The Evolution of mCRPC in the Last Decade

Apresentação em tema: "The Evolution of mCRPC in the Last Decade"— Transcrição da apresentação:

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 estudos clínicos patrocinados pelas empresas: GSK, Janssen, Astellas, Bayer 2. Atuo como speaker de eventos das empresas: Janssen, Astra Zeneca, Ferring, Ache, Bayer, Astellas 3. Participo como membro do advisory board das empresas: Janssen, Bayer, Astellas 4. Não possuo ações de quaisquer destas companhias farmacêuticas.

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6 Óbitos Estimados CaP - 2015 1,6 min 28 min INCa, 2015
Cancer Statistics 2015

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13 40s 50s 60s 70s 80s 90s 00s 2010s 1996: Mitoxantrona 1985: Leuprolida
Charles Huggins 1985: Leuprolida 1989: Flutamide 1981: Agonistas LHRH 1996: Mitoxantrona 40s 50s 60s 70s 80s 90s 00s 2010s

14 < 2004 oncologia - paliação controle álgico localizado
localmente avançado metastático prostatectomia radioterapia terapia hormonal radioterapia oncologia - paliação controle álgico terapia hormonal? suporte clínico

15 Câncer de Próstata Metastático
< 2004 terapia hormonal avançado Orquiectomia Agonistas LHRH Antagonistas LHRH Anti - androgênicos

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17 Mecanismos de Resistência à Castração

18 Retirada ou troca do anti-androgênio
Progressão após ADT < 2004 Progressão terapia hormonal avançado Retirada ou troca do anti-androgênio DES Cetoconazol Corticóides Outros

19 Respostas Clínicas: Manipulação Hormonal de 2ª Linha
Q U I M O T E R A P Retirada de Anti-androgênio % Bicalutamida % Nilutamida % DES % Ketoconazole (+ corticóide) % Corticosteroides % Acetato Megestrol % Duração média de resposta: 2-4 meses. Impacto a longo prazo? Sobrevida?

20 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

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22 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

23 40s 50s 60s 70s 80s 90s 00s 2010s 1996: Mitoxantrona 1985: Leuprolida
Charles Huggins 1985: Leuprolida 1989: Flutamide 1981: Agonistas LHRH 1996: Mitoxantrona 40s 50s 60s 70s 80s 90s 00s 2010s 2004: Docetaxel

24 Docetaxel

25 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

26 Prostate Cancer Continuum
Nível de PSA Terapia local Terapia hormonal de 1ª linha Quimioterapia Imunoterapia de 2ª linha Morte Tempo A terapia de primeira linha para doença localizada deve incluir a prostatectomia radical, a radioterapia ou a combinação das duas terapias.1 Na doença não metastática, a elevação dos níveis de PSA pode indicar recorrência da doença, que pode ser tratada com a terapia de privação androgênica (orquiectomia ou terapia hormonal química).1 Depois de algum tempo, grande parte dos pacientes com doença sensível a hormônios desenvolve resistência à terapia hormonal e progressão de doença, inclusive doença metastática. No cenário da doença metastática assintomática, a imunoterapia deve ser considerada.1 Nesse estágio, a quimioterapia pode ser indicada, apesar de alguns pacientes com doença metastática sem sintomas poderem escolher postergar a quimioterapia.1 Um ponto-chave deste slide é o papel da via de sinalização do receptor de andrógeno ao longo do curso do câncer de próstata (barra laranja), mesmo sob níveis de castração da testosterona circulante (barra verde mais escuro).2 Dados clínicos e pré-clínicos suportam o papel central do receptor de andrógeno e sua sinalização na progressão do câncer de próstata.2,3 A sinalização do receptor de andrógeno contribui para a progressão de doença, apesar dos níveis de castração da testosterona sérica.4 Dois diferentes estudos suportam os achados que o CRPC, previamente denominado androgênio-independente ou hormônio-refratário é hoje reconhecidamente direcionado pela via de sinalização do receptor de andrógeno, em parte devido à superexpressão do próprio receptor de andrógeno.3,5 Referências: Higano CS. Chapter 28 in: W.D. Figg et al. (eds.), Drug Management of Prostate Cancer, 321 DOI / _28, © Springer Science+Business Media, LLC 2010 Scher HI, et al. Increased survival with enzalutamida in prostate cancer after chemotherapy. N Engl J Med. 2012; 367: Tran, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009;324(5928): Schweizer MT, et al. Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. Ther Adv Urol. 2012;4(4): Fizazi K, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet [Epub ahead of print].

