dr marcelo lavarda [Modo de compatibilidad]

Manejo Sistémico del Cáncer de Próstata
Resistente a Hormonoterapia
Dr Marcelo Lavarda
Servicio de Oncología y Hematología Clínica
Sanatorio Allende
Córdoba
Carcinoma de Próstata Hormono Resistente
Terminología Sugerida
Andrógeno (hormona) Independiente: AIPC
Inexacto: Cáncer de Próstata todavía responde a
andrógenos (hormonas)
Refractariedad Hormonal: HRPC
Inexacto: Cáncer de Próstata todavía responde a bajos
niveles andrógenos (hormonas)
Resistente a Castración: CRPC
Término Favorecido pero puede ser peyorativo, negativo
Resistencia Endocrina u Hormonal: ERPC
Propuesto como políticamente Correcto
Historia Natural del Cáncer de Próstata
Under UROLOGIST care
Androgen
deprivation
Under ONCOLOGIST care
First-line therapy
Therapies after
LHRH agonists
and
antiandrogens
Local
therapy
Death
Salvage
therapy
Burden of
disease
Under
the care of
Symptomatic
ONCOLOGIST
Asymptomatic
Nonmetastatic
Castrate sensitive
Metastatic
Castrate resistant
Higano C, Figg WD, Drug management of prostate cancer; 2010.
Historia Natural del Cáncer de Próstata
• A 20 años, el riesgo de
mortalidad para pacientes 55 74 años con Gleasson 2 - 4 es
Survival
menor a 10 %
Non–prostate cancer mortality
Age at Diagnosis (Yrs)
55-59
OS
0
20
40
60
80
100
Alive, %
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
Gleason Score 6
Gleason Score 7
Gleason Score 8-10
0 5 10 15 20 0 5 10 15 20 0 5 10 15 20 0 5 10 15 20
Yrs Following Diagnosis
Albertsen P, JAMA. 2005;293:2095-2101.
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
Deceased, %
Other Cause
Mortality
70-74
100
80
60
40
20
0
Prostate cancer mortality
Prostate
Cancer
Mortality
60-64
65-69
Gleason Score 5
Opciones Terapéuticas para Cáncer de
Próstata
Sipuleucel-T*[8]
LHRH
Zoledronic Acid[4]
agonists*[1,2]
Mitoxantrone[3]
1984-1989
1996
Cabazitaxel*[7]
Denosumab[9]
Abiraterone*[10]
Docetaxel*[5,6]
2002
2004
....
2010
2011
MDV3100[11]
* Approved agent for PCa
Reversible AR
blockers[1,2]
Radium-223[12]
However, this rapid change has left many unanswered questions,
including the optimal selection and sequence
of therapy
1. 1. The Leuprolide Study Group. NEJM. 1984;311:1281-1286. 2. Crawford ED, NEJM 1989;321:419-424. 3. Tannock IF, J
Clin Oncol. 1996;14:1756-1764. 4. Saad F, J Natl Cancer Inst. 2002;94:1458-1468.
5. Petrylak DP, NEJM 2004;351:15131520. 6. Tannock IF, NEJM. 2004;351:1502-1512. 7. de Bono JS, Lancet. 2010;376:1147-1154. 8. Kantoff PW, NEJM
2010;363:411-422. 9. Fizazi K, Lancet. 2011;377:813-822. 10. de Bono JS, NEJM 2011;364:1995-2005. 11. Scher HI,
ASCO GU 2012. 12. Parker C, et al. ASCO GU 2012.
