Tratamiento en Cáncer de Próstata
en progresión con niveles de
castración de testosterona (CPRC)
Dr Pablo Maroto
Hospital de Sant Pau
Natural History of Prostate Cancer
Androgen
Deprivation
Chemotherapy
Death
Local
Therapy
Therapies After
LHRH Agonists and
Antiandrogen
Under the care of
Symptomatic
ONCOLOGIST
Asymptomatic
Non Metastatic
Castration Sensitive
Post Chemo
Metastatic
Castration Resistant
• Typical presentation of patients as they move through the different stages.
The line represents level burden of disease. Time is not proportional
Abbreviation: LHRH=luteinizing hormone-releasing hormone.
Phase III Docetaxel Studies in CRPC Demonstrating
Survival Benefit
TAX 327
N = 1,006
RA
ND
O
MI
S
E
Mitoxantrone 12 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
Docetaxel 30 mg/m2/wk
Prednisone 10 mg q day
5 on; 1 off x 6 cycles
Docetaxel 75 mg/m2
Prednisone 10 mg q day
Q 21 days up to 10 cycles
SWOG 9916
N = 770
aWarfarin
and aspirin.
SWOG = Southwest Oncology Group.
Tannock et al, 2004; Petrylak et al, 2004.
RA
ND
O
MI
S
E
Mitoxantrone 12 mg/m2
Prednisone 5 mg bid
Q 21 days
Docetaxel 60 mg/m2 D2
Estramustine 280 mg D1–5a
Dexamethasone 20 mg, tid D1–2
Opciones de tratamiento en CPRC en
segunda línea
•
Prevención de EREs
•
Segundas líneas hormonales
–
–
Abiraterona
Enzalutamida
•
Quimioterapia: Cabazitaxel
•
Con enfermedad predominantemente ósea
–
Radioisótopos: Radium 223
RANKL: Mediador en el “Círculo Vicioso” de destrucción ósea de la
metástasis
RANKL
RANK
Tumor
Cell
PTHrP, BMP,
TGF-β, IGF, FGF,
VEGF, ET1, WNT
PDGF, BMPs
TGF-β, IGFs
FGFs
Activated
Osteoclast
Osteoblasts
Adapted from Roodman D. N Engl J Med. 2004;350:1655.
Denosumab interrumpiría el “Círculo Vicioso”
RANKL
RANK
Tumor
Cell
PTHrP, BMP,
TGF-β, IGF, FGF,
VEGF, ET1, WNT
Formation
Inhibited
Denosumab
PDGF, BMPs
TGF-β, IGFs
FGFs
Osteoblasts
Adapted from Roodman D. N Engl J Med. 2004;350:1655.
Apoptotic
Osteoclast
Study Design: International, Randomized, Double-Blind,
Active-Controlled Study
Key Inclusion
• Hormone-refractory
(castration resistant)
prostate cancer and bone
metastases
Key Exclusion
• Current or prior IV
bisphosphonate treatment
Denosumab 120 mg SC and Placebo
IV* every 4 weeks (N = 950)
Zoledronic acid 4 mg IV* and
Placebo SC every 4 weeks (N = 951)
• Calcium and Vitamin D supplemented in both treatment groups
• Accrual period from May 2006 to December 2008
• Analysis cut-off date October 2009
*Per protocol and Zometa® 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.
Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)
Cumulative Mean Number of SREs per
Patient
2.0
Rate Ratio = 0.82 (95% CI: 0.71, 0.94)
P = 0.008
1.8
18%
Risk
Reduction
1.6
1.4
1.2
1.0
0.8
0.6
Events
0.4
Denosumab
Zoledronic acid
0.2
0.0
0
3
6
9
12
15
18
21
24
Month
*Events occurring at least 21 days apart
27
494
584
30
33
36
TROPIC: Cabazitaxel vs Mitoxantrone
¿Es importante una
mCRPC patients who progressed during and
rama control
after treatment with a docetaxel-based regimen
(N=755)
con mitoxantrone?
Stratification factors
ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease
cabazitaxel 25 mg/m² q 3 wk
+ prednisone* for 10 cycles
(n=378)
mitoxantrone 12 mg/m² q 3 wk
+ prednisone* for 10 cycles
(n=377)
*Oral prednisone/prednisolone: 10 mg daily.