27 Quimioterapia - Docetaxel
Estratégia terapêutica definida pela especialidade: Efeitos colaterais Dúvida eficácia Perda do paciente Acostumados qtx Tratamento dor TAX 327 Urologista Oncologista perda / diminuição eficácia terapêutica tratamentos desnecessários ou fora de época

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29 R Ferraldeschi et al Oncogene, 2015

30 R Ferraldeschi et al Oncogene, 2015

31 Disease Progression A manutenção da via de sinalização do receptor de androgênio tem um papel chave na progressão do câncer de próstata. Mudanças na biologia molecular do câncer de próstata reativam a via de sinalização do receptor de androgênio mesmo com os baixos níveis de androgênio. As adaptações são as seguintes: Manutenção da biossíntese de andrógeno pela adrenal e pelo próprio tumor Superexpressão do RA AR mutante Variantes de splicing do RA Regulação ascendente de cofatores de AR Ativação dos RA por inibidores de tirosina-quinase A via de sinalização do AR é o mecanismo chave para a progressão do CRPC e é um objetivo lógico no tratamento do câncer de próstata. CRPC = câncer prostático resistente à castração. Referências 1- Heinlein CA, Chang C. Endocr Rev 2004;25:276–308. 2- Hu R et al. Expert Rev Endocrinol Metab 2010;5:753–64. 1- Heinlein CA, Chang C. Endocr Rev 2004;25:276– Hu R et al. Expert Rev Endocrinol Metab 2010;5:753–64.

32 MAINTAINED AR ACTIVITY IN CRPC Persistent Androgen Production
Intra-tumoral testosterone in CRPC tumors are restored to equivalent or even higher levels than in non-castrate prostates. Generated from conversion of circulating adrenal androgens or possibly by de novo synthesis of androgens by CRPC cells

33 R Ferraldeschi et al Oncogene, 2015

34 MAINTAINED AR ACTIVITY IN CRPC
AR mutations Mutations in the hinge region and LBD usually confer increased transactivational activity and reduced ligand specificity. Promiscuous activation of the AR by weak adrenal androgens and other steroid hormones. Conversion of AR antagonists (flutamide and bicalutamide) into potent agonists.

35 MAINTAINED AR ACTIVITY IN CRPC
AR overexpression Displayed in up to 80% of CRPC Amplification of the AR gene Can confer AR hypersensitivity to low levels of androgens and can result in continued tumor proliferation despite minimal androgen concentrations

36 MAINTAINED AR ACTIVITY IN CRPC
AR splice variants Truncated AR splice variants (AR-Vs) that contain an intact AR NTD and DNA- binding domain, but lack the LBD, which is the target of current hormonal agents AR-V7 levels and function cannot be suppressed.

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38 MAINTAINED AR ACTIVITY IN CRPC
Cross-talk with other signal transduction pathways Other signaling pathways and their interactions with AR signaling are also critically implicated in PCa progression. Phosphatidylinositol 3-kinase (PI3K)/Akt Phosphatase and tensin homolog (PTEN)

39 MAINTAINED AR ACTIVITY IN CRPC Cross talk with DNA damage pathways
PARP (Poly ADP-ribose polymerase) family of enzymes modifies a subset of nuclear proteins, and is known to have a critical role in DNA damage repair and transcription. PARP inhibitors - impressive and durable responses in CRPC.

