163–77

Inclusion criteria
Presented By Nicholas James at 2015 ASCO Annual Meeting

Docetaxel & ZA comparisons: patients

Outcome measures

STAMPEDE
CARACTERÍSTICAS DE LOS PACIENTES
Factor de estratificación
WHO PS 2 1%
✔
WHO PS 1 21%
Mediana de edad 65 años (40-84) ✔
Metastásicos (85% met óseas) 61% ✔
N+ M0 15% ✔
N0 M0, alto riesgo 24% ✔
Análogo LHRH 98% ✔
Radioterapia prevista
29%
(72% en N0 M0)
✔
Tratamiento local previo 6%
Otros factores de estratificación: Centro. Tratamiento con AINE/AAS

STAMPEDE

Docetaxel: Failure-free survival
STAMPEDE
FAILURE-FREE SURVIVAL

Treatment effect by metastatic status: FFS

STAMPEDE
TOXICIDAD

Docetaxel treatment

GETUG15
Gravis G, et al. Eur Urol 2015 Nov 21. pii: S0302-2838(15)01103-3. [Epub ahead of print]

STUDY ENPOINTS

GETUG15 – SUPERVIVENCIA GLOBAL
Follow-up: 82.9 mo

GETUG15 - SUPERVIVENCIA EN FUNCIÓN DEL
VOLUMEN TUMORAL

GETUG15 – SUPERVIVENCIA LIBRE DE
PROGRESIÓN BIOQUÍMICA

Gravis G, et al. Lancet Oncol 2013; 14: 149–58
GETUG15
TOXICIDAD

CONCLUSION-2
Presented By Gwenaelle Gravis at 2015 Genitourinary Cancers Symposium

• Did early docetaxel allow more non LHRH therapy in
patients with high volume disease that made a major
improvement in decreasing early prostate cancer deaths?
• E3805: 601 instances ADT + D vs 255 ADT alone = 2.35x
• GETUG15: 264 instances ADT + D vs 137 ADT alone = 1.92x
CHAARTED GETUG-15
ADT+D
N=397
ADT
N=393
ADT+D
N=192
ADT
N=193
Median OS (mos) 57.6 44 58.9 54.2
No. failed 145 174 142 156
Early Docet 397 0 192 0
Total CRPC 204 of 145 255 of 174 72 of 157 137 of 168
Total non-LHRH Rx 204 + 397
= 601
255 72 + 192
=264
137

METAANÁLISIS DE VALE
Vale CL, et al. Lancet Oncol 2016;17(2):243-56

Vale CL, et al. Lancet Oncol 2016;17(2):243-56

Clínicamente
Localizado
Tratamiento local
Deprivación androgénica
+ Docetaxel
Metastásico
hormonosensible
Resistente a la
Castración
Agentes de 2ª línea*
*Docetaxel. Cabazitaxel. Abiraterona. Enzalutamida, Radium223

CHANCE OF BENEFIT WITH
EARLY DOCETAXEL FOR MHSPC:
COMPETING RISKS FOR DEATH
High Volume Low Volume
Young Certain Probable
Life expectancy
~ 5 years
(Frail elderly)
Probable Less likely

SECUENCIACIÓN EN EL CPRCm
Enrique Gallardo

SECUENCIACIÓN EN CPRCm
• Escenarios diversos en CPRC
• Algunos datos prospectivos
• La mayoría de datos disponibles son retrospectivos
• La elección inicial puede afectar negativamente el resto
– Deterioro del paciente
– Desarrollo de resistencias
• Resistencia intrínseca  Terapias hormonales
• Resistencia adquirida  Terapias hormonales,
quimioterapia
• Resistencias cruzadas
• No existen biomarcadores predictores

DISTINTAS SITUACIONES CLÍNICAS EN CPRCm
ASINTOMÁTICO MÍNIMAMENTE
SINTOMÁTICO
SINTOMÁTICO
PROGRESIÓN PSA PROGRESIÓN ÓSEA PROGRESIÓN
VISCERAL
BAJA CARGA
TUMORAL
ALTA CARGA
TUMORAL

