Nieuwe Ontwikkelingen in de Behandeling van Prostaatkanker
Prostaatkanker = chronische ziekte Radiotherapie Prostatectomie
Hormonen
Prostaatkanker = chronische ziekte Stijgend PSA: diagnostiek: MRI, PET-choline prostaat: prostatectomie radiotherapie lymfklieren: radiotherapie medicijnen
Metastatic Disease and Castrate Resistence Pre-chemo
1 st line chemo
2nd line treatment
Testosteron
2nd line treatment of CRPC
Prof. Johann de Bono The story of perseverance and of serendipity
Cholesterol Cyp11A
Pregnenolone
Cyp17
Cyp17
17α α-hydroxypregnenolone
Progesterone
Cyp17 Cyp17
17α-hydroxyprogesterone
DHEA
Cyp17/HSD3β2
Androstenedione
CYP17: an important enzyme
17βHSD
Testosterone CYP3A4/3A5
SRD5A2 SRD5A1
CYP1B1
Testosterone breakdown
DHT AR
AAG
COU-AA-301: Overall Survival 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
0 0
100
200
300
400
500
600
700
Days from Randomization
de Bono et al, ESMO abstract LBA5, 2010 Slide adapted of J. de Bono
Bijwerkingen abiraterone » » » » » »
Hoge bloeddruk Vasthouden van vocht Laag kalium Vermoeidheid Misselijkheid Leverschade
Abiteraterone (na chemotherapie) 16/34 (47%) pts ≥50% PSA daling 22/34 (65%) pts ≥30% PSA daling
PSA is geen maat voor overleving !!!!! geregistreerd maar nog niet vergoed Reid et al., JCO 2010 28:1489-95
3 nov 2011: MDV3100 geeft 4.8 maanden verlenging in overleving
Cabazitaxel
www.oncology.sanofi-aventis.com
Cabazitaxel: Improving Tubulin Targeting
1Aller
docetaxel
cabazitaxel
Microtubules stabilization1
+++
+++
Activity in docetaxel sensitive tumors2
+++
+++
Activity in docetaxel-resistant tumors1,3,4
–
+++
Brain penetration5,6
–
+++
AW et al. Proc Am Assoc Cancer Res. 2000;41:1923; 2Vrignaude P et al. Proc Am Assoc Cancer Res. 2000;41:214; 3Bissery MC. Curr Pharm Des. 2001;7:1251-1257; 4Bissery MC et al. Proc Am Assoc Cancer Res. 2000; abstract 1364; 5Cisternino S et al. Br J Pharmacol. 2003;138:1367-1375; 6Dykes DJ et al. Proc Am Assoc Cancer Res. 2000;41:301.
Primary endpoint: overall survival 30% reduction in the relative risk of death 100
Proportion of OS (%)
Median OS (months) Hazard ratio
80
MP
CBZP
12.7
15.1 0.70
95% CI
0.59–0.83
P value
<0.0001
60 Cabazitaxel Mitoxantrone 40
28% 20
17% 0 0 Number at risk
MP CBZP
377 378
6
12
18
24
30
300 321
188 231
67 90
11 28
1 4
Time (months)
OS, overall survival; CBZP, cabazitaxel+prednisone; MP, mitoxantrone+prednisone
De Bono J, et al. Lancet 2010;376:1147–54
Bijwerkingen cabazitaxel • Koorts bij laag aantal witte bloedcellen • Diarree • Vermoeidheid • Misselijkheid
Alpharadin
Immunotherapie (versterking afweer tegen kanker)
T-lymfocyte
Dendritische cel
Provenge (dendritische cel therapie)
Recombinant Prostatic Acid Phosphatase (PAP) antigen combines with resting antigen presenting cell (APC)
APC takes up the antigen
Antigen is processed and presented on surface of the APC
Fully activated, the APC is now sipuleucelT INFUSE PATIENT
Active Tcell
T-cells proliferate and attack cancer cells
The precise mechanism of sipuleucel-T in prostate cancer has not been established.
Sipuleucel-T activates T-cells in the body
Inactive T-cell
Sipuleucel-T (Provenge®) Manufacturing Process Day 1
Day 2-3
Day 3-4
Leukapheresis
Sipuleucel-T is manufactured
Patient is infused
Apheresis Center
Dendreon
Doctor’s Office
COMPLETE COURSE OF THERAPY: 3 CYCLES
Kaplan– Kaplan–Meier Estimates of Overall Survival.
Kantoff PW et al. N Engl J Med 2010;363:411-422.
Beurskoers Dendreon
Ipilimumab (MDX-010)
• anti-human CTLA-4 Antibody
• blocks the binding of CTLA-4 to B7
• fully human IgG1k antibody
• does not mediate ADCC
Klinische resultaten PSA responses 6/28 pts; Radiologic responses 2/24 (PR), 11/24 (SD) 100
ac tual survival predic ted survival
Percent survival
75 Med.surv. 31.8 mths; 20 dead, 8 alive
50
25 Med.pred.surv. 19 mths p=0.0099
0 0
10
20
30
40
months
50
60
70
Antistoffen
Serological analysis: autoantibodies
PNPO
NRP2
PSMA
NRP2 antibody induction after prostate GVAX T cell response associated with disease No PNPO seroconversion observed after monotherapy is associated with prolonged survival. stabilization and decrease in serum PSA. prostate GVAX monotherapy. Murphy et al, Tjoa et al Prostate 1999 and 2007. Harding et al. US patent 20100150946 Harding et al, Unpublished data
100
three two one none
Percent survival
N=8; m ed. survival 57 m ths 75
N=4; m ed. survival 37.5 m ths
50
25
N=8; m ed. survival 22.5 m ths N=8; m ed. survival 19.5 m ths
p = 0.028
0 0
10
20
30
40
50
60
70
months
Patients that demonstrate increased seroreactivity againts PSMA, PNPO and NRP2 survive significantly longer
Spin-off Fase III studie: Ipilimumab voor chemotherapie Fase III studie: Ipilimumab na chemotherapie
New Drugs Fight Prostate Cancer, but at High Cost By ANDREW POLLACK
Published: June 27, 2011 Provenge:
$ 90.000 per treatment
Docetaxel:
$ 30.000 per treatment (N=6)
Carbazitaxel:
$ 32.000 per treatment (N=4)
Abiraterone:
$ 25.000 per treatment $ 177.000 per patient
Ipilimumab:
$ 90.000 per treatment
XL-184 Denosumab
Innovatieve benaderingen
1928: scissor technique
1968: (David) Flosbury flop
• Dank U allen voor deelname aan studies ! • Toegang tot nieuwe geneesmiddelen voor alle patiënten! • Snelle toegang tot nieuwe geneesmiddelen!
