Tratamiento en Cáncer de Próstata en progresión con

niveles de castración de testosterona (CPRC)

Dr Pablo MarotoHospital de Sant Pau

Abbreviation: LHRH=luteinizing hormone-releasing hormone.

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

Under the care of ONCOLOGISTUnder the care of ONCOLOGIST

Castration Sensitive

Asymptomatic

Non Metastatic

Castration Resistant

Metastatic

Symptomatic

Local Therapy

Androgen Deprivation

Therapies After LHRH Agonists and Antiandrogen

Chemotherapy

Post Chemo

Death

RANDOMISE

Mitoxantrone 12 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 75 mg/m2

Prednisone 10 mg q dayQ 21 days up to 10 cycles

Docetaxel 30 mg/m2/wkPrednisone 10 mg q day5 on; 1 off x 6 cycles

N = 1,006

TAX 327

SWOG 9916 Mitoxantrone 12 mg/m2

Prednisone 5 mg bidQ 21 days

Docetaxel 60 mg/m2 D2Estramustine 280 mg D1–5a

Dexamethasone 20 mg, tid D1–2

N = 770

aWarfarin and aspirin.SWOG = Southwest Oncology Group.

Tannock et al, 2004; Petrylak et al, 2004.

Phase III Docetaxel Studies in CRPC

Demonstrating Survival Benefit

RANDOMISE

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 RANKL: Mediador en el “Círculo Vicioso” de destrucción ósea de la metástasisla metástasis

PTHrP, BMP,TGF-β, IGF, FGF,VEGF, ET1, WNT

Osteoblasts

Activated Osteoclast

PDGF, BMPsTGF-β, IGFs

FGFs

Adapted from Roodman D. N Engl J Med. 2004;350:1655.

RANKL

RANKTumor

Cell

Denosumab interrumpiría el “Círculo Vicioso”Denosumab interrumpiría el “Círculo Vicioso”

PDGF, BMPsPDGF, BMPsTGF-β, IGFsTGF-β, IGFs

FGFsFGFs

OsteoblastsOsteoblasts

RANKLRANKL

RANKRANK

DenosumabDenosumabTumor Tumor CellCell

FormationFormationInhibitedInhibited

Apoptotic Apoptotic OsteoclastOsteoclast

PTHrP, BMP,PTHrP, BMP,TGF-β, IGF, FGF,TGF-β, IGF, FGF,VEGF, ET1, WNTVEGF, ET1, WNT

Adapted from Roodman D. N Engl J Med. 2004;350:1655.

Study Design: Study Design: International, Randomized, Double-International, Randomized, Double-Blind, Active-Controlled StudyBlind, Active-Controlled Study

Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951)

Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950)

Key Inclusion•Hormone-refractory (castration resistant) prostate cancer and bone metastases

Key Exclusion•Current or prior IV bisphosphonate treatment

*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.

• Calcium and Vitamin D supplemented in both treatment groups• Accrual period from May 2006 to December 2008• Analysis cut-off date October 2009

Time to First and Subsequent On-Study SRE* Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)(Multiple Event Analysis)

*Events occurring at least 21 days apart

Rate Ratio = 0.82 (95% CI: 0.71, 0.94)

Month

0.0

2.0

0 3 6 9 12 15 18 21 24 27

Cum

ula

tive M

ean N

um

ber

of

SR

Es

per

Pati

ent

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

18%18%

Risk Reduction

Denosumab Zoledronic acid 584

494

Events

P = 0.008

TROPIC: Cabazitaxel vs MitoxantroneTROPIC: Cabazitaxel vs Mitoxantrone

Primary endpoint: OSSecondary 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

cabazitaxel 25 mg/m²cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles

(n=378)

mitoxantrone 12 mg/m²mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=377)

*Oral prednisone/prednisolone: 10 mg daily.

Stratification factorsECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease

mCRPC patients who progressed during and after treatment with a docetaxel-

based regimen (N=755)

¿Es importante una

rama control con

mitoxantrone?

Primary Endpoint: Overall Survival (ITT Analysis)

28

11

4

1

231

188

90

67300377 MP

321378 CBZP

Numberat risk

Proportionof OS (%)

80

60

40

20

0

100

0 months 6 months 12 months 18 months 24 months 30 months

15.112.7

Median OS (months)

0.59–0.8395% CI

<.0001P-value

0.70Hazard Ratio

CBZPMP

11

FactorHazard 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 (0.59–0.83)

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)0 1 20.5 1.5

0 1 20.5 1.5

Most Frequent Grade ≥3 Treatment-Emergent AEs*Safety Population

1.934.20.322.9Nausea

1.922.6010.2Vomiting

1.916.70.53.8Hematuria

57.495.739.488.4Any adverse event

1.911.603.5Abdominal pain

3.816.2312.1Back pain

4.620.52.412.4Asthenia

Grade ≥3 (%)Grade ≥3 (%) All grades (%)All grades (%)

36.7

46.6

7.5

CBZP (n=371)

4.9

6.2

7.5

3

0.3

1.3

27.5Fatigue

10.5Diarrhea

1.3Febrile neutropenia

MP (n=371)

¿Cómo condiciona el tratamiento la toxicidad?