40 MAINTAINED AR ACTIVITY IN CRPC Alternative Steroids Receptors
Glucocorticoids Receptors are only found in around 30% of CRPC patients. This percentage increases after ADT AR and GR share the same chromatin binding sites and GR can regulate a large number of genes considered to be AR pathway-specific.

41 MAINTAINED AR ACTIVITY IN CRPC
Others Alteration of coregulators and pioneer factors Post-translational modification of AR

42 Development of New Therapies
Hormonal Receptor Pathway Chemotherapy Radionuclide therapy Immunotherapy

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

44 3-Acetoxy-17-(3-pyridyl) androsta-5,16-diene
Abiraterone 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 3-Acetoxy-17-(3-pyridyl) androsta-5,16-diene MW = Abiraterone acetate is an orally available, androgen biosynthesis inhibitor that selectively and irreversibly inhibits CYP17 (P450c17), an enzyme also known as 17-hydroxylase/17,20-lyase The CYP17 enzyme is involved in the formation of dihydroepiandrostenedione (DHEA) and androstenedione, which is ultimately metabolized into testosterone As a CYP17 inhibitor, abiraterone acetate inhibits testosterone production in the testis, adrenal gland, and prostate To date, more than 1000 patients have been treated with abiraterone acetate in phase 1, 2, and 3 clinical trials Barrie S, et al. Br J Cancer. 1993: 67(Suppl ):75. Attard G, et al. Br J Urol Int. 2005; 96: Montgomery B, et al. AACR.- GU 2009; poster. Attard G, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26: 1. Barrie S, et al. Br J Cancer. 1993;67(suppl ): Attard G, et al. Br J Urol Int. 2005;96: 3. Montgomery B, et al. AACR-GU 2009; poster. 4. Attard G, et al. J Clin Oncol. 2008;26:

45 Mechanism of action Abiraterone X X CYP17: 17α-hydroxylase
CYP17: C17,20-lyase Androgen Receptor Cholesterol Pregnenolone Progesterone 17α-OH- Pregnenolona 17α-OH- Progesterona DHEA Androstenediona 17α-OH- Pregnenolone 17α-OH- Progesterone DHEA Androstenedione Testosterone DHT Testosterone DHT REFS: 1- Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol Oct 1;26(28): doi: /JCO Epub 2008 Jul 21. Erratum in: J Clin Oncol May 20;30(15):1896. PubMed PMID: 2- Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int Dec;96(9): Review. PubMed PMID: X X 1. Attard G et al. BJU Int. 2005;96: Attard G et al. J Clin Oncol. 2008;26: Bula de ZYTIGATM. 12/ K08Z121100

46 Aldosterone Mineralocorticoid- like effect
Positive drive + Aldosterone Mineralocorticoid- like effect ACTH - Prednisone + + + Abiraterone Cholesterol Pregnenolone Progesterone 17α-OH- Pregnenolona 17α-OH- Progesterona DHEA Androstenediona Testosterona DHT 17α-OH- Pregnenolone 17α-OH- Progesterone DHEA Androstenedione Testosterone DHT X X REFS: 1- Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol Oct 1;26(28): doi: /JCO Epub 2008 Jul 21. Erratum in: J Clin Oncol May 20;30(15):1896. PubMed PMID: 2- Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int Dec;96(9): Review. PubMed PMID: 3- Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA Aug 18;282(7): PubMed PMID: Krasner AS. JAMA. 1999;282:671-6. Abbreviations: DHEA=dehydroepiandrosterone; DHT=dihydrotestosterone Cortisol 1. Attard G et al. BJU Int. 2005;96: Attard G et al. J Clin Oncol. 2008;26: Bula de ZYTIGATM. 12/ K08Z121100

47 Androgenic Signaling Oral Inhibitor
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

48 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 Enzalutamide is an oral inhibitor of AR signaling that blocks AR interaction, inhibits translocation of the AR to the nucleus, impairs androgen receptor binding to DNA, and inhibits coactivator recruitment and receptor-mediated DNA transcription. Because enzalutamide targets androgen-AR signalling through binding of the AR itself, rather than through CYP17 inhibition, there is no requirement for corticosteroids. Reference Hoffman-Censits J, Kelly WK. Enzalutamide: a novel antiandrogen for patients with castrate-resistant prostate cancer. Clin Cancer Res 2013;19: 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