ALGUNOS DATOS PROSPECTIVOS

“THE EMBARRASSMENT OF RICHES”
Agent Status Control arm
OS
(months)
Hazard
ratio
p value
SIPULEUCEL-T QT naïve Placebo 25.8 0.78 0.03
ABIRATERONE-P QT naïve Prednisone 34.7 0.81 0.0033
ENZALUTAMIDE QT naïve Placebo 32.4 0.70 <0.0001
DOCETAXEL-P QT naïve Mitoxantrone 18.9 0.76 0.009
ABIRATERONE-P Post-docetaxel Prednisone 15.8 0.74 <0.0001
ENZALUTAMIDE Post-docetaxel Placebo 18.4 0.63 <0.0001
CABAZITAXEL-P Post-docetaxel Mitoxantrone 15.1 0.70 <0.0001
RADIUM 223 Pre&Post-docetaxel Placebo 14.9 0.70 <0.001
DENOSUMAB* Bone mets Zoledronic 20.7* 0.82 0.008
Kantoff PW, et al. N Engl J Med 2010;363:411-22. Ryan CJ, et alLancet Oncol 2015;16(2):152-60. Tannock IF, et al. N Engl J Med 2004; 351(15):1502-12.
De Bono JS, et al. Lancet 2010;376:1147-54. Fizazi K, et al. Lancet Oncol 2012;13(10):983-92. Scher HI, et al. N Engl J Med 2012;367(13):1187-97.
Parker C, et al. N Engl J Med 2013;369:213-23. Fizazi K, et al. Lancet 2011;377(9768):813-22. Beer TM, et al. N Engl J Med 2014;371(5):424-33.

Radium-223
Abiraterone acetate
(Chemo-naïve-302)
Enzalutamide
(Post-chemo)
Abiraterone acetate
(Post-chemo-301)
Cabazitaxel
Sipuleucel-T
Docetaxel
Abiraterone acetate
(Chemo-naïve-302)
Enzalutamide
(Post-chemo)
Sipuleucel-T
Abiraterone acetate
(Post-chemo-301)
Cabazitaxel
Docetaxel
US approvals
EU approvals
Radium-223
20052004 2006 2007 2008 2009 2010 2011 2012 2014 20152013
Enzalutamide
(Chemo-naive)
Modificado de: Ryan CJ, et al. ESMO 2014, abstr 753
TRATAMIENTOS APROBADOS EN CPRCm

Tumourvolume
Time
Death
First-line
hormonal therapy/
castration
Docetaxel
Local
therapy
Bicalutamide
Flutamide
Nilutamide
Enzalutamide
Abiraterone
Cabazitaxel
Radium 223
Asymptomatic Symptoms
Non-metastatic Metastatic
Hormone sensitive Castration resistant
Sipuleucel-T
Abiraterone
Enzalutamide
Radium 223
Second-line
hormonal
therapies
NATURAL HISTORY OF PROSTATE CANCER
Docetaxel
Denosumab

Tumourvolume
Time
Death
First-line
hormonal therapy/
castration
Docetaxel
Local
therapy
Bicalutamide
Flutamide
Nilutamide
Enzalutamide
Abiraterone
Cabazitaxel
Radium 223
Sipuleucel-T
Abiraterone
Enzalutamide
Second-line
hormonal
therapies
Docetaxel
Denosumab
Radium 223

Tumourvolume
Time
Death
First-line
hormonal therapy/
castration
Docetaxel
Local
therapy
Bicalutamide
Flutamide
Nilutamide
Enzalutamide
Abiraterone
Cabazitaxel
Radium 223
Second-line
hormonal
therapies
Docetaxel
Denosumab
Radium 223
Sipuleucel-T
Abiraterone
Enzalutamide

Scher HI, et al. J Clin Oncol 2016;34(12):1402-18

Tumourvolume
Time
Death
First-line
hormonal therapy/
castration
Radium 223
Docetaxel
Local
therapy
Enzalutamide
Abiraterone
Cabazitaxel
Radium 223
Docetaxel
Denosumab
Docetaxel
Sipuleucel-T
Abiraterone
Enzalutamide

• En los estudios prospectivos, los pacientes
incluidos no habían recibido ninguno de los
otros tratamientos (excepto docetaxel).
• No existen datos prospectivos de la eficacia de
estos agentes administrados de forma
secuencial.

