Tratamiento en C

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Tratamiento en Cáncer de Próstata en progresión
con niveles de castración de testosterona (CPRC)
Dr Pablo MarotoHospital de Sant Pau
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Natural History of Prostate Cancer

• Typical presentation of patients as they move
  through the different stages. The line
  represents level burden of disease. Time is not
  proportional

Abbreviation LHRHluteinizing hormone-releasing
hormone.
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Phase III Docetaxel Studies in CRPC Demonstrating
Survival Benefit
N 1,006
Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21
days
N 770
Docetaxel 60 mg/m2 D2 Estramustine 280 mg
D15a Dexamethasone 20 mg, tid D12
aWarfarin and aspirin. SWOG Southwest Oncology
Group.
Tannock et al, 2004 Petrylak et al, 2004.
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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

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RANKL Mediador en el Círculo Vicioso de
destrucción ósea de la metástasis
RANKL RANK
Tumor Cell
PTHrP, BMP,TGF-ß, IGF, FGF,VEGF, ET1, WNT
PDGF, BMPs TGF-ß, IGFs FGFs
Activated Osteoclast
Osteoblasts
Adapted from Roodman D. N Engl J Med.
20043501655.
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Denosumab interrumpiría el Círculo Vicioso
RANKL RANKDenosumab
Tumor Cell
FormationInhibited
PTHrP, BMP,TGF-ß, IGF, FGF,VEGF, ET1, WNT
PDGF, BMPs TGF-ß, IGFs FGFs
Apoptotic Osteoclast
Osteoblasts
Adapted from Roodman D. N Engl J Med.
20043501655.
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Study Design International, Randomized,
Double-Blind, Active-Controlled Study
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.
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Time to First and Subsequent On-Study SRE
(Multiple Event Analysis)
Risk Reduction
2.0
Rate Ratio 0.82 (95 CI 0.71, 0.94)
P 0.008
1.8
1.6
1.4
1.2
Cumulative Mean Number of SREs per Patient
1.0
0.8
0.6
Events
0.4
Denosumab
494
0.2
Zoledronic acid
584
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Month
Events occurring at least 21 days apart
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TROPIC Cabazitaxel vs Mitoxantrone
Stratification factors ECOG PS (0, 1 vs. 2)
Measurable vs. non-measurable disease
Oral prednisone/prednisolone 10 mg daily.
Primary endpoint OS Secondary endpoints
Progression-freesurvival (PFS), response rate,
and safety
Inclusion Patients with measurable disease must
have progressed by RECIST otherwise must have
had new lesions or PSA progression
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Primary Endpoint Overall Survival (ITT Analysis)
Proportionof OS ()
Numberat risk
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Factor Hazard ratio(95 CI) ? f a v o r s C B Z P f a v o r s M P ?

All patients 0.70 (0.590.83)
ECOG status 0,1 0.68 (0.570.82)
ECOG status 2 0.81 (0.481.38)
Measurable disease No 0.72 (0.550.93)
Measurable disease Yes 0.68 (0.540.85)
No. of prior chemo 1 0.67 (0.550.83)
No. of prior chemo 2 0.75 (0.551.02)
Age lt65 0.81 (0.611.08)
Age 65 0.62 (0.500.78)
Rising PSA No 0.88 (0.611.26)
Rising PSA Yes 0.65 (0.530.80)
Total docetaxel dose lt225 mg/m² 0.96 (0.491.86)
Total docetaxel dose 225 to 450 mg/m² 0.60 (0.430.84)
Total docetaxel dose 450 to 675 mg/m² 0.83 (0.601.16)
Total docetaxel dose 675 to 900 mg/m² 0.73 (0.481.10)
Total docetaxel dose 900 mg/m² 0.51 (0.330.79)
Progression During last docetaxel treatment 0.65 (0.470.90)
Progression lt3 months since last docetaxel dose 0.70 (0.550.91)
Progression 3 months since last docetaxel dose 0.75 (0.511.11)


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Most Frequent Grade 3 Treatment-Emergent
AEsSafety Population
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Resistance to castration is there still a way to
play with hormonal drugs
Scher H et al, J Clin Oncol 2005
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LHRH analogues
Antiandrogens
LHRH
Brain
Pituitary
ACTH
LH
Adrenal Gland
Testis
Testosterone
Androgens
Antiandrogen
Prostate Cancer
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Abiraterone Inhibición síntesis teste, adrenal,
intratumoral?
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CYP17 blockade inhibits androgen synthesis
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The Effects of MDV3100 on the Androgen Receptor
Are Distinct from Bicalutamide
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Ligand
HSP 90
LBD
HD
DBD
NTD
2
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POL II
3
DNA
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COU-AA-301 Fase III post-quimioterapia

• Objetivo principal
• OS
• Objetivos secundarios
• TTPP
• rPFS
• Respuesta PSA

Pacientes

• N1195
• 1 o 2 regímenes de QT previa, uno de ellos
  docetaxel

Gráfico extraído de de Bono, J.S. et al.
Abiraterone and increased survival in metastasic
prostate cancer. NEJM 2011364(21)1995-2005.
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Diseño del estudio ALSYMPCA
TRATAMIENTO 6 injections at 4-week intervals
PACIENTES
ESTRATIFICACIÓN
N 922
Planned follow-up is 3 years
Clinicaltrials.gov identifier NCT00699751.
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ALSYMPCA Supervivencia Global
100
HR 0.695 95 CI, 0.552-0.875P 0.00185
90
80
70
60
Radium-223, n 541 Median OS 14.0 months

50
40
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Placebo, n 268 Median OS 11.2 months
20
10
0
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0
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ALSYMPCA Tiempo al primer SRE
100
HR 0.610 95 CI, 0.461-0.807 P 0.00046
90
80
70
Radium-223, n 541 Median 13.6 months
60
50
Without SRE
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Placebo, n 268 Median 8.4 months
30
20
10
0
Month 0 3 6 9 12 15 18 21
Radium-223 541 379 214 111 51 22 6 0
Placebo 268 159 74 30 15 7 2 0
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ALSYMPCA Efectos adversos de interés
All Grades All Grades Grades 3 or 4 Grades 3 or 4
Radium-223 n () Placebo n () Radium-223 n () Placebo n ()
Haematologic
Anaemia 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)

Non-Haematologic
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)
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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 lt0.0001
Enzalutamide3 (AFFIRM 2012) Post- Docetaxel Placebo 0.63 0.0001
Abiraterone4 (COU-AA-301 2010) Post-docetaxel Placebo Prednisone 0.65 lt0.001
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No hay criterios definitorios para recomendar un
tratamiento para un paciente dado
Seguro?
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• PMR 60 a. ECOG 0. Gleason 9. Respuesta hormona
  previa lt12 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
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GRACIAS