Nieuwe Ontwikkelingen in de Behandeling van Prostaatkanker

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1 Nieuwe Ontwikkelingen in de Behandeling van Prostaatkanker

2 Prostaatkanker = chronische ziekte Radiotherapie Prostatectomie Hormonen

3 Prostaatkanker = chronische ziekte Stijgend PSA: diagnostiek: MRI, PET-choline prostaat: prostatectomie radiotherapie lymfklieren: radiotherapie medicijnen

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5 Metastatic Disease and Castrate Resistence Pre-chemo 1 st line chemo 2nd line treatment

6 Testosteron

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8 2 nd line treatment of CRPC Prof. Johann de Bono The story of perseverance and of serendipity

9 Cholesterol Cyp11A Pregnenolone Cyp17 Cyp17 Progesterone Cyp17 17α-hydroxyprogesterone 17α-hydroxypregnenolone Cyp17 DHEA Cyp17/HSD3β2 Androstenedione 17βHSD CYP17: an important enzyme Testosterone CYP3A4/3A5 SRD5A2 SRD5A1 CYP1B1 Testosterone breakdown AR DHT AAG

10 COU-AA-301: Overall Survival HR = ( ) P < Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) Survival (%) Placebo: 10.9 months (95%CI: 10.2, 12.0) Days from Randomization de Bono et al, ESMO abstract LBA5, 2010 Slide adapted of J. de Bono

11 Bijwerkingen abiraterone» Hoge bloeddruk» Vasthouden van vocht» Laag kalium» Vermoeidheid» Misselijkheid» Leverschade

12 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 :

13 3 nov 2011: MDV3100 geeft 4.8 maanden verlenging in overleving

14 Cabazitaxel

15 Cabazitaxel: Improving Tubulin Targeting docetaxel cabazitaxel Microtubules stabilization Activity in docetaxel sensitive tumors Activity in docetaxel-resistant tumors 1,3,4 +++ Brain penetration 5, Aller AW et al. Proc Am Assoc Cancer Res. 2000;41:1923; 2 Vrignaude P et al. Proc Am Assoc Cancer Res. 2000;41:214; 3 Bissery MC. Curr Pharm Des. 2001;7: ; 4 Bissery MC et al. Proc Am Assoc Cancer Res. 2000; abstract 1364; 5 Cisternino S et al. Br J Pharmacol. 2003;138: ; 6 Dykes DJ et al. Proc Am Assoc Cancer Res. 2000;41:301.

16 Primary endpoint: overall survival 30% reduction in the relative risk of death Proportion of OS (%) MP CBZP Median OS (months) Hazard ratio % CI P value < Cabazitaxel Mitoxantrone 28% 0 17% Time (months) Number at risk MP CBZP OS, overall survival; CBZP, cabazitaxel+prednisone; MP, mitoxantrone+prednisone De Bono J, et al. Lancet 2010;376:

17 Bijwerkingen cabazitaxel Koorts bij laag aantal witte bloedcellen Diarree Vermoeidheid Misselijkheid

18 Alpharadin

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21 Immunotherapie (versterking afweer tegen kanker) T-lymfocyte Dendritische cel

22 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 sipuleucel- T INFUSE PATIENT Active T- cell Inactive T-cell T-cells proliferate and attack cancer cells Sipuleucel-T activates T-cells in the body The precise mechanism of sipuleucel-t in prostate cancer has not been established.

23 Sipuleucel-T (Provenge ) Manufacturing Process Day 1 Leukapheresis Day 2-3 Sipuleucel-T is manufactured Day 3-4 Patient is infused Apheresis Center Dendreon Doctor s Office COMPLETE COURSE OF THERAPY: 3 CYCLES

24 Kaplan Meier Estimates of Overall Survival. Kantoff PW et al. N Engl J Med 2010;363:

25 Beurskoers Dendreon

26 Ipilimumab (MDX-010) anti-human CTLA-4 Antibody fully human IgG1k antibody blocks the binding of CTLA-4 to B7 does not mediate ADCC

27 Klinische resultaten PSA responses 6/28 pts; Radiologic responses 2/24 (PR), 11/24 (SD) 100 ac tual survival predic ted survival Percent survival Med.pred.surv. 19 mths Med.surv mths; 20 dead, 8 alive p= months

28 Antistoffen

29 Serological analysis: autoantibodies PSMA T cell response associated with disease stabilization and decrease in serum PSA. Murphy et al, Tjoa et al Prostate 1999 and NRP2 NRP2 antibody induction after prostate GVAX monotherapy is associated with prolonged survival. Harding et al. US patent PNPO No PNPO seroconversion observed after prostate GVAX monotherapy. Harding et al, Unpublished data Percent survival N=8; m ed. survival 57 m ths N=4; m ed. survival 37.5 m ths three two one none N=8; m ed. survival 22.5 m ths N=8; m ed. survival 19.5 m ths p = months Patients that demonstrate increased seroreactivity againts PSMA, PNPO and NRP2 survive significantly longer

30 Spin-off Fase III studie: Ipilimumab voor chemotherapie Fase III studie: Ipilimumab na chemotherapie

31 New Drugs Fight Prostate Cancer, but at High Cost By ANDREW POLLACK Published: June 27, 2011 Provenge: Docetaxel: Carbazitaxel: Abiraterone: $ per treatment $ per treatment (N=6) $ per treatment (N=4) $ per treatment $ per patient Ipilimumab: $ per treatment XL-184 Denosumab

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33 Innovatieve benaderingen 1928: scissor technique 1968: (David) Flosbury flop

34 Dank U allen voor deelname aan studies! Toegang tot nieuwe geneesmiddelen voor alle patiënten! Snelle toegang tot nieuwe geneesmiddelen!