VOLUMEN 26, Nº28 2008VOLUMEN 26, Nº28 2008

Prostate Cancer: Moving Forward by Prostate Cancer: Moving Forward by Reinventing the Wheel ... But This Reinventing the Wheel ... But This

Time It Is RoundTime It Is Round

Resistance to castration: is there still a way to play with hormonal drugs

Scher H et al, J Clin Oncol 2005

1

4

3

2

ACTHLH

Brain

LHRH

Pituitary

LHRH analogues Antiandrogens

Prostate Cancer

Testosterone

Testis

AdrenalGland

ACTHLH

Brain

LHRH

Androgens

LHRH Analogue

Pituitary

Prostate Cancer

Testosterone

Testis

AdrenalGland

Androgens

Antiandrogen

AbirateroneAbiraterone: Inhibición síntesis teste, adrenal, ¿intratumoral?: Inhibición síntesis teste, adrenal, ¿intratumoral?

Prostate CancerProstate Cancer

TestosteroneTestosterone

TestisTestis AdrenalAdrenalGlandGland

ACTHACTHLHLH

BrainBrain

LHRHLHRH

AndrogensAndrogens

PituitaryPituitary

InhibitorInhibitor

Inhibitor?Inhibitor?

? De novo synthesis? De novo synthesis

RO

MW = 391.55

N

3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene

RO = AcO

CYP17 blockade inhibits androgen synthesisCYP17 blockade inhibits androgen synthesis

Ligand

1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM

2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++

3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -

4. Coactivator recruitment• DHT: ++++• Bicalutamide: ++• MDV3100: -

The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide

1

2

3

4

DNA

POL II

HSP 9

0

LBD

HD

DBD

NTD

COU-AA-301: Fase III post-quimioterapia

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.

Abiraterona 1000 mg/díaPrednisona 10 mg/día

N=797

Objetivo principal

•OS

Objetivos secundarios

•TTPP

•rPFS

•Respuesta PSA

PlaceboPrednisona 10 mg/día

N=398ALEA

TO

RIZ

AC

IÓN

2:1

•N=1195

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

Pacientes

Gráfico extraído de: de Bono, J.S. et al. Abiraterone and increased survival in metastasic prostate cancer. NEJM: 2011;364(21):1995-2005.

¿Influye en la decisión de tratar

la necesidad de prednisona?

¿Metástasis viscerales también?

¿Tiene importancia

la respuesta por PSA?

TRATAMIENTO

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care

RAND

OMISED

2:1

N = 922

PACIENTES

• Confirmed symptomatic CRPC

• ≥ 2 bone metastases

• No known visceral metastases

• Post-docetaxel or unfit for docetaxel

Diseño del estudio ALSYMPCA

Clinicaltrials.gov identifier: NCT00699751.

• Total ALP: < 220 U/L vs ≥ 220 U/L• Bisphosphonate use: Yes vs No• Prior docetaxel: Yes vs No

ESTRATIFICACIÓN

Planned follow-up is 3 years

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

ALSYMPCA: Supervivencia Global

0

10

20

30

40

50

60

70

80

90

100

%Radium-223, n = 541Median OS: 14.0 months

Placebo, n = 268Median OS: 11.2 months

HR 0.695; 95% CI, 0.552-0.875P = 0.00185

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

ALSYMPCA: Tiempo al primer SRE

0

10

20

30

40

50

60

70

80

90

100

% W

ith

ou

t S

RE

HR 0.610; 95% CI, 0.461-0.807 P = 0.00046

Radium-223, n = 541Median: 13.6 months

Placebo, n = 268Median: 8.4 months

ALSYMPCA: Efectos adversos de interés

All Grades Grades 3 or 4

Radium-223 n (%)

Placebon (%)

Radium-223 n (%)

Placebon (%)

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)

Resumen: Resultados Ensayos fase III en CPRC

Agent (trial, year) Disease State Comparator Hazard Ratio P value

Radium-223(ALSYMPCA 2011)

Symptomatic Bonemetastases

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)Post-Docetaxel Placebo 0.63 0.0001

Abiraterone4

(COU-AA-301 2010) Post-docetaxel Placebo Prednisone 0.65 <0.001

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