KASTRASYONA DĠRENÇLĠ

PROSTAT KANSERĠ TEDAVĠSĠ

Dr. Kamil ÇAM

Düzce Üniversitesi Tıp Fakültesi

Üroloji AD

KASTRASYONA DĠRENÇLĠ PROSTAT KANSERĠ TEDAVĠSĠ

• TANIM

• DÜN– Prednizon

– Mitoxantrone

• BUGÜN– Docetaxel

– Bone targeted terapi – Zoledronic Acid

• YARIN– Abiraterone

– MDV3100

– Cabazitaxel

– Satraplatin

– Sipuleucel-T

– Radium-223

– Bone targeted terapi – Denosumab

• UZAK GELECEK

KASTRASYONA DĠRENÇLĠ PROSTAT KANSERĠ

•BAġARISIZ

KÜRATĠF Tx

•METASTATĠK

HASTALIKSEMPTOMATĠK

BĠOKĠMYASAL

ASEMPRTOMATĠK

METASTAZLAR

KDPCaPSA

24+ AY

12-36 AY

6-24 AY

Mo M+ M+

HORMONAL

TEDAVĠMORTALĠTE

TANIM

• HT– LHRH agonistleri

– LHRH antagonisti

– OrĢiektomi

– Nonsteroidal antiandrojenler

• T ------AR signalling devam

Androjen Rezistans

Scher, H. I. et al. J Clin Oncol; 23:8253-8261 2005

AR Signalling

Copyright © American Society of Clinical Oncology

TANIMAR signalling

• AR– Gen amplifikasyonu ile AR upregülasyonu

– Mutasyonlar

• Tümöral T sentezi

• Bazı enzimlerin ekspresyonu– P-450c17 (CYP17)

• Diğer

TANIM

EAU Guidelines, 2011

DÜN

PALYASYON

• Prednizon– %40 ağrı

• Mitoxantrone-Prednizon– Faz III RCT

– n = 161

– Ġlk klinik etkinliği gösterilen

– Palyasyon

– FDA 1996

DÜNMitoxantrone - Prednizon

P

(n=81)

M+P

(n=80)p Value

Palyatif yanıt 12% 29% 0.01

Yanıt süresi 18 wks 43 wks 0.0001

PSA ( %50 ) 22% 33% 0.11

Sürvi 10.3m 10.3m 0.27

GEÇMĠġTE STANDART

BUGÜNSÜRVĠ

• Docetaxel

–Ġlk sağkalım avantajı gösterilen

• Bisfosfonatlar

–Zoledronic Asit

Docetaxel

• TAX 327Tannock et al. N Eng J Med 2004;351:1502-1512

• SWOG Petrylak et al. N Eng J Med 2004;351:1513-1520

TAX-327

Docetaxel 75 mg/m2 q3 hft

+ Prednizon 5 mg bid

Mitoxantrone 12 mg/m2

q3 hft

+ Prednizon 5 mg bid

R

A

N

D

O

M

Ġ

Z

A

S

Y

O

N

Docetaxel 30 mg/m2 hft

5 of 6 hft

+ Prednizon 5 mg bid

n=1.006

Tannock IF. N Engl J Med 2004;351:1502-1512.

TAX-327

M

(n=337)

TAX qw

(n=334)

TAX q3w

(n=335)p Value

PSA % 32 48 45 0.001

Ağrı kontrolü % 22 31 35 0.01

QoL % 13 23 22 0.009

TAX-327 Sürvi

Median

survival Hazard

(mos) ratio p-value

Combined: 18.2 0.83 0.03

D 3 wkly: 18.9 0.76 0.009

Mitoxantrone 16.4 – –

Pro

bab

ilit

y o

f S

urv

ivin

g

0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Mitoxantrone

Months

R

A

N

D

O

M

I

Z

A

T

I

O

N

SWOG 9916

n=770 patients

KD Pca

Mitoxantrone 12 mg/m2 d1

+ Prednisone 5 mg bid

d1-21 q3 weekly

Docetaxel 60 mg/m2 d2

+ Estramustine 280 mg tid

d1-5 q3 weekly

Petrylak DP. N Engl J Med 2004;351:1513-1520.

TAX-327 - SWOG 9916 Docetaxel x 3 hft

• ĠLK KEZ SAĞKALIM UZAMASI

–Ort. Sağkalım 2,5 ay

• QoL–Ağrı yanıtı

• PSA yanıtı

Tannock IF. N Engl J Med 2004;351:1502-1512.

Petrylak DP. N Engl J Med 2004;351:1513-1520.

