Docetaxel
Transkript
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) – p0.0001 • 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