DATOS CLÍNICOS RETROSPECTIVOS

• Agente hormonal seguido de agente hormonal
– Abiraterona tras enzalutamida
– Enzalutamida tras abiraterona
• Agente hormonal seguido de quimioterapia

EFFICACY OF ABIRATERONE FOLLOWING
ENZALUTAMIDE IN MCRPC
OSPFS
Response
Rate
PSA
response
No. ptsReffAuthor
11.4 mo3.7 mo11%4%30
Annals of Oncology
2013
K. L. Noonan
7.2 mo2.7 mo8%8%39
Annals of Oncology
2013
Y. Loriot
NR6.6 moNRNR2314
The Lancet Oncology
2014
CN Sternberg
15.8 mo5.6 mo14.8%29.5%1195
The Lancet Oncology
2012
K. Fizazi

EFFICACY OF ENZALUTAMIDE FOLLOWING
ABIRATERONE IN CHEMO-NAÏVE MCRPC
OSPFS
Response
Rate
PSA50No. ptsReffAuthor
8.5 mo3.6 moNR12.5%8ASCO GU 2014Tian Zhang
NRNANR36%28ASCO GU 2014Heather H. Cheng
NR1.4 mo017.3%23ASCO GU 2014GS Sandhu
NR4.9 moNR27%26ASCO GU 2014
Francisco Emilio
Vera-Badillo
10.6 mo4.6 moNR22%47Eur Urology 2015Arun A. Azad
NR4.7 moNR33.3%30The Prostate 2014Daniel L. Suzman
NR2.8 moNR30%33ASCO GU 2014Matthew R. Smith
8.5 mo3.6 mo011%9
Clin Genitourinary
Cancer 2015
Tian Zhang
32.4 mo
Not
reached
59%78%1717
New Engl J of
Medicine 2014
Tomasz M. Beer

EFFICACY OF DOCETAXEL FOLLOWING ABIRATERONE IN MCRPC
OSPFS
Response
Rate
PSA50No. ptsReffAuthor
12.5 mo4.6 mo11%26%35Annal of Oncology 2012J. Mezynski
NR4.4 moNR38.7%31The Prostate 2014Daniel L. Suzman
NR4.4 moNR38%24Eur Urol 2014Michael T. Schweizer
NRNRNR30%40ASCO GU 2014Arun A Azad
NR5.1 mo055%13
Clin Genitourinary Cancer
2015
Tian Zhang
12.4 moNRNR48%23
Clin Genitourinary Cancer
2014
Rahul Aggarwal
NR7.59*NR47%265ASCO GU 2015Johann S. De Bono
19.2 moNR12%52.4%1006
J Clin Oncol 2008
Clin Cancer Res 2008
Dominik R. Berthold
• Abiraterone pretreatment may lead to decreased responsiveness to docetaxel
• Docetaxel appears to be:
 More active than enzalutamide after abiraterone
 Active in abiraterone resistance
* Time to PSA progression

RESISTENCIAS EN CPRCm

LA RESISTENCIA PRIMARIA ES INTRÍNSECA A
CUALQUIER MODALIDAD DE TRATAMIENTO
HORMONAL
Despite regressions of great
magnitude, it is obvious that
there are many failures of
endocrine therapy to control the
disease.
Charles Huggins
Nobel lecture
December 13, 1966

Mukherji D, et al. Cancer Metastasis Rev 2014;33(2-3):555-66
PATRONES DE RESPUESTA EN MCPRC

PRIMARY RESISTANCE TO AR-TARGETED AGENTS
Abiraterone
(COU-AA-301)
Enzalutamide
(AFFIRM)
Primary resistance
1 out of 3 patients
Primary resistance
1 out of 4 patients
De Bono et al. N Engl J Med 2011;364:1995–2005
Scher H et al. N Engl J Med. 2012;367:1187-97
Radiological progression-free survival

Abiraterone/P1 Enzalutamide2
COMBINATION OF AR-TARGETED AGENTS DOES
NOT OVERCOME PRIMARY RESISTANCE
1. Efstathiou E et al. J Clin Oncol 2012;30:637-43
2. Efstathiou E et al. Eur Urol. 2015 Jan;67(1):53-60
3. Efstathiou E et al. J Clin Oncol 2014; 32 (suppl); abstract 5000
Enzalutamide +
abiraterone/P3
PSAChange(%)
-100
-90
-75
-50
-30
0
25
50
75
100
PSA ≥30%: 61% (34/56)
PSA ≥50%: 50% (28/56)
PSA ≥90%: 16% (9/56)
29 %
PSAChange(%)
-100
-90
-75
-50
-30
0
25
50
75
100
PSAChange(%)
-100
-90
-75
-50
-30
0
25
50
75
100
27%
29% 12%
PSA ≥30%: 55% (30/55)
PSA ≥50%: 50% (25/55)
PSA ≥90%: 20% (11/55)
PSA ≥30%: 83.6% (41/49)
PSA ≥50%: 75.5% (37/49)
PSA ≥90%: 44.9% (22/49)
3 different open-label phase II study of 60 patients with bone mCRPC treated with abiraterone
acetate plus prednisone (P), enzalutamide, or combination of both
Transiliac bone marrow biopsies before treatment, at 8 weeks and at end of treatment

