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The Evolution of mCRPC in the Last Decade

The Evolution of mCRPC in the Last Decade. July, 2017. Declaração de Conflito de Interesses. De acordo com a Resolução 1595/2000 do Conselho Federal de Medicina e RDC 102/2000 da ANVISA, declaro que: 1. Participo de estudos clínicos patrocinados pelas empresas :

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The Evolution of mCRPC in the Last Decade

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  1. The Evolution of mCRPC in the Last Decade July, 2017

  2. Declaração de Conflito de Interesses De acordo com a Resolução 1595/2000 do Conselho Federal de Medicina e RDC 102/2000 da ANVISA, declaro que: 1. Participo de estudosclínicospatrocinadospelasempresas: GSK, Janssen, Astellas, Bayer 2. Atuocomospeaker de eventos das empresas: Janssen, Astra Zeneca, Ferring, Ache, Bayer, Astellas 3. Participocomomembro do advisory board das empresas: Janssen, Bayer, Astellas 4. Nãopossuoações de quaisquerdestascompanhiasfarmacêuticas.

  3. ÓbitosEstimados CaP - 2015 1,6 min 28 min INCa, 2015 Cancer Statistics 2015

  4. 1996:Mitoxantrona 1985:Leuprolida 40s 50s 60s 70s 80s 90s 00s 2010s Charles Huggins 1989: Flutamide 1981: Agonistas LHRH

  5. < 2004 prostatectomia radioterapia terapia hormonal radioterapia terapia hormonal? suporteclínico oncologia - paliação controleálgico

  6. Câncer de Próstata Metastático < 2004 terapiahormonal Orquiectomia Agonistas LHRH Antagonistas LHRH Anti - androgênicos

  7. Mecanismos de ResistênciaàCastração

  8. Progressão após ADT < 2004 Progressão terapiahormonal Retiradaoutroca do anti-androgênio DES Cetoconazol Corticóides Outros

  9. RespostasClínicas: Manipulação Hormonal de 2ª Linha Q U I M I O T E R A P I A • Retirada de Anti-androgênio15-30% • Bicalutamida 25% • Nilutamida 25% • DES 30-55% • Ketoconazole (+ corticóide) 20-60% • Corticosteroides 20-80% • AcetatoMegestrol15% Duração média de resposta: 2-4 meses. Impacto a longo prazo? Sobrevida?

  10. Câncer de Próstata - Evolução • Doença irá com o tempo tornar-se resistentes à ADT, com subsequente desenvolvimento de metástases a distância e evolução para o óbito (1 a 2 anos). CALGB meta-análise

  11. 1998 Walter Mendes – 65 anos • Dor lombar progressiva associada a hematúria macroscópica; sem avaliação prostática prévia. • PSA 50, FAP >, toque T4, Gleason 5+5, CO superscan • Orquiectomia, artrodese de coluna • Boa resposta inicial, com posterior progressão – flutamida • Piora clínica, dor importante • Óbito em 2000

  12. 1996:Mitoxantrona 1985:Leuprolida 40s 50s 60s 70s 80s 90s 00s 2010s Charles Huggins 1989: Flutamide 1981: Agonistas LHRH 2004: Docetaxel

  13. Docetaxel

  14. Docetaxel for mCRPC Median survival D3 – 19.2 months D1 – 17.8 months M – 16.3 months Improvements also in: • QOL • Pain • PSA response Tannock, N Engl J Med, 2004

  15. ProstateCancerContinuum Terapia local Terapia hormonal de 1ª linha Terapia de 2ª linha Morte Quimioterapia Imunoterapia Nível de PSA Tempo

  16. Quimioterapia - Docetaxel Estratégia terapêutica definida pela especialidade: • Urologista • Oncologista perda / diminuiçãoeficáciaterapêutica tratamentosdesnecessáriosoufora de época

  17. R Ferraldeschi et al Oncogene, 2015

  18. R Ferraldeschi et al Oncogene, 2015

  19. DiseaseProgression 1- Heinlein CA, Chang C. Endocr Rev 2004;25:276–308. 2- Hu R et al. Expert Rev Endocrinol Metab 2010;5:753–64.

