1 / 38

SOGUG meeting New drugs after docetaxel chemotherapy in patient with mCRPC

SOGUG meeting New drugs after docetaxel chemotherapy in patient with mCRPC. Stéphane OUDARD, MD, PhD Head of the Oncology department Georges Pompidou Hospital, Paris France University Rene Descartes, Paris 5. Currently available secondary hormonal manipulations in CRPC: marginal benefit.

pepper
Download Presentation

SOGUG meeting New drugs after docetaxel chemotherapy in patient with mCRPC

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. SOGUG meetingNew drugs after docetaxel chemotherapy in patient with mCRPC Stéphane OUDARD, MD, PhD Head of the Oncology department Georges Pompidou Hospital, Paris France University Rene Descartes, Paris 5

  2. Currently available secondary hormonal manipulations in CRPC: marginal benefit Rationale: elevated intratumor androgenlevels despite castrate serum levels Includes androgen withdrawal, adrenal testosterone inhibitors, low doses DES, corticosteroids, somatostatin analogues Marginal benefit: PSA response in 10-60% of cases Short duration (< 4-6 months)

  3. Currently available secondary hormonal manipulations in CRPC: marginal benefit

  4. Advanced prostate cancer management Metastatic hormone-sensitiveprostate cancer Metastatic castration-resistant 1st line LHRH analogues DOCETAXELTAXOTERE® Antiandrogens LHRH antagonist Survival benefit vs Mitoxantrone 2004

  5. Metastatic CRPC - First line therapy Docetaxel 75 mg/m2 every 3 weeksis the standard of carein first-linemetastatic CRPC 1Heidenreich A, et al. (2010 update) www.uroweb.org 2Mohler J, et al. (2009 update) www.nccn.org 3Basch EM, et al. J Clin Oncol 2007;25:1–64Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76–8

  6. Cancer progressionduring or after DocetaxelWhat are the options?

  7. Advanced prostate cancer management Metastatic hormone-sensitiveprostate cancer Metastatic castration-resistant 1st line Metastatic Castration-resistant 2nd line UNMETMEDICAL NEED LHRH analogues DOCETAXELTAXOTERE® Antiandrogens LHRH antagonist Survival benefit vs Mitoxantrone 2004

  8. No agent currently approved in patients progressing after Docetaxel Currently available options provide palliation only Retreatment with Docetaxel: Small retrospective studies1-5 In selected patients: good initial responders(PSA decrease ≥ 50%) Effect on PSA seems to decrease with rechallenge5 Progression after Docetaxel: 1Eymard JC, Oudard S et al. BJU Int 2010, 2Ansari et al. Oncol reports 2008; 20: 891-896 3Beer TM et al. Cancer. 2008, 112:326-30 ;4Garmey EG et al, Clin Adv Hematol Oncol. 2008; 6(2):118-1132; 5Gernone et al. EAU 2010 (abstract 896)

  9. Cabazitaxel (Jevtana®): a next generation taxane Both extracted from needles of the European Yew treeTaxus baccata Y X O Y X Docetaxel -OH -OCCH3 Cabazitaxel -OCH3 -OCH3 99th AACR annual meeting, San Diego, April 2008 (abstract #3227)

  10. Cabazitaxel (Jevtana®): selected to overcome taxane resistance Some patients do not answer to Docetaxel (acquired or constitutional resistance). This may be due to various mechanisms: affinity for multidrug resistant (MDR) membrane-associated P-glycoprotein (PgP) efflux pump, alterations of tubulin, overexpression Bcl-2, Aurora-A … Cabazitaxel: Poor affinity for the PgP efflux pump greater penetration of the blood brain barrier compared with docetaxel and paclitaxel Active in vitro and in vivo on tumors resistant to Docetaxel H R Taxane • Docetaxel and paclitaxel have a strong affinity for the PgP pump • If the PgP pump is overexpressed, it drives drug out of tumor cell Mita AC et al, Clin Cancer Res. 2009, 15, 723-730

  11. Cabazitaxel: A next-generation taxane • Preclinical data • Activity against tumor cells and tumor models that are resistant to, or not sensitive tocurrently available taxanes¹,² • As potent as docetaxel against sensitive cell lines and tumor models¹,² • Phase I studies • Dose-limiting toxicity was neutropenia • Antitumor activity in mCRPC including docetaxel-resistant disease3 ¹Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84.²Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552. 3Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.