WHO ARE THE NON RESPONDERS TO ABIRATERONE?
Who are the NON responders?
(defined as patients
treated for ≤4 months)
Bone marrow biopsy:
- Intense AR nuclear expression
- CYP17 expression
P<0.001
Primary resistance
in 1 out of 4 patients
YES
82% responders
(12/13)
NO
18% responders
(2/12)
Open-label phase II study of 62 mCRPC patients treated with abiraterone + prednisone.
Transilial bone marrow biopsies before treatment, at 8 weeks and at end of study.
Primary resistance
in 1 out of 4 patients
Efstathiou E, et al. J Clin Oncol 2012;30:637-43

WHO ARE THE NONRESPONDERS TO ENZA?
Efstathiou E, et al. Eur Urol 2015;67:53-60
Primary resistance
Moderate benefit (4-6 mths)
Prolonged benefit (>6 mths)
25%
67%
100%
50%
0%
9%
33%
ARv7 presence ERG presenceHigh AR nuclear
+ CYP17 expression
Percentageofpatients
60 patients with bone mCRPC treated with enzalutamide. Transilial bone marrow biopsies
before treatment and at 8 wk of treatment

MECANISMOS DE RESISTENCIA EN CPRC
• Dependientes del receptor androgénico
• Resistencia a quimioterapia
– EMT. Mutaciones de tubulina. P-glicoproteína.
TMPRSS-ERG
• Fenotipos agresivos
– Tumores neuroendocrinos. Célula pequeña.
Indiferenciados.
• Heterogeneidad tumoral

Co-reguladores
del RA
Variantes splice
del RA
Cambios
epigenéticos
Amplificación
del RA
Persistencia de
andrógenos
Mutaciones del
RA
Proteína del
Retinoblastoma
CPRCm
Dependientes del
ligando
Independientes
del ligando
MECANISMOS DE RESISTENCIA RELACIONADOS
CON RECEPTOR ANDROGÉNICO

AR SPLICE VARIANTS
IN CRPC
Schematic of AR and
variant mRNA
Ware KE, et al. Endocr Relat Cancer 2014;21(4):T87-T103

Antonarakis ES, et al. N Engl J Med 2014;371:1028-38

SPLICE VARIANT AR-V7 CONFERS
PRIMARY RESISTANCE TO ABI-ENZ
Enzalutamide Abiraterone
Antonarakis ES, et al. N Engl J Med 2014;371:1028-38

PREVALENCE OF AR-V7 ACCORDING TO THERAPY
0
10
20
30
40
50
60
70
80
Pre Enza & Abi Post Enza Post Abi Post Enza & Abi
%prevalence
Antonarakis ES, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 5001)

MUTACIONES DEL RECEPTOR DE ANDRÓGENOS
http:androgendb.mcgill.ca//map.gif

ABIRATERONE: AR POINT MUTATIONS
• 3 pacientes presentaban mutación L702H:
- Mutación activada por corticoides
- Se trataba de pacientes en curso de Abi o Enza pero que
tomaban corticoides
• 1 paciente presentaba la mutación W742C:
-Mutación activada por Bicalutamida
• 1 paciente presentaba la mutación T878A:
-Mutación activada por la progestágenos
Carreira S, et al. Sci Transl Med 2014;6 254ra125

AR L702H MUTATION (GLUCOCORTICOID-ACTIVATED)

ABIRATERONE AND AR T878A MUTATION

AR-F876L CONFERS AN ANTAGONIST-TO-
AGONIST SWITCH FOR ENZALUTAMIDE
Korpal M, et al. Cancer Discov 2013;3:1030-1043

TMPRSS-ERG FUSIONS
Gen de fusión
específico del
cáncer de próstata.
ERG se une a la
tubulina y
disminuye la
interacción taxano-
tubulina.
TMPRSS-ERG
induce la transición
EM.