Carcinoma de Próstata Hormono Resistente
Docetaxel
Uso de Docetaxel reemplaza a Mitoxantrone como tratamiento estándart
SWOG 99-16: Docetaxel/estramustine
mejoría en sobrevida 2 meses vs
Mitoxantrone
100
100
80
80
60
40
Weekly
docetaxel
20
Docetaxel
q3w
OS (%)
OS (%)
TAX-327: Docetaxel mejoría en sobrevida,
dolor, PSA y calidad de vida vs Mitoxantrone]
Docetaxel + estramustine
(217 deaths; median: 17.5 mos)
60
40
20
Mitoxantrone
P = .02
Mitoxantrone
+ prednisone
(235 deaths;
median: 15.6 mos)
0
6
9 12 15 18 21 24 27 30 33
Mos
1. Tannock IF, N Engl J Med. 2004;351:1502-1512.
2. Petrylak DP, N Engl J Med. 2004;351:1513-1520.
0
12
24
Mos
36
48
Carcinoma de Próstata Hormono Resistente
Cabazitaxel Segunda Línea
Stratified by ECOG PS
(0, 1 vs 2) and measurable vs
nonmeasurable disease
Patients with
mCRPC progressing
on docetaxel
(N = 755)
•
•
Cabazitaxel 25 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 378)
Mitoxantrone 12 mg/m2 IV q3w +
Prednisone 10 mg/day PO for 10 courses
(n = 377)
Primary endpoint: OS
Secondary endpoints: PFS, response rate, safety
de Bono JS, Lancet. 2010;376:1147-1154.
Carcinoma de Próstata Hormono Resistente
Cabazitaxel Segunda Línea
Patients Remaining Alive (%)
100
Median OS for MP vs CBZP: 12.7 vs 15.1 mos
HR : 0.72 (95% CI: 0.61-0.84; P < .0001)
80
60
40
Censored
MP
CBZP
20
Combined median
follow-up: 13.7 mos
0
0
Patients at Risk, n
MP 377
CBZP 378
6
12
18
24
30
94
137
31
60
9
19
Mos
299
321
de Bono JS, Lancet. 2010;376:1147-1154.
195
241
Data cutoff:
March 10, 2010
Inmunoterapia en Cáncer de Próstata Hormono
Resistente
Sipuleucel-T (IMPACT)
100
Probability of Survival (%)
HR : 0.78 (95% CI: 0.61-0.98; P = .03)
80
Sipuleucel-T
Placebo
60
40
20
21.7 mos
0
0
12
24
36
48
60
Mos Since Randomization
Kantoff PW, N Engl J Med. 2010;363:411-422.
72
Abiraterone
Mecanismo de Acción
Pregnenolone
Deoxycorticosterone
Corticosterone
Aldosterone
CYP17:
17α-hydroxylase
17OH-Pregnenolone
11-deoxycortisol
Cortisol
x2
CYP17:
C17,20-lyase
DHEA
x3
Androstenedione
Attard G, J Clin Oncol. 2008;26:4563-4571.
Testosterone
< 1 ng/dL
Estradiol
< 80 ng/dL
< 2 ng/dL
Inhibidores del Eje Androgénico
Androgen
Biosynthesis
Inhibitors (ABI):
Ketoconazole
Abiraterone
TAK700
ABI
ARI
Chen Y, et al. Lancet Oncology. 2009;10:981-991
Second generation
AR inhibitors (ARI):
Enzalutamide
(MDV3100)
ARN509
COU-AA-301: Abiraterona
• Abiraterone aumenta SV vs Placebo con beneficio en todos los subgrupos
n
HR (95% CI)
1068
0.64 (0.53-0.78)
<4
659
0.64 (0.50-0.82)
≥4
536
Group
Baseline ECOG 0-1
BPI
0.68 (0.53-0.85)
Previous chemotherapy
1 regimen
833
0.63 (0.51-0.78)
2 regimens
362
0.74 (0.55-0.99)
PSA only
363
0.59 (0.42-0.82)
Radiographic
832
0.69 (0.56-0.84)
363
0.70 (0.52-0.94)
Progression type
Visceral disease
de Bono JS, N Eng J Med. 2011;364:1995-2005.
Carcinoma de Próstata Hormono Resistente
COU-AA-301: Abiraterona
100
HR: 0.646 (95% CI: 0.54-0.77;
P < .0001)
Survival (%)
80
Abiraterone acetate
Median OS: 14.8 mos
(95% CI: 14.1-15.4)
60
40
Placebo
Median OS: 10.9 mos
(95% CI: 10.2-12.0)
20
0
0
3
6
9
12
15
18
21
Mos
Median OS with 2 previous chemos:
14.0 mos AA vs 10.3 mos placebo
de Bono J, N Engl J Med. 2011;364:1995-2005.