49 Current Approvals – ‘pre-docetaxel’
Abiraterone + prednisolone1 Enzalutamide3 Abi + Pred Placebo + HR p n 546 542 OS (mo)1 34.7 30.3 0.81 0.0033 rPFS (mo)2 16.5 8.2 0.52 0.0001 ttPSA (mo)2 11.1 5.6 0.5 <0.0001 PSA (%)2 68 29 ttCtx (mo)2 26.5 16.8 0.61 Enza Placebo HR P n 872 845 OS (mo)3 35.3 31.3 0.77 <0.0002 rPFS (mo)3 20 5.4 0.32 <0.0001* ttPSA (mo)4 11.2 2.8 0.17 <0.001 PSA (%)4 78 3 ttCtx (mo)4 28.0 10.8 0.35 *p value not type I error adjusted or corrected 1. Ryan CJ, et al. Lancet 2015; Feb;16(2): Rathkopf DE et al. Eur Urol 2016; 66: Beer TM, et al. Poster (#5036) presented at ASCO Annual Meeting Beer TM, et al. N Engl J Med 2014;371(5):

50 Current Approvals – ‘post-docetaxel’
Abiraterone + prednisolone Enzalutamide Abi + Pred Placebo + HR p n 797 398 OS (mo) 15.8 11.2 0.74 <.0001 rPFS (mo) 5.6 3.6 0.66 ttPSA (mo) 8.5 6.6 0.63 PSA (%) 29.5 5.5 Enza Placebo HR p n 800 399 OS (mo) 18.4 13.6 .63 <0.001 rPFS (mo) 8.3 2.9 0.40 ttPSA (mo) 3.0 0.25 PSA (%) 54 2 Fizazi K, et al. Lancet Oncol 2012; 13: ; Scher HI, et al. N Engl J Med 2012; 367(13):

51 Toxicity comparisons Ryan CJ, et al. N Engl J Med 2013; 368(2): ; Beer TM, et al. N Engl J Med 2014;371(5):

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

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

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

55 TROPIC de Bono JS, Lancet 2010:1147.
Resistance — Although both androgen synthesis inhibitors and androgen receptor antagonists can significantly alter the natural history of castrate resistant prostate cancer, progressive disease and resistance to these agents will eventually develop in most cases. The mechanisms for resistance are not fully understood and are the subject of ongoing research. One possible mechanism to explain the lack of activity of these agents in approximately one-third of patients and the development of resistance in almost all of those who do respond is the presence of variants in the androgen receptor [11]. The androgen receptor isoform splice variant 7 (AR-V7) lacks the binding site for androgen, while retaining the activating site that stimulates tumor growth. The potential importance of the AR-V7 splice variant was illustrated by a study of 62 men, 31 of whom were treated with enzalutamide and 31 with abiraterone [11]. Levels of RNA that encode for AR-V7 were measured in circulating tumor cells. Among men with positive levels of RNA for AR-V7, no PSA responses were observed with either enzalutamide or abiraterone (0 of 12 and 0 of 6, respectively). Among patients in whom the AR-V7 was not detected, PSA responses were seen in 10 of 19 patients treated with enzalutamide and 17 of 25 patients treated with abiraterone. In secondary analyses of these cohorts, progression-free and overall survival were shorter in patients whose tumors contained the AR-V7 splice variant. These findings require confirmation in larger studies. Although the AR-V7 splice variant predicts resistance to enzalutamide and abiraterone, preliminary evidence suggests that it is not associated with resistance to docetaxel chemotherapy [12]. de Bono JS, Lancet 2010:1147.