Reig O, et al. Eur Urol 2016 Feb 29. [Epub ahead of print]
Brief Correspondence
TMPRSS2-ERGin Blood and Docetaxel Resistance in Metastatic
Castration-resistant Prostate Cancer
O`scar Reiga,b,y
, Mercedes Marıń-Aguileraa,c,y
, Gemma Carrerad
, Natalia Jimeńeza,c
,
Laia Pareá,c
, Susana Garcıá-Recioa,c
, Lydia Gabab
, Maria Verońica Pereirab
,
Pedro Fernańdeze,f
, Aleix Prat a,b,f
, Begonã Melladoa,b,
*
a
Translational Genomics and Targeted Therapeutics in Solid TumoursGroup, Institut d’InvestigacionsBiome`diquesAugust Pi i Sunyer (IDIBAPS), Barcelona,
Spain; b
Medical Oncology Department, Hospital Clıńic, Barcelona, Spain; c
Fundacio´ Clıńic per a la Recerca Biome`dica, Barcelona, Spain; d
Medical Oncology
Department, Hospital Plato´, Barcelona, Spain; e
Department of Pathology, Hospital Clıńic, Barcelona, Spain; f
University of Barcelona, Barcelona, Spain
Article info
Article history:
Accepted February 11, 2016
Associate Editor:
James Catto
Keywords:
Biomarker
Docetaxel
Prostate cancer
Resistance
TMPRSS2-ERG
Abstract
TMPRSS2-ERGrearrangement is a genetic alteration exclusive to prostate cancer, asso-
ciated with taxane resistance in preclinical models. Its detection in blood samples of
metastatic resistant prostate cancer (mCRPC) patients may indicate the presence of
circulating tumour cells with thisgenetic alteration and may predict taxaneresistance.
To test this hypothesis, we evaluated TMPRSS2-ERG expression using quantitative
reverse transcription polymerase chain reaction in peripheral blood mononuclear cells
and tumour tissuefrom mCPRCpatientstreated with taxanes. Weexamined peripheral
blood mononuclear cells from 24 healthy controls, 50 patients treated with docetaxel,
and 22 with cabazitaxel. TMPRSS2-ERG was detected in 0%, 16%, and 22.7%of them,
respectively. In docetaxel-treated patients TMPRSS2-ERG detection correlated with
lower prostatic-specific antigen (PSA) response rate (12.5%vs 68.3%, p=0.005), PSA-
progression-free survival (PFS; 3.1 mo vs 7.5 mo, p< 0.001), clinical/radiological-PFS
(3.1movs8.2mo,p< 0.001),and it wasindependently associated with PSA-PFS(hazard
ratio3.7; p=0.009) andclinical/radiological-PFS(hazard ratio6.3; p< 0.001).Moreover,
TMPRSS2-ERGalso predicted low PSA-PFSto cabazitaxel. At progression, a switch from
negative to positive TMPRSS2-ERG was observed in 41%of patients with undetected
TMPRSS2-ERGat the baseline sample. Tissue TMPRSS2-ERGexpression correlated with
lower PSA-PFS (p=0.02) to docetaxel. Our findings support the potential role of
TMPRSS2-ERGdetection as a biomarker to tailor treatment strategies.
Patient summary: Taxanes are the most active chemotherapy agents in metastatic
resistant prostate cancer. However, not all patients respond to this therapy. In the
present study we show that the detection of TMPRSS2-ERG in blood from metastatic
resistant prostatecancer patientspredictsresistancetodocetaxel andit may beuseful to
select treatment and to avoid possible toxicities in refractory patients.

CABAZITAXEL IMPIDE LA TRANSLOCACIÓN
NUCLEAR DEL AR
Mellado B, et al. Clin Genitourin Cancer 2015 Dec 28. [Epub ahead of print]

