CPRC: Novas terapiascom ganho de sobrevida

Lucas Nogueira

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, Bayer, Astra Zeneca, Astellas, Ferring, Ache

3. Participo como membro do advisory board das empresas:

Janssen, Bayer, Astellas

4. Não possuo ações de quaisquer destas companhias farmacêuticas.

Óbitos Estimados CaP - 2015

1,6 min

28 minINCa, 2015

Cancer Statistics 2015

CPRC: Doença Heterogênea

Rajal B. Shah, Cancer Research, 2004

R Ferraldeschi et al Oncogene, 2015

R Ferraldeschi et al Oncogene, 2015

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

Progressão da Doença

Development of New Therapies

Homonal Receptor Pathway

Chemotherapy

Radionuclide therapy

Immunotherapy

Evolução do tratamento...

1984-1989

...but this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy

Mitoxantrone3 Docetaxel5,6*

Sipuleucel-T8*

LHRH agonists1*

1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et al. J Clin Oncol.

1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J

Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8. Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol.

2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197. 12. Parker C, et al. N Engl J

Med. 2013;369:213-223

1996 2002 2004 . . . . 2010

Abiraterone10*

Reversible AR

blockers2

Cabazitaxel7*

2011

Denosumab9

Radium 22312

Zoledronic Acid4

2012

Enzalutamide11*

2013 2013

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

Abiraterone

• CYP17 (P450c17) oral irreversible inhibitor 1,2

o 17α –hydroxylase (IC50 = 4 nM)

o C17,20-lyase (IC50 = 2.9 nM)

o Kiapp < 1 nM for lyase activity

• Suppression of serum and tissue

androgens 3,4

3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene

MW = 391.55

1. Barrie S, et al. Br J Cancer. 1993;67(suppl ):75. 2. Attard G, et al. Br J Urol Int. 2005;96:1241-1246. 3. Montgomery B, et al. AACR-GU 2009; poster. 4. Attard G, et al. J Clin Oncol. 2008;26:4563-4571.

Testosterone

DHT

Abiraterone

CholesterolPregnenolone

Progesterone

17α-OH-Pregnenolona

17α-OH-Progesterona

DHEA

Androstenediona

CYP17:

17α-hydroxylase

CYP17:

C17,20-lyase

AndrogenReceptor

Testosterone

DHT

17α-OH-Pregnenolone

17α-OH-Progesterone

DHEA

AndrostenedioneX X

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.

Testículo Adrenal

ACTHACTH

++

Positivedrive

CholesterolPregnenolone

Progesterone

17α-OH-Pregnenolona

17α-OH-Progesterona

DHEA

Androstenediona

Testosterona

DHT

Cortisol

++

17α-OH-Pregnenolone

17α-OH-Progesterone

DHEA

Androstenedione

Testosterone

DHT

Aldosterone

Mineralocorticoid-

like effect

Abiraterone

XX

++

Prednisone

++

--

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.

Enzalutamide

4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-

fluoro-N-methylbenzamide

Androgenic Signaling Oral Inhibitor

Enzalutamide Targets Multiple Steps in the Androgen

Receptor Signaling Pathway in the Tumour Cell

Hoffman-Censits J, et al. J Clin Cancer Res 2013;9:1335-9

PROSTATE CANCER CELL

CELL

NUCLEUS

CELL CYTOPLASM

ANDROGEN

RECEPTOR

ANDROGEN

1X

Competitively inhibits androgen binding to androgen receptors with higher affinity

than bicalutamide

2

Inhibits androgen receptor nuclear translocation

X

3

Inhibits androgen receptor interaction with DNA

XInduces cell death,

decreases proliferation,

and decreases tumour volume*

Current Approvals – ‘pre-docetaxel’

Enzalutamide3

1. Ryan CJ, et al. Lancet 2015; Feb;16(2):152-60. 2. Rathkopf DE et al. Eur Urol 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

Abi +Pred

Placebo +Pred

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 <0.0001

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 <0.001

ttCtx (mo)4 28.0 10.8 0.35 <0.001

Abiraterone + prednisolone1

*p value not type I error adjusted or corrected

Current Approvals – ‘post-docetaxel’

Enza Placebo HR p

n 800 399

OS (mo) 18.4 13.6 .63 <0.001

rPFS (mo) 8.3 2.9 0.40 <0.001

ttPSA (mo) 8.3 3.0 0.25 <0.001

�PSA (%) 54 2 <0.001

Fizazi K, et al. Lancet Oncol 2012; 13: 983-992; Scher HI, et al. N Engl J Med 2012; 367(13): 1187-97