56 TROPIC – Overall Survival
Resistance — Although both androgen synthesis inhibitors and androgen receptor antagonists can significantly alter the natural history of castrate resistant prostate cancer, progressive disease and resistance to these agents will eventually develop in most cases. The mechanisms for resistance are not fully understood and are the subject of ongoing research. One possible mechanism to explain the lack of activity of these agents in approximately one-third of patients and the development of resistance in almost all of those who do respond is the presence of variants in the androgen receptor [11]. The androgen receptor isoform splice variant 7 (AR-V7) lacks the binding site for androgen, while retaining the activating site that stimulates tumor growth. The potential importance of the AR-V7 splice variant was illustrated by a study of 62 men, 31 of whom were treated with enzalutamide and 31 with abiraterone [11]. Levels of RNA that encode for AR-V7 were measured in circulating tumor cells. Among men with positive levels of RNA for AR-V7, no PSA responses were observed with either enzalutamide or abiraterone (0 of 12 and 0 of 6, respectively). Among patients in whom the AR-V7 was not detected, PSA responses were seen in 10 of 19 patients treated with enzalutamide and 17 of 25 patients treated with abiraterone. In secondary analyses of these cohorts, progression-free and overall survival were shorter in patients whose tumors contained the AR-V7 splice variant. These findings require confirmation in larger studies. Although the AR-V7 splice variant predicts resistance to enzalutamide and abiraterone, preliminary evidence suggests that it is not associated with resistance to docetaxel chemotherapy [12]. de Bono JS, Lancet 2010:1147.

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

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

59 Radium-223 Targets Bone Metastases
Calcium mimic Incorporated in new hydroxyapetite bone metastases excreted via the GI tract Half life – 11 days Ca Sr Ba Ra

60 High-energy α-particles cause double-strand DNA breaks in surrounding cells with minimal adjacent cell damage Low-LET b-radiation produces single-strand DNA breaks1 Single-strand breaks are easily repaired using the opposite strand as a template1 Single-strand breaks are less likely to induce cell death1 b-emitters a-emitters High-LET a-particles produce double-strand DNA breaks1,2 Double-strand breaks are difficult to repair1,2 Failure to repair double-strand breaks leads to apoptosis (programmed cell death)1 Misrepaired double-strand breaks create chromosomal aberrations that result in mitotic cell death1 LET, linear energy transfer. 1. Hall E, Giaccia A. Radiobiology for the Radiologist. 6th Ed. Philadelphia: Lippincott William & Wilkins; 2006; 2. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

61 ALSYMPCA: Overall Survival
Resistance — Although both androgen synthesis inhibitors and androgen receptor antagonists can significantly alter the natural history of castrate resistant prostate cancer, progressive disease and resistance to these agents will eventually develop in most cases. The mechanisms for resistance are not fully understood and are the subject of ongoing research. One possible mechanism to explain the lack of activity of these agents in approximately one-third of patients and the development of resistance in almost all of those who do respond is the presence of variants in the androgen receptor [11]. The androgen receptor isoform splice variant 7 (AR-V7) lacks the binding site for androgen, while retaining the activating site that stimulates tumor growth. The potential importance of the AR-V7 splice variant was illustrated by a study of 62 men, 31 of whom were treated with enzalutamide and 31 with abiraterone [11]. Levels of RNA that encode for AR-V7 were measured in circulating tumor cells. Among men with positive levels of RNA for AR-V7, no PSA responses were observed with either enzalutamide or abiraterone (0 of 12 and 0 of 6, respectively). Among patients in whom the AR-V7 was not detected, PSA responses were seen in 10 of 19 patients treated with enzalutamide and 17 of 25 patients treated with abiraterone. In secondary analyses of these cohorts, progression-free and overall survival were shorter in patients whose tumors contained the AR-V7 splice variant. These findings require confirmation in larger studies. Although the AR-V7 splice variant predicts resistance to enzalutamide and abiraterone, preliminary evidence suggests that it is not associated with resistance to docetaxel chemotherapy [12]. Parker C, et al. N Engl J Med. 2013;369(3):