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
Primary Endpoint: Overall Survival (ITT Analysis)
Proportion
of OS (%)
MP
100
CBZP
Median OS (months)
15.1
12.7
Hazard Ratio
80
0.70
0.59–0.83
95% CI
P-value
<.0001
60
40
20
0
Number
at risk
0 months
6 months
12 months
18 months
24 months
30 months
MP
377
300
188
67
11
1
CBZP
378
321
231
90
28
4
Factor
Hazard ratio
(95% CI)
All patients
0.70 (0.59–0.83)
ECOG status: 0,1
0.68 (0.57–0.82)
ECOG status: 2
0.81 (0.48–1.38)
Measurable disease: No
0.72 (0.55–0.93)
Measurable disease: Yes
0.68 (0.54–0.85)
No. of prior chemo: 1
0.67 (0.55–0.83)
No. of prior chemo: ≥2
0.75 (0.55–1.02)
Age: <65
0.81 (0.61–1.08)
Age: ≥65
0.62 (0.50–0.78)
Rising PSA: No
0.88 (0.61–1.26)
Rising PSA: Yes
0.65 (0.53–0.80)
Total docetaxel dose: <225 mg/m²
0.96 (0.49–1.86)
Total docetaxel dose: ≥225 to 450 mg/m²
0.60 (0.43–0.84)
Total docetaxel dose: ≥450 to 675 mg/m²
0.83 (0.60–1.16)
Total docetaxel dose: ≥675 to 900 mg/m²
0.73 (0.48–1.10)
Total docetaxel dose: ≥900 mg/m²
0.51 (0.33–0.79)
Progression: During last docetaxel treatment
0.65 (0.47–0.90)
Progression: <3 months since last docetaxel dose
0.70 (0.55–0.91)
Progression: ≥3 months since last docetaxel dose
0.75 (0.51–1.11)
 favors CBZP

0
0
0.5
1
0.5
1
|
favors MP
1.5
10
1.5
2
2
Most Frequent Grade ≥3 Treatment-Emergent AEs*
Safety Population
CBZP (n=371)
MP (n=371)
All grades (%) Grade ≥3 (%) All grades (%) Grade ≥3 (%)
Any adverse event
Febrile neutropenia
Diarrhea
88.4
39.4
95.7
57.4
1.3
1.3
7.5
7.5
10.5
0.3
46.6
6.2
3
36.7
4.9
2.4
20.5
4.6
3
16.2
3.8
¿Cómo condiciona
27.5
el tratamiento
Asthenia
12.4
la toxicidad?
Back pain
12.1
Fatigue
Nausea
22.9
0.3
34.2
1.9
Vomiting
10.2
0
22.6
1.9
Hematuria
3.8
0.5
16.7
1.9
Abdominal pain
3.5
0
11.6
1.9
VOLUMEN 26, Nº28 2008
Prostate Cancer: Moving Forward by
Reinventing the Wheel ... But This
Time It Is Round
Resistance to castration: is there still a
way to play with hormonal drugs
3
4
1
2
Scher H et al, J Clin Oncol 2005
LHRH analogues
Antiandrogens
LHRH
LHRH Analogue LHRH
Brain
Brain
Pituitary
Pituitary
LH
LH
ACTH
Adrenal
Gland
Testis
Adrenal
Gland
Testis
Testosterone
Testosterone
ACTH
Androgens
Androgens
Antiandrogen
Prostate Cancer
Prostate Cancer
Abiraterone: Inhibición síntesis teste, adrenal, ¿intratumoral?
LHRH
MW =
391.55
Brain
RO
Pituitary
LH
3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene
Inhibitor
ACTH
Adrenal
Gland
Testis
Testosterone
N
Androgens
Inhibitor?
Prostate Cancer
? De novo synthesis
CYP17 blockade inhibits androgen synthesis
The Effects of MDV3100 on the
Androgen Receptor Are Distinct from Bicalutamide
Ligand
LBD
HSP 90
1. AR Binding Affinity
1
HD
DBD
•
•
•
DHT
~ 5nM
Bicalutamide ~160 nM
MDV3100
~35 nM
2. Nuclear Import
•
•
•
NTD
2
DHT:
Bicalutamide:
MDV3100:
++++
++++
++
3. DNA Binding
•
•
•
4
DHT:
Bicalutamide:
MDV3100:
++++
++
-
POL II
4. Coactivator recruitment
•
•
•
3
DNA
DHT:
Bicalutamide:
MDV3100:
++++
++
-
COU-AA-301: Fase III postquimioterapia
¿Influye en la
Fase
III, multicéntrico,
decisión
de tratar aleatorizado, doble ciego, para estudiar los
beneficios
clínicos de abiraterona junto a prednisona, en pacientes
la necesidad
con de
cáncer
de próstata metastásico que han progresado tras uno o
prednisona?