  12. De Bono J et al. Lancet, 2010, 376:1147-54

  13. TROPIC: Phase III registration study 146 Sites in 26 Countries mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease 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) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint:Overall Survival Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression De Bono J et al. Lancet, 2010, 376:1147-54

  14. Patient characteristics ECOG PS: ECOG performance status; PSA: Prostate-specific antigen. Population with a very advanced disease De Bono J et al. Lancet, 2010, 376:1147-54

  15. TROPIC trial: Pre-protocol treatments A heavily pretreated population who progressedrapidly after first line docetaxel De Bono J et al. Lancet, 2010, 376:1147-54

  16. TROPIC Trial: overall survival (Primary endpoint) 100 80 60 40 Censored MP 20 CBZP Combined medianfollow-up: 13.7 months 0 0 6 12 18 24 30 Numberat Risk MP CBZP Proportion of OS (%) Time (months) 377 378 299 321 195 241 94 137 31 60 9 19 28% reduction in the risk of death De Bono J et al. Lancet, 2010, 376:1147-54

  17. TROPIC Trial: Progression-free survival 100 80 60 40 Censored MP 20 CBZP Combined medianfollow-up: 13.7 months 0 0 3 6 9 12 15 18 21 Time (months) Numberat Risk MP CBZP PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death. Proportion of PFS (%) 377 378 117 168 55 92 30 55 12 18 9 6 6 1 4 1 25% reduction in risk of progression De Bono J et al. Lancet, 2010, 376:1147-54 17

  18. TROPIC Trial: Response rate and time to progression MP (n=377) CBZP (n=378) Hazard ratio(95% CI) P-value Tumor assessment Response rate* (%) 4.4 14.4 – 0.0005 Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <0.0001 PSA assessment Response rate* (%) 17.8 39.2 – 0.0002 Median TTP (months) 3.1 6.4 0.75 (0.63–0.90) 0.001 Pain response rate (N patients) (168) (174) Response rate (%) 7.7 9.2 0.91(0.69-1.19) 0.63 TTP: time to progression ; *50% decrease or more in PSA De Bono J et al. Lancet, 2010, 376:1147-54 18

  19. Treatment exposure on study drug *as percentage of total number of treatment cycles An excellent dose intensitywith few dose reductions or treatment delays De Bono J et al. Lancet, 2010, 376:1147-54

  20. Most Frequent Treatment-EmergentAdverse Events* *Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm. Low rate of grade 3-4 peripheral neuropathy (1% in each group) De Bono J et al. Lancet, 2010, 376:1147-54 20

  21. Comparison of Cabazitaxel and docetaxeland mitoxantrone hematotoxicity according to the line of treatment Tax327 study: docetaxel and mitoxantrone given in first-line setting Tropic study: cabazitaxel and mitoxantrone given in second-line setting

  22. TROPIC Trial: Fatal Events 22

  23. Conclusion on Cabazitaxel study Cabazitaxel demonstrated a statistically and clinically significant survival improvement compared with mitoxantrone in study population 15.1 months vs 12.7 months 28% reduced risk of death (HR=0.72, P <.0001) Survival benefit consistent across subgroups Secondary endpoints of PFS, RR, and TTP also significantly improved Safety profile was manageable Proactive management of side effects recommended (neutropenia/diarrhea) Cabazitaxel is the first treatment to show a survival benefit in patients with mCRPC after failure of docetaxel-based therapy 23