Median OS with 1 previous chemo:
15.4 mos AA vs 11.5 mos placebo
Carcinoma de Próstata Hormono Resistente
Abiraterona en Pacientes sin Quimioterapia Previa
Ryan, C.NEJM 2013;368:138-48.
Carcinoma de Próstata Hormono Resistente
Abiraterona en Pacientes sin Quimioterapia Previa
Ryan, C.NEJM 2013;368:138-48.
Carcinoma de Próstata Hormono Resistente
Abiraterona en Pacientes sin Quimioterapia Previa
Ryan, C.NEJM 2013;368:138-48.
Carcinoma de Próstata Hormono Resistente
Abiraterona en Pacientes sin Quimioterapia Previa
Ryan, C.NEJM 2013;368:138-48.
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
Randomized 2:1
Enzalutamide 160 mg PO daily
(n = 800)
Patients with
mCRPC progressing
on docetaxel
(N = 1199)
Placebo PO daily
(n = 399)
• Primary endpoint: OS
• Key secondary endpoints: PSA response, soft-tissue objective
response, radiographic PFS, time to PSA progression
Scher HI, ASCO GU 2012. .
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
N Engl J Med 2012;367:1187-97
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
N Engl J Med 2012;367:1187-97
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
N Engl J Med 2012;367:1187-97
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
SRE Free (%)
HR: 0.621 (P < .0001)
100
90
80
70
Enzalutamide: 16.7 mos
(95% CI: 14.6-19.1)
60
50
40
30
20
10
0
Placebo: 13.3 mos
(95% CI: 5.5-NYR)
0
Pts at Risk, n
Enzalutamide 800
Placebo
399
3
6
676
278
548
196
De Bono JS, ASCO 2012. Abstract 4519.
9
12
15
Time to Event (Mos)
379
128
209
68
87
33
18
21
24
19
11
2
0
0
0
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
HR: 0.631 (95% CI: 0.529-0.752; P < .001)
37% reduction in risk of death
100
Enzalutamide: 18.4 mos
(95% CI: 17.3-NYR)
50
Placebo: 13.6 mos
(95% CI: 11.3-15.8)
0
0
Enzalutamide 800
Placebo
399
Scher HI, ASCO GU 2012.
6
12
701
317
400
167
OS (Mos)
18
72
33
24
7
3
0
0
Carcinoma de Próstata Hormono Resistente
Enzalutamida
AFFIRM
N Engl J Med 2012;367:1187-97
Carcinoma de Próstata Hormono Resistente
Radium-223
ALSYMPCA
Stratified by total ALP, previous docetaxel, and
bisphosphonate use; randomized 2:1
Up to 6 treatments at 4-wk intervals
Patients with symptomatic
CRPC and ≥ 2 bone
metastases with no known
visceral metastases, either
post-docetaxel or unfit
for docetaxel
(N = 921)
Radium-223 50 kBq/kg +
BSC
Placebo (saline) +
BSC
Primary endpoint: OS
Secondary endpoints: time to first SRE, time to total ALP progression, total ALP
response, ALP normalization, time to PSA progression, safety, QoL
Parker C, ASCO GU 2012. Abstract 8.
Carcinoma de Próstata Hormono Resistente
Radium-223
ALSYMPCA
100
HR: 0.695 (95% CI: 0.552-0.875;
P = .00185)
90
80
OS (%)
70
60
Radium-223 (n = 541)
Median OS: 14.0 mos
50
40
Placebo (n = 268)
Median OS: 11.2 mos
30
20
10
0
0
3
6
Pts at Risk, n
Parker C, 2012 ASCO GU Abstract 8.
