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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