DOCETAXEL
CABAZITAXEL
BAJA AFINIDAD POR PGP

Van Soest RJ, et al. Eur Urol 2015;67(6):981-5

AR-V7 IS NOT ASSOCIATED TO PRIMARY
RESISTANCE TO TAXANES

Antonarakis ES, et al. JAMA Oncol 2015;1(5):582-591

Onstenk W, et al. Eur Urol 2015;68:939-45

EFFICACY OF CABAZITAXEL FOLLOWING ABIRATERONE
IN MCRPC
OSPFS
Response
Rate
PSA 50No. ptsReffAuthor
8.2 moNR15.3%31.5%24
Clinical Genitourinary Cancer
2014
Avishay Sella
10.9 mo4.4 moNR35%79European Urology 2014Nader Al Nakouzi
20.3 mo5.5 mo15%41%*37European Urology 2014Carmel J. Pezaro
12 mo5 mo14%28%#110European Urology 2014Orazio Caffo
11.8 moNRNRNR36
Clinical Genitourinary Cancer
2015
Guru Sonpavde
15.1 mo2.8 mo14.4%39.2%755Lancet 2010J.S de Bono
CABAZITAXEL RETAIN EFFICACY AFTER DOCETAXEL AND ABIRATERONE
* Four patients received also enzalutamide
# Sixteen patients received also enzalutamide

CABAZITAXEL PSA RESPONSE DOES NOT SEEM
INFLUENCED BY PRIOR AR TARGETED AGENTS
Pezaro CJ, et al. Eur Urol 2014;66:459-465
59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior
abiraterone and 9 of whom had received prior enzalutamide.
There was no correlation between a favourable biochemical response to
abiraterone and response to subsequent cabazitaxel

Neuroendocrine PCa found in soft tissue metastasis
seems to increase over recent years.
This fact may be correlated with the use of potent
AR inhibitors such as Enzalutamide or Aberaterone.
These data suggest that NE cells may escape
hormonal castration and that active inhibition of
the AR may promote aggressive disease.
EVOLUTION TO NEUROENDOCRINE PHENOTYPE
IN TUMOR PROGRESSION IN PCa

Terry S, Beltran H. Front Oncol 2014;4:60

Priemer DS, et al. Endocr Pathol 2016;27:123–135

Beltran H, et al. Nat Med 2016;22(3):298-305

INTER-PATIENT PATHOLOGICAL HETEROGENEITY
• CRPC is a heterogeneous group of diseases
– Different histologic patterns were identified from 30 rapid autopsy CRPC samples
– Immunohistochemistry revealed differential AR expression
• 31% Tumor samples expressed >50% AR
• 41.5% Tumor samples expressed <10% AR
0 20 40 60 80 100
Bone
Liver
Lymph node
Lung
Soft tissue
Dura
Adrenal
Brain
Pancreas
Kidney
Testis
Percentage of Cases
Small cell
(n=2)
Undifferentiated
(n=1)
Signet ring
(n=1)
Gleason
grade 5
(n=4)
Gleason
grade 4
(n=3)
Gleason
grade 4 and 5
(n=18)
NE Differentiation
(n=3)
Gleason grade 3
(n=3)
Metastatic Sites Histologic Appearance
Shah RB, et al. Cancer Res 2004; 64:9209–16. © 2004 American Association for Cancer Research.
Shah RB, et al. Cancer Res 2004;64(24):9209-9216

Reid AHM et al. Br J Cancer 2010;102:678-684
EL CÁNCER DE PRÓSTATA ES UNA ENFERMEDAD
HETEROGÉNEA

High CTC phenotypic heterogeneity predicted for shorter overall and progression free survival times on AR Tx but not Taxane Tx*
Presented By Howard Scher at Genitourinary Cancers Symposium 2016

High CTC phenotypic heterogeneity predicts a better outcome with a Taxane over AR Tx in a *Multivariate Model”

The prevalence of a CTC subtype (Type K) predicts a poor outcome to both AR and Taxane Tx

MOLECULAR MARKER EXPRESSION IN mCRPC
Efstathiou E, et al. Eur Urol 2015;67(1):53-60

• No disponemos de biomarcadores
suficientemente validados que permitan la
estratificación de los pacientes para mejorar la
probabilidad de respuesta.
• No obstante, es posible identificar grupos de
pacientes en CPRCm a partir de factores
pronósticos.
¿CÓMO SELECCIONAR FÁRMACOS Y
PACIENTES?