9
12
15
Mos
18
21
24
27
Carcinoma de Próstata Hormono Resistente
Radium-223
ALSYMPCA
All Grades
Adverse Event, n (%)
Grade 3/4
Radium-223
(n = 509)
Placebo
(n = 253)
Radium-223
(n = 509)
Placebo
(n = 253)
Hematologic
•Anemia
•Neutropenia
•Thrombocytopenia
136 (27)
20 (4)
42 (8)
69 (27)
2 (1)
14 (6)
54 (11)
9 (2)
22 (4)
29 (12)
2 (1)
4 (2)
Nonhematologic
•Bone pain
•Diarrhea
•Nausea
•Vomiting
•Constipation
217 (43)
112 (22)
174 (34)
88 (17)
89 (18)
147 (58)
34 (13)
80 (32)
32 (13)
46 (18)
89 (18)
6 (1)
8 (2)
10 (2)
6 (1)
59 (23)
3 (1)
4 (2)
6 (2)
2 (1)
Parker C, 2012 ASCO GU Abstract 8.
Interacción entre MET y VEGFR en
Tumores Óseos
• MET es activado en metástasis
óseas
Stroma
Angiogenesis
VEGF
– Células Tumorales
expresan MET
Proliferation
differentiation
survival
HGF
Osteoblast
VEGF
HGF
HGF
VEGF
NP-1
– Activación del MET por
HGF en forma autocrina y
paracrina
– Osteoblastos y
Osteoclastos expresan
MET y VEGFRs
Zhang S, et al. Mol Cancer. 2010;9:9.
MET
HGF
Migration
proliferation
survival
Osteoclast
VEGF
Migration
proliferation
survival
Tumor Cell
Carcinoma de Próstata Hormono Resistente
Rol de MET
Androgen Deprivation Activates MET Signaling
Stromal
HGF
AR
MET
Androgen deprivation
HGF
AR
X
MET
(autocrine + paracrine)
Activated MET Is Highly Expressed in Bone Metastases
Zhang S, et al. Mol Cancer. 2010;9:9.
Carcinoma de Próstata Hormono Resistente
Cabozantinib vs Placebo
Baseline
Bone Scan Evaluable (N = 108)
Wk 12
Complete resolution
21 (19)
Partial resolution
61 (56)
Stable
23 (21)
Docetaxel pretreated
Hussain M, ASCO 2011.
Abstract 4516.
% Best Change From Baseline
Progressive disease
100
80
60
20
0
-20
-40
-60
-80
-100
n (%)
Pts With Baseline t-ALP
Levels ≥ 2 x ULN and
≥ 12 Wks of Follow-up (N = 28)
100
80
60
40
20
0
-20
-40
-60
-80
-100
3 (3)
Bisphosphonate treated
Bisphosphonate naive
Samples From Wk 6 and 12
(N = 118)
n (%)
Bone metastases and bone
pain at baseline (n = 83): pain
improvement at Wk 6 or 12
56
(67)
Narcotics for bone pain at
baseline (n = 67): pain
improvement at Wk 6 or 12
47
(70)
Evaluable for narcotics change
(n = 55): decrease or
discontinuation of narcotics
7/27 (26%) patients discontinued
narcotics entirely
Hussain M, ASCO 2011. Abstract 4516.
31
(56)
20
0
-20
Nonrandomized Expansion Trial
Prospective: Pts With Average
Worst Pain ≥ 4 at Baseline
**
*
Improved
Randomized Discontinuation
Trial; Post Hoc Investigator
Survey
% Change in Average Worst Pain From Baseline
Cabozantinib
Dolor Óseo y Uso de Narcóticos
-40
-60
-80
-100
Previous docetaxel
Previous docetaxel +
abiraterone and/or cabazitaxel
*Previous radionuclide therapy
Median best pain reduction from baseline: 46%
Cabozantinib
Estudios Fase III Randomizados
Patients with bone-metastatic
CRPC, moderate to severe bone
pain, and previous treatment
with docetaxel, abiraterone, or
enzalutamide
(Planned N = 246)
Patients with bone-metastatic
CRPC, and previous treatment
with docetaxel, abiraterone, or
enzalutamide
(Planned N = 246)
Cabozantinib 60 mg QD +
Mitoxantrone Placebo
Primary endpoint:
durable pain response
at Wk 12
Mitoxantrone/Prednisone +
Cabozantinib Placebo
Cabozantinib 60 mg QD +
Placebo
Secondary endpoints:
bone scan response by
IRF, OS
OS Endpoint Trial[2]
Primary endpoint: OS
Secondary endpoints:
bone scan response by
IRF
Prednisone 5 mg BID +
Placebo
1. ClinicalTrials.gov. NCT01522443.
2. ClinicalTrials.gov. NCT01605227.
Pain Endpoint Trial[1]
Dasatinib
Inhibición del Src
• Src permanece sobreexpresado en células tumorales de
Cáncer de Próstata
• La función normal del Osteoclasto depende de quinasa
Src
• La inhibición del Src inhibe:
– Proliferación de células tumorales
– Proliferación de Osteoclastos
– Actividad y Osteólisis de Osteoclastos
Maximum PSA
Change From Baseline (%)
200
Tumor Size (by RECIST)
PSA
150
100
50
0
-50
-100
-150
Yu EY, Clin Cancer Res. 2009;15:7421-7428.
Maximum uNTx
Change From Baseline (%)
50
40
30
20
10
0
-10
-20
-30
-40
-50
160
140
120
100
80
60
40
20
0
-20
-40
-60
-80
-100
100
Maximum BAP
Change From Baseline (%)
Maximum Tumor Size
Change From Baseline (%)
Carcinoma de Próstata Hormono Resistente
Dasatinib: Estudios Fase II – No Qtp previa
Urine N-Telopeptide
Bisphosphonate
No bisphosphonate
Bone Alkaline Phosphatase
80
60
40
20
0
-20
-40
-60
-80
Bisphosphonate
No bisphosphonate
Carcinoma de Próstata Hormono Resistente
Dasatinib: Estudio Fase III
Patients with
metastatic
CRPC and evidence
of progression
(Planned N = 1500)
Docetaxel +
Prednisone +
Placebo daily
Docetaxel +
Prednisone +
Dasatinib 100 mg/day PO
Primary endpoint: OS
Secondary endpoints: ∆ uNTx, time to first SRE, ∆ pain intensity, time to PSA
progression, tumor response rate, PFS, safety/tolerability
ClinicalTrials.gov. NCT00744497
Carcinoma de Próstata Hormono Resistente
Estrategias Dirigidas a Enfermedad Ósea
• Prevención de fractura en Estadios Tempranos
Bifosfonatos y Denosumab cada 6 meses
• Retardar la aparición de Metástasis Óseas
Denosumab aumenta SLE (no uso estándart)
• Tratamiento de Metástasis Óseas en Carcinoma de
Próstata Hormono Resistente
• Tratamiento de Metástasis Óseas en Carcinoma de
Próstata Hormono Sensible
Denosumab ?
• Nuevos Agentes
Carcinoma de Próstata Hormono Resistente
Eventos Óseos: Consecuencias Clínicas
Eventos Óseos
Consecuencias Clínicas
•
•
•
•
•
•
•
•
•
•
Fracturas Patológicas
Compresión Medular
Uso de Radioterapia
Cirugía de Metásis Óseas
Hipercalcemia
Cambio en tratamiento
Sistémico
Dolor Óseo
Uso de Analgésicos
Calidad de Vida
Menor Sobrevida
Carcinoma de Próstata Hormono Resistente
Parmidronato
Eligibility Criteria
Prostate cancer with
confirmed skeletal
metastases
Bone pain secondary to bone
metastases
No previous bisphosphonate
R
A
N
D
O
M
I
Z
E
D
SRE (Study Wk 27), n (%)
Pamidronate 90 mg q3w x 9
(n = 169)
Placebo q3w x 9
(n = 181)
Pamidronate
Placebo
Any SRE
42 (25)
46 (25)
Radiation to bone (pain relief)
25 (15)
29 (16)
Vertebral fracture
11 (7)
10 (6)
Spinal cord compression
5 (3)
3 (2)
Surgery to bone
5 (3)
6 (3)
Small EJ, J Clin Oncol. 2003;21:4277-4284.