BUGÜN

SÜRVĠ

STANDART KEMOTERAPĠ

Docetaxel 75 mg/m2 q3 hft + Prednizon 5 mg bid

BUGÜNBisfosfonatlar

• Osteoclast-mediated kemik rezorpsiyon inhibitörü

• Zoledronic asit– Prostat kanserinde etkinliği gösterilen ilk ajan

Zoledronic Asit

RANDOMIZED

placebo q 3 wk

+ daily oral vitamin D 400 IU and calcium 500 mg

zoledronic acid 4 mg q 3 wk

0 15 months

Core analysis

24 months

Final analysis

n=214

n= 208

zoledronic acid 8 mg q 3 wkn=221

Zoledronic asitĠskelet Sistemi Komplikasyonları

33

44

0

10

20

30

40

50

60

Zoledronic acid 4 mg (n=214) Placebo (n=208)

Perc

en

t o

f p

ati

en

ts

p=0.021

Saad F. J Natl Cancer Inst 2004;96(11):879-882.

Zoledronic asitĠskelet Sistemi Komplikasyonları OluĢma Zamanı

n n n n n n n

Zol 4 mg 214 149 97 70 47 35 3Placebo 298 128 78 44 32 20 3

Saad F. J Natl Cancer Inst 2004 96(11):879-882.

0

20

40

60

80

100

0 120 240 360 480 600 720Days

Pe

rce

nt

of

pa

tie

nts

wit

ho

ut

ev

en

t

Median, days p value

Zoledr. 4 mg 488 .009Placebo 321

BUGÜN

SÜRVĠ

STANDART KEMOTERAPĠ

Docetaxel 75 mg/m2 q3 hft + Prednizon 5 mg bid

+

Kemik metastazları (+)----- Zoledronic asit

YARIN

• Post-Docetaxel

• Pre-Docetaxel

• Docetaxel ile kombine

• Alternatif daha etkin

YARIN

–Abiraterone

–MDV3100

–Cabazitaxel

–Satraplatin

–Sipuleucel-T (Provenge)

–Radium-223

–Bone targeted therapy – Denosumab

SAĞKALIM AVANTAJI

Abiraterone

• Androjen biyosentez inhibitörü–cytochrome P450 – CYP-17 enzim

• Testesteron ve estrodiol sentezini bloke

COU-AA-301

Abiraterone 1000 mg daily

Prednisone 5 mg BID

N=797

Primary end point:

• OS (25% improvement; HR

0.8; 12 mo vs 15 mo)

Secondary end points (ITT):

• TTPP

• rPFS

• PSA response

• QoL (FACT-P, EORTC-QLQ-C30)

Efficacy endpoints (ITT)

Placebo daily

Prednisone 5 mg BID

n=398

RANDOMIZED

2:1

• 1195 patients with

progressive, mCRPC

• Failed 1 or

2 chemotherapies,

one of which

contained docetaxel

Patients

de Bono et al. NEJM 2011 May;364:1995-2005.

Ġnterim analiz

OS (p< 0.0001)

Plasebo kolu iptal

COU-AA-301

ESMO October 2010

OS (ESMO 2010)

HR = 0.646 (0.54-0.77) P < 0.0001

Placebo:

10.9 months (95%CI: 10.2, 12.0)

0 100 200 300 400 500 600 700

0

20

40

60

80

100

Su

rviv

al (%

)

Days from Randomization

Abiraterone acetate:

14.8 months (95%CI: 14.1, 15.4)

2 Prior Chemo OS: 1 Prior Chemo OS

14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo

ASCO 2011

• Takip = 20.2 ay

• Median OS (Abst. 4517)– 15.8 vs 11.2 (4.6 ay)

– p0.0001

• Palyasyon (Abst. 4520)– % 44.4 vs. %27

– p=0.0002

MDV3100

• Potent androgen receptör antagonisti

– DHT --x– AR

– Nüklear translokasyonu

– DNA bağlanmasını

Scher et al. Lancet, 2010 April;375:1437-1446.

Phase II Results

Faz III AFFIRM

Hastalar

• mCRPCa

• Failed 1 or 2 prior chemo-therapies, one of which was docetaxel

• n=1680

RANDOMIZED

2:1

MDV3100 160 mg p.o. qd

+

Prednisone

Placebo

+

Prednisone

Efficacy

Endpoints

• Overall survival

Faz III AFFIRM

• Kapandı

• Sonuçlar

Cabazitaxel

• Taxane

• Tubulin bağlanma

• Docetaxel rezistant tumors

• FDA 2010

Faz III TROPIC

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)

Docetaxel altında progresyon

(N=755)

de Bono et al. Lancet 2010 October;376:1147-1154.