FACTORES PRONÓSTICOS EN CPRCm
Gleason
Niveles de PSA
Tiempo de doblaje del PSA (PSA-DT)
ECOG PS
Presencia de dolor
Tratamiento con opiáceos
Metástasis viscerales
Niveles basales de andrógenos
Respuesta y duración del tratamiento hormonal previo
Respuesta previa a docetaxel
Tipo de progresión (factores de progresión)
Niveles basales de albúmina, fosfatasas alcalinas, LDH, hemoglobina

INDICATORS OF INCREASED RISK FOR PRIMARY
RESISTANCE TO AR PATHWAY-TARGETED AGENTS
Yes No Abstain Grade of consensus
High Gleason score 53% 42% 5% No consensus
Short duration of response to
first-line ADT
86% 14% 0% Strong
Visceral metastases 10% 90% 0% Strong
Rapid PSA doubling time 15% 80% 5% Strong
Testosterone level 0% 100% 0% Strong
Anemia 0% 95% 5% Strong
High LDH 10% 90% 0% Strong
Alkaline phosphatase 0% 100% 0% Strong
Degree of bone pain 5% 95% 0% Strong
Decreased performance status 5% 95% 0% Strong
Fitzpatrick JM, et al. Eur J Cancer 2014;50:1617-27

Dependencia androgénica
•Remisión prolongada a la
castración
•Metástasis ganglionares y/o
osteoblásticas
•Correlación entre PSA y
volumen tumoral
•Ausencia o baja intensidad de
síntomas
•Niveles de andrógenos
Neoplasia indiferenciada
•Intervalo corto hasta la
resistencia a la castración
•Metástasis osteolíticas
•Metástasis viscerales
•PSA bajo respecto al volumen
tumoral
•Rasgos neuroendocrinos o de
célula pequeña
SELECCIÓN DE PACIENTES

Assess prognostic factors
Algorithm for first-line treatment in patients with
mCRPC
Patient with mCRPC
Pacient UNFIT
for chemotherapy
OTHER TREATMENT
1.Asymptomatic patient:
Hormone therapy
2.Symptomatic patient:
Radium 223 vs hormone
therapy
Pacient FIT
for chemotherapy
•PSA-DT <55 days
•Gleason 8 to 10
•High LDH
•High alkaline phosphatase
•Hormonal response < 9 mo
•Anemia
Asymptomatic or minimally
symptomatic
Presence of
hepatic
metastases
Symptomatic and/or
deterioration of
general condition
due to tumor
CHEMOTHERAPY
CONSIDER
CHEMOTHERAPY (**)
HORMONE THERAPY
•PSA-DT >55 days (*)
•Gleason  7
•Normal LDH
•Normal alkaline phosphatase
•Hormonal response > 9 mo
El perfil del paciente es importante a la hora de elegir el primer tratamiento del
PLAN TERAPÉUTICO
Maroto P…, Gallardo E..., Gómez-Veiga F..., et al. Crit Rev Oncol Hematol. 2016;100:127-36

Pacientes con CPRCm tras progresión a docetaxel
Considerar la situación general del paciente y
la extensión de la enfermedad
Tratamiento paliativo
Tratamiento activo
Contraindicación para cabazitaxel
Progresión precoz a docetaxel
CABAZITAXEL
Otro tratamiento
Progresión a docetaxel por :
dolor + PSA + criterios radiológicos
CABAZITAXEL
Baja probabilidad de
respuesta a nuevas maniobras
hormonales (*)
Resto de pacientes
Considerar CABAZITAXEL en pacientes con:
•Dolor de difícil control
•Presencia de metástasis viscerales
•Discordancia entre el PSA y la carga tumoral.
•PSADT corto.
•Rápido crecimiento de las lesiones metastáticas.
•Gleason ≥ 8 en el tumor primario.
•Descenso del PSA < al 30% con docetaxel.
SÍNO
SÍ
NO
SÍ
NO
CABAZITAXEL
SÍ
*Aunque no existen criterios claros para identificar a estos pacientes, se pueden considerar
aquí situaciones como progresión precoz a 1ª línea de hormonoterapia (< 7 meses), o falta
de respuesta o progresión a 2ª línea de hormonoterapia.
Niveles de recomendación por expertos basado en
la evidencia clínica disponible
y la experiencia clínica
>
Gallardo E, et al. Crit Rev Oncol Hematol 2013;88(2):357-67

• La elección inicial puede afectar negativamente la
evolución de la enfermedad.
• Indicador precoz de resistencia al tratamiento.
• Beneficio mayor cuantas más líneas de
tratamiento.
• El orden de los fármacos puede impactar en la
supervivencia.