  24. Cabazitaxel: Further development Which dose of cabazitaxel to use 25 or 20 mg/m2? Is cabazitaxel as effective as docetaxel in first-line setting? Is cabazitaxel more or less hematotoxic than docetaxel? Will cabazitaxel be evaluated in early stages? 24

  25. Castration-resistant prostate cancer New agents in development Pre-Docetaxel Docetaxel Post-Docetaxel • Cabazitaxel • Abiraterone • MDV3100 • TAK-700 • Sunitinib • Ipilimumab

  26. Abiraterone: oral & irreversible inhibitionof CYP17 Low-dose steroid replacement decreases ACTHand minimizes mineralocorticoid-related toxicity Cholesterol Desmolase Pregnenolone Progesterone Deoxy-corticosterone Corticosterone Aldosterone CYP1717αhydroxilase 17α-OH-Pregnenolone ACTH x6reducedby low-dosesteroids 17α-OH-Progesterone 17-Deoxy-corticol Cortisol CYP17C17, 20-lyase 5α-reductase DHEA Androstenedione Testosterone DHT CYP19: aromatase Estradiol Inhibits testosterone productionin testis, adrenal glands and prostate Attard et al. J. Clin. Oncol. 2008, 26: 4563-71

  27. Abiraterone in second-line metastatic CRPC – COU-AA-301 study R A N D O M I Z E 2:1 Abiraterone: 1000 mg daily Prednisone 5 mg BIGn=797 Patients Progressive mCRPC Failed 1 or 2 chemoregimen, including 1 with docetaxel Placebo daily Prednisone 5 mg BIGn=797 • Stratification factors: • ECOG PS [0-1 versus 2] • Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs 4-10 [present] • Prior chemotherapy[1 vs 2] • Type of progression [PSA onlyvs radiographic progression] 147 sites in 13 countries(US, Europe, Australia, Canada) Primary endpoint: Overall SurvivalSecondary end points: TTPP, rPFS, PSA response De Bono J et al. ESMO 2010

  28. Comparison of Cabazitaxel and Abiraterone phase III studies in mCRPC

  29. MDV3100: an improved AR antagonist? Higher affinity for the androgen receptor than bicalutamide Prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex Induces tumour cell apoptosis No AR agonist activity in castrate-resistant setting Induces tumour responses in CRPC patients who have failed other hormone therapies AR: Antiandrogen Receptor Tran C, et al. Science2009;324:787–90

  30. MDV 3100 Phase I-II study PSA response Chemotherapy-Naïve (n=65) Post-Chemotherapy (n=75) PSA Change from Baseline 62% (40/65) >50% Decline 51% (38/75) >50% Decline Scher HI, et al. Lancet [published on-line april 2010]

  31. MDV3100 (AFFIRM) - phase III studypost-docetaxel R A N D O M I Z E MDV3100.- 160 mg QD (n=780) mCRPCafter up to 2 lines chemo, 1 withdocetaxel Placebo QD (n=390) 2:1 N=1170 Primary end point: overall survival *ClinicalTrials.gov identifier: NCT00974311

  32. Other antiandrogens in development • TAK-700 (Orteronel) (phase III post-docetaxel) • TOK-001, CYP17 inhibitor (phase I/II) • SARDS • ARN-509 (phase II) • HDAC Inhibitors • Steroid sulfatase inhibitors • Co-factor antagonists

  33. Conclusion • Management of CRPC is rapidly evolving • Clinical trial data with abiraterone and MDV-3100 confirm continued AR addiction in patients with mCRPC • Highlights continued importance of the AR axis, even in advanced disease • Docetaxel is the standard in first-line mCRPC • Progression after Docetaxel is no more an unmet need: • Cabazitaxel shows a significant survival advantagecompared to the active agent mitoxantrone/prednisone • Abiraterone also provides survival advantage versus placebo • The most appropriate sequencing of Abiraterone and Cabazitaxel remains to be determined

More Related