62 Adverse events from ALSYMPCA
Selected adverse events of interest from ALSYMPCA (NCT ) [18]

63 A partir de 2010 diversas novas opções surgiram:
Até 2004 a única opção de tratamento para mCRPC sintomático era o uso de mitoxantrona De 2004 a 2010 o docetaxel foi a primeira droga a demonstrar ganho de SG significativo A partir de 2010 diversas novas opções surgiram: Sipuleucel-T Cabazitaxel Abiraterona Enzalutamida Radium-223 A despeito do número de novas opções de tratamento, a doença permanece incurável With growing insights into the biology of advanced prostate cancer, the pace of drug development has been unprecedented. The immunotherapy sipuleucel-T, cytotoxic chemotherapies do- cetaxel and cabazitaxel, androgen biosynthesis inhibitor abiraterone, androgen receptor (AR) antagonist enzalutamide, and alpha-emitting radiopharmaceutical radium-223 have all im- proved the survival of men with CRPC in randomized phase III studies [3–9] (see Table 1). With effective new treatments, men with advanced prostate cancer are living longer and maintaining better quality of life [10–14]. Cabazitaxel, abiraterone, radium- 223, and enzalutamide have all been approved for use in the same post-docetaxel setting; however, we currently lack biomarkers to guide treatment selection or prospective data addressing optimal sequencing of novel therapeutics. Six drugs with different mechanisms of action have been shown to prolong overall survival (OS) in CRPC patients, namely the tubulin targeting chemotherapies doc- etaxel and cabazitaxel, the immunotherapy sip- uleucel-T, the androgen biosynthesis inhibitor abiraterone, the second generation androgen receptor (AR) antagonist enzalutamide and the alpha-emitting radiopharmaceutical radium-223

64 Docetaxel/estramustine
Treatment options for mCRPC Trial Setting Agent OS benefit QOL benefit TAX-327 Docetaxel  SWOG 99-16 Docetaxel/estramustine - TROPIC Post-docetaxel Cabazitaxel COU-AA-301 Abiraterone COU-AA-302 Pre-docetaxel AFFIRM Enzalutamide PREVAIL ALSYMPCA Pre/Post-docetaxel Radium-223 IMPACT Sipuleucel-T Tannock IF, et al. N Engl J Med 2004; 351(15): ; Petrylak DP, et al. N Engl J Med 2004;351: ; De Bono JS, et al. Lancet 2010; 376(9747): ; de Bono JS, et al. N Engl J Med 2011; 364(21): ; Ryan CJ, et al. N Engl J Med 2013; 368(2): ; Scher HI, et al. N Engl J Med 2012; 367(13): ; Beer TM, et al. N Engl J Med 2014;371(5): ; Parker C, et al. N Engl J Med 2013; 369(3): ; Kantoff PW, et al. N Engl J Med 2010; 363(5):

65 2010 Carlos Mendes – 55 anos Ca reto – amputação reto – 45 anos – RTX - QTX PSA 1 – 2,5 – biopsia ?? RTU prostata – Gleason cistoprostatectomia Progressão – ADT PSA progression – 1,5 Lesão óssea + nódulos retroperitoniais 6 cm – g 5+5 Dor – QTX – Enzalutamida 2 anos – Melhora sintomas Óbito 2016 – sem dor

66 Acummulated Survival Benefit
Therapy Approval Survival Benefit Hazard Ratio Docetaxel + Prednisona 1 2004 2.9 m 0,79 Sipulecel-T 2 2010 4.1 m 0,77 Cabazitaxel + Prednisona 3 2,4 m 0,70 Abiraterona + Prednisona 4 2011 4,6 m 0,74 Enzalutamida 5 2012 4.8 m 0,63 Rádio-223 6 2013 3,6 m 0,69 Total 22,4 m

67 Prognostic / Response predictors
Timing and Sequencing Efficacy Prognostic / Response predictors Cross resistance

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69 Treatment options overview
Death Docetaxel Castration Relative Tumour Volume Local Therapy Combined Androgen Blockade Cabazitaxel Abiraterone Enzalutamide Radium-223 Abiraterone Enzalutamide Radium-223 (Sipuleucel T) Asymptomatic Symptoms Hormone Sensitive Castration Resistant Time