TROPIC

Mitoxantrone Cabazitaxel p Value

OS 12.7m 15.1m 0.0001

PSA %17.8 %39.2 0.0002

Ağrı % 7.7 %9.2 0.63

OS

Proportionof OS (%)

80

60

40

20

0

100

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

15.112.7Median OS (months)

0.59–0.8395% CI

<.0001P-value

0.70Hazard Ratio

CBZPMP

Satraplatin

• Oral 3. jenerasyon sisplatin

• SPARC –Plasebo kontrollü, double-blind

–n=950

–Satraplatin + prednizon vs prednizon

–PFS • 11 vs 9.7 hft (p<0.05)

–OS farklı değil• 61.3 vs 61.4 hft

Sipuleucel-T (Provenge)

• Hücresel ümminite

• “Kanser aĢısı”– Otolog PBMC (APC)

– APC (bir protein (PA2024) ile aktive)

– PA2024

• Prostate antigen

• Prostatic asit fosfataz

• GMCSF (immün hücre aktivatörü)

– Lökoferez ve infuzyon

Sipuleucel-T

• I-– RCT, plasebo-kontrollü, double-blind

– n = 127

– OS p = 0.01 • Small et al. JCO 2006;24:3089-94

• II-– RCT, plasebo-kontrollü

– n = 98

– sürvi • Higano et al. Cancer 2009;115:3670-9

Faz III IMPACT

• RCT

• double-blind

• plasebo-kontrollü

• n = 512

IMPACT

Sipuleucel-T Plasebo p Value

OS 25.8 ay 21.7 ay 0.03

PSA Yanıtı %2.6 %1.3 NS

IMPACTOS (NEJM 2010)

Radium-223

• Radiofarmasötik (alfa)

• Faz II n=64–Radium-223 vs plasebo

–OS= 65 vs 46 hft

• Faz III ALSYMPCA– Interim analiz: sağkalım avantajı

Denosumab

• Ġnsan monoklonal antikor

• RANK ligand– Osteoclast formasyon ve fonksiyonunda bir

mediatör

Denosumab

• Phase III RCT

• plasebo-kontrollü

• double-blind

• n = 1901

Fizazi et al. Lancet 2011 March;377:813-822.

Sonuçlar

DenosumabZoledronic

Acidp Value

n 950 951

Ġlk SRE20.7m

(18.8-24.9)

17.1m

(15.0-19.4)

0.0002 Inferiority

0.0008 Superiority

SRE sayısı 341 (%36) 386 (%41)

Rx 177 (%19) 203 (%21)

Patolojik Kırık 137 (%14) 143 (%15)

Spinal Cord Kompresyonu

26 (%3) 36 (%4)

Operasyon 1 ( %1) 4 ( %1)

ÖZET• Pre-2004

– Mitoxantrone+Prednizon

– Antiandrojen withdrawal

• 2004-2011– Docetaxel +/- Zoledronic asit

• 2011-2012– Abiraterone

– MDV3100

– Cabazitaxel

– Sipuleucel-T

– Denosumab

• GELECEK– YENĠ YAKLAġIMLAR

– YENĠ ĠLAÇLAR

YENĠ YAKLAġIMLAR

• Pre-Docetaxel

–Abiraterone

–MDV3100

• Docetaxel yerine

–Docetaxel vs Cabazitaxel

GELECEK

• Pre-Kemoterapi– Ipilimumab (CTLA4)

– Orteronel (TAK-700), (AR)

– Tasquinimod (angiogenesis)

– PROSTVAC (poxiviral vaccine)

– EMD525797 (integrin inhibitor)

• + Kemoterapi– Docetaxel Lenalidomide (immunovaccine)

– Docetaxel OGX-011 (apoptosis)

– Docetaxel Zibotentan (Endothelin-A Receptor Antagonist)

• Post-Kemoterapi– Orteronel

– Ipilimumab

GELECEK

• HEDEFE YÖNELĠK TEDAVĠLER

B: Bevacizumab

I: Imatinib

A: Atrasentan

Z: Zoledronic Acid

L: Lapatinib

R: Rapamycin

S: Satraplatin

Tax: Docetaxel

VDR: Vit D Receptor

AR: Androgen Receptor

H/n: HER2/neu receptor

OB: osteoblast

OC: osteoclast

ETA: Endothelin A Receptor

MT: Microtubules

Mendiratta, Armstrong et al. Rev Urol;9 Suppl 1: S9-S19, 2007

Atrasentan

Endothelin A

receptorProstate

Kanser Hücresi

Büyüme+ atrasentan

endothelin

ASCO 2011

• Cabozantinib (Abstract 4516)

–TKI (MET ve VEGFR)

–Faz II

• % 75 kemik sintigrafisinde düzelme

• % 67 ağrı

Docetaxel KombineFaz III

• DN101 (Yükek doz Vitamin D)

Scher et al. J Clin Oncol 2011 June;29:2191-2198

• Bevacizumab

Kelley et al. ASCO 2010 (Abstract 4511)

• Sunitinib

ASCO 2011 (Abstract 4515)

• Risedronate

ASCO 2011 (Abstract 4518)

DEVAM EDEN FAZ-III ÇALIġMALAR

2010

2011