Caffo O, et al. Future Oncol 2014;10(6):985-93

PFS
(according to 1-month PSA reduction)
OS
(according to 1-month PSA reduction)
Caffo O, et al. Future Oncol 2014;10(6):985-93

Fuerea AC, et al. Ann Oncol 2014;25 (suppl 4): iv276. Abstract 796P

Association between PSA declines at 4 weeks and overall survival
(OS) in Patients treated with Abiraterone Acetate (AA) for metastatic
Castration Resistant Prostate Cancer (mCRPC) after Docetaxel
Rescigno P, et al. Eur Urol 2016 [Epub ahead of print]

LA SUPERVIVENCIA DEL CP HA IDO MEJORANDO A LO LARGO
DEL TIEMPO GRACIAS A LA ADICIÓN DE NUEVOS FÁRMACOS

Cuando se adminsitra CBZ
en 2ª linea, el 44% pueden
recibir AA en 3ª línea
Cuando se adminsitra AA
en 2ª linea, sólo el 13,7%
pueden
recibir CBZ en 3ª línea
SECUENCIACIÓN CON CABAZITAXEL Y ABIRATERONA TRAS
DOCETAXEL EN PACIENTES CON CPRCM
Schnadig ID, et al. J Clin Oncol 31, 2013 (suppl 6; abstr 79)

OUTCOMES WITH DIFFERENT SEQUENCES OF CABAZITAXEL AND
ABIRATERONE ACETATE FOLLOWING DOCETAXEL IN METASTATIC
CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)
OS: Tiempo hasta la
muerte desde la 2ª
línea de tto
TXT CBZ AA RIP
TXT AA CBZ RIP
Sonpavde G, et al. Eur J Cancer 2013; 49(Suppl 2):S698 (Abstr 2905)

A RETROSPECTIVE STUDY ON CABAZITAXEL AND ABIRATERONE ACETATE
SEQUENTIAL TREATMENT (CAST) IN DOCETAXEL TREATED METASTATIC
CASTRATE-RESISTANT PROSTATE CANCER PATIENTS
Diseño
• Estudio retrospectivo de 112 pacientes de
12 hospitales holandeses
• Objetivo: determinar la secuencia optima
en pacientes que pueden recibir tto con
CBZ y AA tras docetaxel
• End points: SG,SLP, respuesta PSA.
TXT CBZ AA
TXT AA CBZ
61 pts
68 pts
Wissing MD, et al. Eur J Cancer 2013; 49(Suppl 2):S698 (Abstr 2904)

RADIUM-223 – ESTUDIO ALSYMPCA
Parker C, et al. N Engl J Med 2013;369:213-23

Radium Ra 223
dichloride
Placebo
Median OS (months) 14.9 11.3
Hazard ratio 0.70
95% CI 0.58-0.83
P < 0.0001
Radium Ra 223 dichloride
Placebo
Month
Ra 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
Median OS Δ: 3.6 months
Parker C, et al. N Engl J Med 2013;369:213-23
ALSYMPCA – RADIUM 223 VS PLACEBO
BENEFICIO DE SUPERVIVENCIA

CONCLUSIONES
• Perfiles clínicos (y moleculares) para identificar y
seleccionar pacientes y fármacos desde la
primera línea de tratamiento.
• Identificar precozmente resistencias para poder
hacer un cambio de estrategia (stop and change).
• Parece que mayor número de tratamientos
conllevan mayor beneficio.
• Incluir la quimioterapia en la secuencia y no
perder la oportunidad.

CONCLUSIONES
• Existe resistencia cruzada entre los diferentes
tratamientos que influyen en el receptor androgénico
• La adquisición de resistencias es un proceso dinámico
• Los mejores resultados se observan con la
administración de cabazitaxel
EL BENEFICIO DE SUPERVIVENCIA SE RELACIONA CON EL
NÚMERO DE TRATAMIENTOS LIFE-EXTENDING RECIBIDOS 
NO PERDER LA OPORTUNIDAD DE LA QUIMIOTERAPIA

M, Nakazawa et al.Annals of Oncology 00: 1–7, 2015
Objetivo: analizar los cambios del estado de AR-V/ en 14 pacientes
que recibieron 37 tratamientos y que fueron AR-V7 + en algún
momento de su enfermedad

ROLE OF DNA REPAIR MECHANISMS
Mateo J, et al. Ann Oncol 2014;25(suppl 4):v1-v41. ESMO 2014, Abstract LBA20

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