Abiraterone + prednisolone Enzalutamide

Abi +Pred

Placebo +Pred

HR p

n 797 398

OS (mo) 15.8 11.2 0.74 <.0001

rPFS (mo) 5.6 3.6 0.66 <.0001

ttPSA (mo) 8.5 6.6 0.63 <.0001

�PSA (%) 29.5 5.5 <.0001

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

Prostate Acid Phosphatase/GM-CSF

APC = antigen presenting cell

GM-CSF = granulocyte-macrophage colony-stimulating

factor

MoA = mechanism of action

Sipuleucel-T

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

Sipuleucel-T

Cabazitaxel

Mechanism of Action

TaxaneBinds to intracellular microtubules, suppressing microtubuledynamics

Drug Design, Development and Therapy 2011:5 117–124

TROPIC

de Bono JS, Lancet 2010:1147.

de Bono JS, Lancet 2010:1147.

TROPIC – Overall Survival

Cabazitaxel - Safety

Drug Design, Development and Therapy 2011:5 117–124

Radium 223

Alfa particles – double-strand DNA breaks

Short range penetration –2-10 cells

223RaCl2

Radium-223 Targets Bone Metastases

• Calcium mimic

• Incorporated in new hydroxyapetitebone metastases

• excreted via the GI tract

• Half life – 11 days

Ca

Sr

Ba

Ra

High-energy α-particles cause double-strand DNA breaks in surrounding cells with minimal adjacent cell damage

ββββ-emitters

αααα-emitters• High-LET α-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

• Low-LET β-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

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.

ALSYMPCA: Overall Survival

Parker C, et al. N Engl J Med. 2013;369(3):213-23.

Adverse events from ALSYMPCA

1984-1989

...but this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy

Mitoxantrone3 Docetaxel5,6*

Sipuleucel-T8*

LHRH agonists1*

1. The Leuprolide Study Group. N Engl J Med. 1984;311(20):1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321(7):419-424. 3. Tannock I et al. J Clin Oncol.

1996;14(6):1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94(19):1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351(15):1513-1520. 6. Tannock I, et al. N Engl J

Med. 2004;351(15):1502-1512. 7. de Bono JS, et al. Lancet. 2010;376(9747):1147-1154. 8. Kantoff P, et al. N Engl J Med. 2010;363(5):411-422. 9. Fizazi K, et al. J Clin Oncol.

2009;27(10)1564-1571. 10. de Bono JS, et al. N Engl J Med. 2011;364(21):1995-2005. 11. Scher HI, et al. N Engl J Med. 2012;367(13):1187-1197. 12. Parker C, et al. N Engl J

Med. 2013;369:213-223

1996 2002 2004 . . . . 2010

Abiraterone10*

Reversible AR

blockers2

Cabazitaxel7*

2011

Denosumab9

Radium 22312

Zoledronic Acid4

2012

Enzalutamide11*

2013 2013

Trial Setting AgentOS

benefitQOL benefit

TAX-327 Docetaxel � �

SWOG 99-16

Docetaxel/estramustine

� -

TROPIC Post-docetaxel Cabazitaxel � -

COU-AA-301

Post-docetaxel Abiraterone � �

COU-AA-302

Pre-docetaxel Abiraterone � �

AFFIRM Post-docetaxel Enzalutamide � �

PREVAIL Pre-docetaxel Enzalutamide � �

ALSYMPCAPre/Post-docetaxel

Radium-223 � �

IMPACTPre/Post-docetaxel

Sipuleucel-T � -

Tannock IF, et al. N Engl J Med 2004; 351(15):1502-12; Petrylak DP, et al. N Engl J Med 2004;351:1513-20; De Bono JS, et al.

Lancet 2010; 376(9747):1147-54; de Bono JS, et al. N Engl J Med 2011; 364(21): 1995-2005; Ryan CJ, et al. N Engl J Med

2013; 368(2):138-148; Scher HI, et al. N Engl J Med 2012; 367(13): 1187-97;

Beer TM, et al. N Engl J Med 2014;371(5):424-433; Parker C, et al. N Engl J Med 2013; 369(3): 213-223; Kantoff PW, et al. N

Engl J Med 2010; 363(5): 411-422

Treatment options for mCRPC

Acummulated Survival Benefit

Therapy ApprovalSurvivalBenefit

HazardRatio

Docetaxel + Prednisona 1 2004 2.9 m 0,79

Sipulecel-T 2 2010 4.1 m 0,77

Cabazitaxel + Prednisona 3 2010 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

Take Home Message

• CPRC: doença heterogênea

• Evidências inequívocas do envolvimento do eixode sinalização do RA no CPRC

• Novas terapias disponíveis

• Questionamentos em relação à melhor sequênciade tratamento

• Necessidade urgente de biomarcadores paradiagnóstico e tratamento

Obrigado !!!