Carcinoma de Próstata Hormono Resistente
Ácido Zoledrónico
Eligibility Criteria
Patients with prostate
cancer
Castration resistant
Bone metastases
(N = 643)
•
•
•
R
A
N
D
O
M
I
Z
E
D
Zoledronic acid 4 mg q3w
(n = 214)
Zoledronic acid 4 mg q3w
(initially 8 mg)
(n = 221)
Placebo q3w
(n = 208)
Patients in 8-mg arm reduced to 4 mg because of 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
Saad F, J Natl Cancer Inst. 2002;94:1458-1468.
Carcinoma de Próstata Hormono Resistente
Ácido Zoledrónico Eventos Óseos
Percent Without Event
100
80
60
40
20
Median, Days
P Value
488
321
.009
ZOL 4 mg
Placebo
0
0
120
240
Days
360
480
•
SREs: ZOL 4 mg 38%; placebo 49% (P = .028) 11% absolute risk reduction in ≥ 1 SRE
•
Pain/analgesia scores increased less with ZOL
•
No improvement in tumor progression, QoL, OS
600
Saad F, ASCO 2003. Abstract 1523. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.
720
Carcinoma de Próstata Hormono Resistente
Denosumab vs Ácido Zoledrónico
Patients with CRPC and bone
metastases, and no
current or past IV
bisphosphonate treatment
(N = 1901)
Denosumab 120 mg SC +
Placebo IV* q4w
(n = 950)
Zoledronic acid 4 mg IV* +
Placebo SC q4w
(n = 951)
Calcium and vitamin D supplemented in both treatment groups
Primary endpoint: time to first on-study SRE (fracture, radiation or surgery to bone, spinal cord
compression)
*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.
Fizazi K, Lancet. 2011;377:813-822.
Proportion of Subjects Without SRE
Denosumab vs Ácido Zoledrónico
Tiempo al Primer Evento Óseo
1.00
HR: 0.82 (95% CI: 0.71-0.95;
P = .0002, noninferiority;
P = .008, superiority)
18%
Risk
reduction
0.75
0.50
KM Estimate of
Median Mos
20.7
Denosumab
17.1
Zoledronic acid
0.25
0
0
3
Patients at Risk, n
Fizazi K, Lancet. 2011;377:813-822.
6
9
12
15
Study Mo
18
21
24
27
Denosumab vs Ácido Zoledrónico
Efectos Adversos
Subject Incidence, n (%)
Zoledronic Acid
(n = 945)
Denosumab
(n = 943)
Infectious adverse events
375 (39.7)
402 (42.6)
Infectious serious adverse events
108 (11.4)
130 (13.8)
Acute-phase reactions (first 3 days)
168 (17.8)
79 (8.4)
Renal adverse events*
153 (16.2)
139 (14.7)
12 (1.3)
22 (2.3)
• Yr 1
5 (0.5)
10 (1.1)
• Yr 2
8 (0.8)
22 (2.3)
Hypocalcemia
55 (5.8)
121 (12.8)
New primary malignancy
10 (1.1)
18 (1.9)
Cumulative rate of ONJ†
Fizazi K, Lancet. 2011;377:813-822.
Carcinoma de Próstata Hormono Resistente
Algoritmo Terapéutico
Maintain castration serum levels of testosterone and use denosumab or zoledronic acid
with vitamin D and calcium if bone metastases are present
No
Symptomatic
Visceral disease
Sipuleucel-T
Secondary hormone therapy
• Antiandrogen
• Antiandrogen withdrawal
• Ketoconazole or abiraterone
acetate (level 2B)
• Steroids
• DES or other estrogen
Clinical trial
Mottet N, Eur Urol. 2011;59:572-583.
NCCN. Clinical practice guidelines in oncology:
prostate cancer. v.1.2012.
Yap TA, et al. Nat Rev Clin Oncol. 2011; 8:597-610.
Yes
Docetaxel
Mitoxantrone
Abiraterone acetate
Palliative radiotherapy or radionuclide
(radium-223 ?) for symptomatic bone
metastases
Clinical trial
Abiraterone acetate
Cabazitaxel
Salvage chemotherapy
Docetaxel rechallenge
Mitoxantrone
Secondary hormone
therapy
Sipuleucel-T
Enzalutamide
Clinical trial
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