Experiencia y Futuro del tratamiento con Enzalutamida

Experiencia y Futuro del tratamiento con

Enzalutamida

Desarrollo clínico en cáncer próstata

Time

PSA

Metastatic

Symptoms

Castration Resistant

Non-Metastatic

Asymptomatic

Castration Sensitive

MetastaticNon-metastatic

Castration resistantCastration sensitive

First-line hormonal therapy/

castration

Docetaxel + prednisone

Localtherapy

Second-line hormonal therapies

Bicalutamide,flutamide,

nilutamide, etc.

Cabazitaxel + prednisone

Enzalutamide

Abiraterone acetate + prednisone

Sipuleucel-T


AFFIRM

3

0 2 4 6 8 10 12

0

20

40

60

80

100

Time to event (months)

PF

S %

Supervivencia libre de enfermedad

Progresión por PSA: aumento >25% sobre nadir

Mediana 5.25 m

Uso Expandido 2012: HSCSP + Htal Asturias. T progresión por PSA

Acceso Expandido: Htal Asturias + HSCSP: Respuesta PSA

-100

-80

-60

-40

-20

0

20

40

60

80

100

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Perfil de PSA en el tiempo. % sobre el basal

%

Semanas

*FDHT: 16β-18F-fluoro-5α-dihidrotestosteronaScher HI, et al. Lancet. 375:1437, 2010

Fase I/II: Inhibición del AR y farmacocinética

Farmacocinética de dosis múltiples

Conc. pre-dosis (Cmín)

Respuesta precoz y supervivencia?

Caffo et al. Fut Oncol 2014; 985


Time

PSA

Metastatic

Symptoms


Non-Metastatic

Asymptomatic





castration


Localtherapy



nilutamide, etc.


Enzalutamide


Sipuleucel-T


AFFIRM

ABIRATERONA ---- ENZALUTAMIDA

Enza tras Abi

N=137Median duration of Rx: 4 months

Enzalutamide in progressive mCRPC previously treated with abiraterone

Planned evaluations•rPFS•OS•PSA response•Time to PSA progression•Safety•Objective response rate•QoL•Time to start other antineoplastic therapy

ADT=androgen-deprivation therapy; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen; QoL=quality of life; rPFS=radiographic PFS.EudraCT 2013-002271-17. Available at https://www.clinicaltrialsregister.eu. Last accessed: April 2014.

Enzalutamide (160 mg QD)

n=200

Progressive mCRPC

Testosterone ≤50 ng/dL

Ongoing ADT

≥6 months prior treatment

with abiraterone

Asymptomatic/mildly

symptomatic

ECOG PS 0–1

• A Phase 4 multicentre, single-arm study• Primary endpoint: rPFS

11

Ongoing trials


Time*Phase 1b; †Phase 2; ‡Phase 3.

PSA

Metastatic

Symptoms


Non-Metastatic

Asymptomatic





castration


Localtherapy



nilutamide, etc.


Enzalutamide


Sipuleucel-T


PREVAIL

AFFIRM

PREVAILCPRC metastásicoNO: Quimioterapia,

ketoconazole, o abirateroneECOG 0-1

BPI (Brief Pain Inventory):

Asintomático (0- 1) o casi asintomático

(2-3)Metástasis viscerales

permitidasPacientes NYHA I-II

NO riesgo de convulsión pero SÎ con medicaciones que bajen el dintel

convulsivoCorticoides permitidos

Objetivos

Co-primarios:

• SG

• rPFS

Enzalutamida160 mg/día

(capsulas) n=872

Placebon=845

RANDOMIZADO

1:1

CRPCm=Cáncer de Próstata resistente a castración metastásico SG=Supervivencia Global; rPFS=Supervivencia Libre de Progresión Radiográfica.

Beer TM, et al. ASCO-GU 2014; Oral presentation; ClinicalTrials.gov identifier: NCT01212991.

Características Enzalutamida (n=872)

Placebo (n=845)

Edad, mediana (rango), a 72 (43−93) 71 (42−93)

PSA, mediana, ng/mL 54.1 44.2

Gleason ≥8 50.6% 52.4%

Puntuación ECOG = 0 67.0% 69.2%

Dolor al inicio 0–1 BPI-SF 66.2% 67.5%

Uso de corticoides al inicio 4.0% 4.3%

Beer TM, et al. ASCO-GU 2014; Oral presentation.

Enfermedad ósea 85.0% 81.7%

Enfermedad de tejidos blandos 59.3% 59.6%

Enfermedad visceral (hepática y/o pulmonar) 11.2% 12.5%

RECIST

Enzalutamida(n=872)

Placebo(n=845) Valor P

Pacientes con enfemedad de tejidos blandos medibles al inicio

396 381

Respuesta Objetiva (RC + RP) 58.8% 5.0% <0.0001

Best overall response

RC 19.7% 1.0%

RP 39.1% 3.9%

Categorías de respuesta según criterios RECIST 1.1.

