Docetaxel

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
KDPCa
PSA
METASTAZLAR
•BAġARISIZ
KÜRATĠF Tx
•METASTATĠK
HASTALIK
HORMONAL
TEDAVĠ
BĠOKĠMYASAL
MORTALĠTE
ASEMPRTOMATĠK
SEMPTOMATĠK
Mo
24+ AY
M+
M+
12-36 AY
6-24 AY
TANIM
• HT
–
–
–
–
LHRH agonistleri
LHRH antagonisti
OrĢiektomi
 Nonsteroidal antiandrojenler
• T ------AR signalling devam
Androjen Rezistans
AR Signalling
Scher, H. I. et al. J Clin Oncol; 23:8253-8261 2005
Copyright © American Society of Clinical Oncology
TANIM
AR 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
DÜN
Mitoxantrone - Prednizon
P
(n=81)
M+P
(n=80)
p Value
Palyatif yanıt
12%
29%
0.01
Yanıt süresi
18 wks
43 wks
 0.0001
22%
33%
0.11
 10.3m
 10.3m
0.27
PSA ( %50 )
Sürvi
GEÇMĠġTE STANDART
BUGÜN
SÜRVĠ
• Docetaxel
–Ġlk sağkalım avantajı gösterilen
• Bisfosfonatlar
–Zoledronic Asit
Docetaxel
•
TAX 327
Tannock et al. N Eng J Med 2004;351:1502-1512
•
SWOG
Petrylak et al. N Eng J Med 2004;351:1513-1520
TAX-327
n=1.006
R
A
N
D
O
M
Ġ
Z
A
S
Y
O
N
Docetaxel 75 mg/m2 q3 hft
+ Prednizon 5 mg bid
Docetaxel 30 mg/m2 hft
5 of 6 hft
+ Prednizon 5 mg bid
Mitoxantrone 12 mg/m2
q3 hft
+ Prednizon 5 mg bid
Tannock IF. N Engl J Med 2004;351:1502-1512.
TAX-327
M
(n=337)
TAX qw
(n=334)
TAX q3w
p Value
(n=335)
PSA %
32
48
45
 0.001
Ağrı kontrolü %
22
31
35
0.01
QoL %
13
23
22
0.009
TAX-327
Sürvi
1.0
Docetaxel 3 wkly
Mitoxantrone
Probability of Surviving
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Combined:
D 3 wkly:
Mitoxantrone
0.2
0.1
Median
survival
(mos)
18.2
18.9
16.4
Hazard
ratio
0.83
0.76
–
p-value
0.03
0.009
–
0.0
0
6
12
18
Months
24
30
SWOG 9916
KD Pca
R
A
N
D
O
M
I
Z
A
T
I
O
N
Docetaxel 60 mg/m2 d2
+ Estramustine 280 mg tid
d1-5 q3 weekly
Mitoxantrone 12 mg/m2 d1
+ Prednisone 5 mg bid
d1-21 q3 weekly
n=770 patients
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
BUGÜN
Bisfosfonatlar
• Osteoclast-mediated kemik rezorpsiyon
inhibitörü
• Zoledronic asit
– Prostat kanserinde etkinliği gösterilen ilk ajan
Zoledronic Asit
R
A
N
D
O
M
I
Z
E
D
n=214
zoledronic acid 4 mg q 3 wk
n=221
zoledronic acid 8 mg q 3 wk
n= 208
placebo q 3 wk
+ daily oral vitamin D 400 IU and calcium 500 mg
0
15 months
Core analysis
24 months
Final analysis
Zoledronic asit
Ġskelet Sistemi Komplikasyonları
p=0.021
60
Percent of patients
44
50
40
33
30
20
10
0
Zoledronic acid 4 mg (n=214)
Placebo (n=208)
Saad F. J Natl Cancer Inst 2004;96(11):879-882.
Zoledronic asit
Percent of patients without event
Ġskelet Sistemi Komplikasyonları OluĢma Zamanı
100
80
60
40
Median, days p value
Zoledr. 4 mg
488
.009
Placebo
321
20
0
0
120
240
360
480
600
720
Days
Zol 4 mg
Placebo
n
n
n
n
n
n
n
214
298
149
128
97
78
70
44
47
32
35
20
3
3
Saad F. J Natl Cancer Inst 2004 96(11):879-882.
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
Patients
• 1195 patients with
progressive, mCRPC
• Failed 1 or
2 chemotherapies,
one of which
contained docetaxel
R
A
N
D
O
M
I
Z
E
D
2:1
Efficacy endpoints (ITT)
Abiraterone 1000 mg daily
Prednisone 5 mg BID
N=797
Placebo daily
Prednisone 5 mg BID
n=398
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)
de Bono et al. NEJM 2011 May;364:1995-2005.
COU-AA-301
ESMO October 2010
Ġnterim analiz
 OS (p< 0.0001)
Plasebo kolu iptal
OS (ESMO 2010)
HR = 0.646 (0.54-0.77) P < 0.0001
100
Abiraterone acetate:
14.8 months (95%CI: 14.1, 15.4)
Survival (%)
80
60
40
Placebo:
10.9 months (95%CI: 10.2, 12.0)
20
2 Prior Chemo OS:
14.0 mos AA vs 10.3 mos placebo
1 Prior Chemo OS
15.4 mos AA vs 11.5 mos placebo
0
0
100
200
300
400
500
Days from Randomization
600
700
ASCO 2011
• Takip = 20.2 ay
• Median OS (Abst. 4517)
– 15.8 vs 11.2 (4.6 ay)
– p0.0001
• Palyasyon (Abst. 4520)
– % 44.4 vs. %27
– p=0.0002
MDV3100
• Potent androgen receptör antagonisti
– DHT --x– AR
– Nüklear translokasyonu
– DNA bağlanmasını
Phase II Results
Scher et al. Lancet, 2010 April;375:1437-1446.
Faz III AFFIRM
Hastalar
• mCRPCa
• Failed 1 or 2
prior chemotherapies,
one of which
was
docetaxel
• n=1680
R
A
N
D
O
M
I
Z
E
D
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
Docetaxel altında progresyon
(N=755)
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)
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
Proportion 100
of OS (%)
Median OS (months)
Hazard Ratio
80
MP
CBZP
12.7
15.1
0.70
95% CI
0.59–0.83
P-value
<.0001
60
40
20
0
0 months
6 months
12 months
18 months
24 months
30 months
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
OS
PSA Yanıtı
Sipuleucel-T
Plasebo
p Value
25.8 ay
21.7 ay
0.03
%2.6
%1.3
NS
IMPACT
OS
(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
Denosumab
Zoledronic
Acid
950
951
Ġlk SRE
20.7m
(18.8-24.9)
17.1m
(15.0-19.4)
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)
n
p Value
0.0002 Inferiority
0.0008 Superiority
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
Prostate
Kanser Hücresi
Büyüme
Endothelin A
receptor
endothelin
+
atrasentan
ASCO 2011
• Cabozantinib (Abstract 4516)
–TKI (MET ve VEGFR)
–Faz II
• % 75 kemik sintigrafisinde düzelme
• % 67 ağrı
Docetaxel Kombine
Faz 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