70 Treatment options overview
Death Docetaxel Castration Relative Tumour Volume Local Therapy Combined Androgen Blockade Cabazitaxel Abiraterone Enzalutamide Radium-223 Abiraterone Enzalutamide Radium-223 (Sipuleucel T) Asymptomatic Symptoms Hormone Sensitive Castration Resistant Time

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73 Presented By Nicholas James at 2015 ASCO Annual Meeting
Slide 1 Presented By Nicholas James at 2015 ASCO Annual Meeting

74 Presented By Nicholas James at 2015 ASCO Annual Meeting
Docetaxel: Survival Presented By Nicholas James at 2015 ASCO Annual Meeting

75 Treatment options overview
Death Docetaxel Castration Relative Tumour Volume Local Therapy Combined Androgen Blockade Cabazitaxel Abiraterone Enzalutamide Radium-223 Abiraterone Enzalutamide Radium-223 (Sipuleucel T) Asymptomatic Symptoms Hormone Sensitive Castration Resistant Time

76 Treatment options overview
Death Docetaxel Castration Relative Tumour Volume Local Therapy Combined Androgen Blockade Cabazitaxel Abiraterone Enzalutamide Radium-223 Abiraterone Enzalutamide Radium-223 (Sipuleucel T) Asymptomatic Symptoms Hormone Sensitive Castration Resistant Time

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79 (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P , .001)

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83 Cross Resistance Mechanism of Action Docetaxel: microtubules  AR
Cabazitaxel: microtubules  AR Abiraterone: CYP17A1  AR Enzalutamide: AR Giannakakou et al: Cancer Res 2013

84 Docetaxel after Abiraterone
(Docetaxel q3w) Phase I-II* (Abiraterone →Docetaxel) PSA decrease ≥ 50% 45% 26% Time to PSA progression (median) 7.7 mo 4.6 mo Overall survival (median) 18.9 mo 12.5 mo *Mezynski et al. Ann Oncol 2012

85 Enzalutamide after Abiraterone
AFFIRM Current Study PSA decrease ≥ 50% 54% 12% Time to PSA progression (median) 8.3 mo 2.8 mo Overall survival (median) 18.4 mo NR Bianchini et al. Eur Urol 2014

86 Abiraterone After Enzalutamide
COU-AA-301 Europe1 (n = 38) North America2 (n = 30) PSA decrease ≥ 50% 29,1% 8% 3% PFS (median) 5,6 mo 2.7 mo 4.0 mo 1. Loriot Y et al. Ann Oncol 2013; 24: 2. Noonan KL et al. Ann Oncol 2013; 24:

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88 Other tumour site examples of multiple treatment pathways defined at diagnosis
Trials reflect this

89 Gleason Score

90 Short response to first ADT (1 year): AR-targeted therapies vs chemotherapy
AR targeted agents1 Docetaxel2 Retrospective analysis in 108 patients with metastatic PCa Poor response to subsequent hormone therapies (including abiraterone, enzalutamide) if time to CRPC with first ADT < 16 months 188 patients with mCRPC in 2 prospective databases High Gleason score and visceral mets more common if early CRPC (≤1 year) Good response to docetaxel irrespective of time to CRPC: Duration of response < 16 mo ≥ 16 mo ↓ PSA ≥50% 18% 58% Median TTP 3 mo 5 mo Duration of response ≤ 1yr > 1yr ↓ PSA ≥50% 67% 81% Median TTP 6.1 mo 7.1 mo Loriot Y et al. ASCO GU 2012 (abstract 213) Huillard ASCO 2013 (abstract 5075)

91 The AR gene locus Lu, J. et al. (2015) Are androgen receptor variants a substitute for the full-length receptor? Nat. Rev. Urol.