  20. MAINTAINED AR ACTIVITY IN CRPC AR splice variants • TruncatedAR splicevariants (AR-Vs) thatcontainanintact AR NTD and DNA- bindingdomain, butlackthe LBD, whichisthetargetofcurrent hormonal agents • AR-V7 levelsandfunctioncannotbesuppressed.

  21. Development of New Therapies Hormonal Receptor Pathway Chemotherapy Radionuclide therapy Immunotherapy

  22. Watson, et al. Nature Rev Cancer 2015 15:701–711

  23. Abiraterone 3-Acetoxy-17-(3-pyridyl)androsta-5,16-diene MW = 391.55 1. BarrieS, et al. Br J Cancer. 1993;67(suppl ):75. 2. AttardG, et al. Br J Urol Int. 2005;96:1241-1246. 3. Montgomery B, et al. AACR-GU 2009; poster. 4. AttardG, et al. J ClinOncol. 2008;26:4563-4571. • CYP17 (P450c17) oral irreversible inhibitor 1,2 • 17α –hydroxylase (IC50 = 4 nM) • C17,20-lyase (IC50 = 2.9 nM) • Kiapp< 1 nM for lyase activity • Suppression of serum and tissue androgens 3,4

  24. Mechanism of action Abiraterone TestosteroneDHT CYP17:17α-hydroxylase CYP17:C17,20-lyase X X Androgen Receptor TestosteroneDHT 1. Attard G et al. BJU Int. 2005;96:1241-6. 2. Attard G et al. J ClinOncol. 2008;26:4563-71. 3.Bula de ZYTIGATM.

  25. Positive drive + ACTH - Prednisone + + + Abiraterone X X Abbreviations: DHEA=dehydroepiandrosterone; DHT=dihydrotestosterone 1. Attard G et al. BJU Int. 2005;96:1241-6. 2. Attard G et al. J ClinOncol. 2008;26:4563-71. 3.Bula de ZYTIGATM.

  26. Enzalutamide Androgenic Signaling Oral Inhibitor 4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide

  27. Enzalutamide Targets Multiple Steps in the Androgen Receptor Signaling Pathway in the Tumour Cell PROSTATE CANCER CELL Competitively inhibits androgen binding to androgen receptors with higher affinity than bicalutamide Androgen X 1 Inhibits androgen receptor nuclear translocation Androgen Receptor X 2 Inhibits androgen receptor interaction with DNA CELL CYTOPLASM Induces cell death, decreases proliferation, and decreases tumour volume* X 3 CELL NUCLEUS Hoffman-Censits J, et al. J Clin Cancer Res 2013;9:1335-9

  28. Current Approvals – ‘pre-docetaxel’ Abiraterone + prednisolone1 Enzalutamide3 *p value not type I error adjusted or corrected • 1. Ryan CJ, et al. Lancet 2015; Feb;16(2):152-60. 2. Rathkopf DE et al. EurUrol 2016; 66: 815-825. 3. Beer TM, et al. Poster (#5036) presented at ASCO Annual Meeting 2015. 4. Beer TM, et al. N Engl J Med 2014;371(5):424-433

  29. Current Approvals – ‘post-docetaxel’ Abiraterone + prednisolone Enzalutamide • Fizazi K, et al. Lancet Oncol 2012; 13: 983-992; Scher HI, et al. N Engl J Med 2012; 367(13): 1187-97

  30. Toxicity comparisons • Ryan CJ, et al. N Engl J Med 2013; 368(2):138-148; Beer TM, et al. N Engl J Med 2014;371(5):424-433

  31. Sipuleucel-T • Prostate Acid Phosphatase/GM-CSF APC = antigen presenting cell GM-CSF = granulocyte-macrophage colony-stimulating factor MoA = mechanism of action

  32. Sipuleucel-T Kantoff P, et al. N Engl J Med 2010;363:411–422

  33. Cabazitaxel Mechanism of Action Taxane Binds to intracellular microtubules, suppressing microtubule dynamics Drug Design, Development and Therapy 2011:5 117–124

  34. TROPIC de Bono JS, Lancet 2010:1147.

  35. TROPIC – Overall Survival de Bono JS, Lancet 2010:1147.

  36. Cabazitaxel - Safety Drug Design, Development and Therapy 2011:5 117–124

  37. Radium 223 • Alfa particles – double-strand DNA breaks • Short range penetration –2-10 cells 223RaCl2

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