Pacientes
•N=1195
•1 o 2 regímenes de
QT previa, uno de
ellos docetaxel
ALEATORIZACIÓN
2:1
dos regímenes de quimioterapia.
Abiraterona 1000 mg/día
Prednisona 10 mg/día
N=797
Objetivo principal
•OS
Objetivos
secundarios
Placebo
Prednisona 10 mg/día
N=398
•TTPP
•rPFS
•Respuesta PSA
Gráfico extraído de: de Bono, J.S. et al. Abiraterone and increased survival in metastasic prostate cancer. NEJM: 2011;364(21):1995-2005.
¿Metástasis
viscerales también?
¿Tiene importancia
la respuesta por
PSA?
Diseño del estudio ALSYMPCA
TRATAMIENTO
PACIENTES
ESTRATIFICACIÓN
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Total ALP:
< 220 U/L vs ≥ 220 U/L
• Bisphosphonate use:
Yes vs No
• Prior docetaxel:
Yes vs No
• Post-docetaxel
or unfit for
docetaxel
R
A
N
D
OM
I
S
E
D
2:1
N = 922
Planned follow-up is 3 years
Clinicaltrials.gov identifier: NCT00699751.
6 injections at
4-week intervals
Radium-223 (50 kBq/kg) +
Best standard of care
Placebo (saline)
+ Best standard of care
ALSYMPCA: Supervivencia Global
100
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185
90
80
70
60
%
Radium-223, n = 541
Median OS: 14.0 months
50
40
30
Placebo, n = 268
Median OS: 11.2 months
20
10
0
Month
0
3
6
9
12
15
18
21
24
27
Radium- 541
223
450
330
213
120
72
30
15
3
0
Placebo 268
218
147
89
49
28
15
7
3
0
ALSYMPCA: Tiempo al primer SRE
100
HR 0.610; 95% CI, 0.461-0.807
P = 0.00046
90
80
% Without SRE
70
Radium-223, n = 541
Median: 13.6 months
60
50
40
Placebo, n = 268
Median: 8.4 months
30
20
10
0
Month
0
3
6
9
12
15
18
21
Radium223
541
379
214
111
51
22
6
0
Placebo
268
159
74
30
15
7
2
0
ALSYMPCA: Efectos adversos de interés
All Grades
Grades 3 or 4
Radium-223
n (%)
Placebo
n (%)
Radium-223
n (%)
Placebo
n (%)
136 (27)
69 (27)
54 (11)
29 (12)
Neutropenia
20 (4)
2 (1)
9 (2)
2 (1)
Thrombocytopenia
42 (8)
14 (6)
22 (4)
4 (2)
Bone pain
217 (43)
147 (58)
89 (18)
59 (23)
Diarrhoea
112 (22)
34 (13)
6 (1)
3 (1)
Nausea
174 (34)
80 (32)
8 (2)
4 (2)
Vomiting
88 (17)
32 (13)
10 (2)
6 (2)
Constipation
89 (18)
46 (18)
6 (1)
2 (1)
Haematologic
Anaemia
Non-Haematologic
Resumen: Resultados Ensayos fase III en CPRC
Agent (trial, year)
Disease State
Comparator
Hazard
Ratio
P value
Radium-223
(ALSYMPCA 2011)
Symptomatic
Bone
metastases
Placebo
0.695
0.00185
Docetaxel1
(TAX327 2004)
Chemo-naive
Mitoxantrone
Prednisone
0.76
0.009
Cabazitaxel2
(TROPIC 2010)
Post-docetaxel
Mitoxantrone
Prednisone
0.70
<0.0001
Enzalutamide3
(AFFIRM 2012)
PostDocetaxel
Placebo
0.63
0.0001
Abiraterone4
Post-docetaxel
Placebo
Prednisone
0.65
<0.001
(COU-AA-301 2010)
No hay criterios definitorios para
recomendar un tratamiento para un
paciente dado
¿Seguro?
PMR: 60 a. ECOG 0. Gleason 9.
Respuesta hormona previa <12 m.
Metástasis hepáticas. PSA de 19.
Respuesta docetaxel intervalo 2
meses sin toxicidades relevantes
JMR: 70 a. ECOG 0. Gleason 7.
Respuesta hormona previa 19 m.
Metástasis Óseas. PSA de 198.
Respuesta docetaxel intervalo 4 meses
Definir un
algoritmo similar
para hormonoterapia
de rescate
GRACIAS