92

93 Non-invasive detection of resistance states
Azad, et al. Clin Cancer Res. 2015;21(10): ; Antonarakis, et al. JAMA Oncol 2015;1(5):582-91; Antonarakis, et al. N Engl J Med. 2014;371(11):

94 F876LF mutation Identified in plasma DNA from ARN-509–treated patients with progressive disease. May confer agonistic activity to enzalutamide and ARN-509.

95 Approach to CRPC: 2017 NO YES yes no
Clinical Metastases YES Symptoms/ Extensive Bone or Visceral mets yes no Hormonal manipulation Clinical trial Docetaxel Consider Abi/Enza Bone only consider Radium 223 Abi/Enza Consider Docetaxel Slow PSADT Rapid PSADT Evaluate for metastases q 6-12 Months Evaluate for metastases q 3-6 months Progression Progression This algorithm outlines the proposed approach for patients with CRPC with agents currently available in Canada. Reference Saad F, Hotte SJ, Catton C, et al. CUA-CUOG Guidelines for the Management of Castration Resistant Prostate Cancer (CRPC): 2013 Update. Accessed June 26, 2013. Abiraterone Enzalutamide Cabazitaxel Docetaxel In the presence of bone metastases denosumab or zoledronic acid is recommended to reduce the risk of skeletal complications Enzalutamide Cabazitaxel Progression Radium 223 Best supportive Care Mitoxantrone Progression Saad F, Hotte SJ, Catton C, et al.

96 2017 Walter Mendes – 65 anos Dor lombar progressiva associada a hematúria macroscópica; sem avaliação prostática prévia. PSA 50, toque T4, Gleason 5+5, CO superscan, MRI Docetaxel + ADT Enzalutamide after progression – Docetaxel - Abiraterone Concomitant Radium 223 Zoledronic acid, Denozumab Longer survival and better QoL

97 Future Directions New Scenarios New Therapies

98 Enzalutamide

99 Combination Abi / Enza / Radium 223

100

101 New Therapies Androgen Receptor Pathway PARP inhibitors
Galeterone – ARMOR 2 ARN – 509 ODM 201 – ARAMIS, ARASENS EPI-001 – NTD PARP inhibitors Olaparib

102 PARP is important for repairing single strand breaks in DNA
Multiple tumour suppressor products are involved in double strand break repair (eg BRCA

103

104 Tumour antigen: PSA vaccinia virus
Prostvac Tumour antigen: PSA vaccinia virus

105 Ipilimumab Fong L, et al. J Clin Oncol. 2008;26: ; Gerritsen W, et al. ESMO Abstract 2850.

106 Treatment until disease progression or intolerable toxicity
Ipilimumab (post-docetaxel) CA : Study design N = 399 Ipilimumab (10 mg/kg) Wks 1, 4, 7, 10 Ipilimumab (10 mg/kg) Every 12 wks Screening Single-dose, bone-directed RT (8 GY) Post-docetaxel CRPC (N = 799) 1:1 N = 400 Placebo Wks 1, 4, 7, 10 Placebo Every 12 wks Treatment until disease progression or intolerable toxicity Primary endpoint: OS Secondary endpoints: Progression-free survival, safety Exploratory endpoint: PSA response rate Gerritsen W, et al. ESMO Abstract 2850. Van den Eertwegh AJ, et al. Lancet Oncol. 2012;13:

107 Ipilimumab (post-docetaxel)
Ipi (n=399) Pbo (n=400) Median OS, mo (95% CI) 11.2 (9.6–12.6) 10.0 (8.4–11.2) HR (95% CI) 0.84 (0.72–0.98) Stratified log-rank* P=0.03 1-yr OS rate 47% 41% 2-yr OS rate 25% 17% 3-yr OS rate** 12% 6% Results: Updated OS n=799 Primary endpoint= OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Months Proportion Alive Ipi Censored Pbo Fizazi K et al., ESMO 2014 Van den Eertwegh AJ, et al. Lancet Oncol. 2012;13:

108 Summary CPRC: heterogeneous disease
Clear evidence of the AR pathway involvement in CRPC New available therapies Doubts regarding timing and sequencing Urgent need for prognostic / response biomarkers

109 Obrigado