RC=respuesta completa; RP=Respuesta parcial; RECIST=Response Evaluation Criteria in Solid Tumors.


Supervivencia libre de Progresión Radiográfica

3 6 15 18 2112

100

80

60

40

20

00

rPF

S (

%)

Meses9

514 256 5 1 034832 128Enzalutamida, n

305 79 0 0 05801 20Placebo, n

Placebo

Enzalutamida

HR=0.186 (95% CI: 0.15–0.23); p<0.0001


Estimated Mediana estimada de rPFS, meses (95% IC): Enzalutamida: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4)

Subgrupo

Nº de pacientesenzalutamida /

placeboHazard ratio

(95% IC)

Todos los pacientes 832 / 801 0.19 (0.15–0.23)

ECOG performance status at baseline = 0 557 / 549 0.15 (0.11–0.20)

ECOG performance status at baseline = 1 275 / 252 0.27 (0.19–0.37)

Edad <75 529 / 517 0.20 (0.15–0.26)

Edad ≥75 303 / 284 0.17 (0.12–0.24)

Región geográfica – North America 214 / 204 0.17 (0.12–0.25)

Región geográfica – Europe 456 / 435 0.21 (0.15–0.28)

Región geográfica – Rest of world 162 / 162 0.14 (0.08–0.25)

Enfermedad visceral (hepática y/o pulmonar) al screening– Sí 97 / 101 0.28 (0.16–0.49)

Enfermedad visceral (hepática y/o pulmonar) al screening– No 735 / 700 0.17 (0.14–0.22)

SLPr: Análisis de subgrupos

0 0.5 1.0 1.5

A favorenzalutamida

A favor placebo

ECOG=European Co-operative Group.



% de pacientes que recibieron tratamientos posteriores

Docetaxel 32.8% 56.7%

Abiraterona 20.5% 45.6%

Cabazitaxel 5.8% 13.0%

Enzalutamida 1.0% 4.4%

Sipuleucel-T 1.4% 1.2%

Enzalutamida(n=872)

Placebo (n=845)

Tratamiento: Duración media (m) 16.6 4.6

Duración ≥ 12 ms 67.9% 18.0%

Tratamiento activo al corte 42.1% 7.2%

% con al menos 1 tratamiento posterior que prolonga la vida

40.3% 70.3%

Supervivencia Global

3 6 30 33 3612

100

80

60

40

20

00

Su

pe

rviv

enci

a (%

)

Meses9

863 850 33 2 0797872 824Enzalutamida, n

835 781 27 2 0701845 744Placebo, n

Placebo

Enzalutamida

HR=0.706 (95% CI: 0.60–0.84); p<0.0001

15

745

644

18

566

484

21

395

328

24

244

213

27

128

102


Mediana estimada de SG, meses (95% IC): Enzalutamida: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR)

T a progresión por PSA

Respuesta PSA

Enzalutamida

(n=854)

Placebo

(n=777)

≥ 50% ≥ 90%

78.0%46.8%

3.5%1.2%

Otros beneficios asociados al tratamiento....

T a inicio de Quimioterapia

HR=0.35 (95% CI: 0.30–0.40); p<0.0001

Toxicidad

Todos los Grados (%) Acontecimientos Grado ≥3 (%)

Enzalutamida(n=871)

Placebo(n=844)

Enzalutamida(n=871)

Placebo(n=844)

Fatiga 35.6 25.8 1.8 1.9

Dolor de espalda 27.0 22.2 2.5 3.0

Estreñimiento 22.2 17.2 0.5 0.4

Artralgia 20.3 16.0 1.4 1.1

Eventos Cardiacos 10.1 7.8 2.8 2.1

Hipertensión 13.4 4.1 6.8 2.3

Aumento ALT 0.9 0.6 0.2 0.1

Convulsiones 0.0† 0.1 0.0† 0.0

*Al menos 20% en enzalutamida y ≥2% más que en placebo; † Unaconvulsión ocurió después de la fecha de cutoff.

ALT=alanina aminotransferasa.

Beer TM, et al. ASCO-GU 2014; Presentación Oral.


Time *Phase 1b; †Phase 2; ‡Phase 3.

PSA

Metastatic

Symptoms


Non-Metastatic

Asymptomatic





castration


Localtherapy



nilutamide, etc.


Enzalutamide


Sipuleucel-T


Neoadjuvant†

TERRAIN†

Monotherapy†

STRIVE†

M0 CRPC ‡

PREVAIL

Enzalutamide post abiraterone†

AFFIRM

PRESIDE

PREMIERE

PLATO

UPWARD

ALLIANCE



PSA

Metastatic

Symptoms


Non-Metastatic

Asymptomatic





castration


Localtherapy



nilutamide, etc.


Enzalutamide


Sipuleucel-T


Neoadjuvant†

TERRAIN†

Monotherapy†

STRIVE†

M0 CRPC ‡


AFFIRM

PRESIDE

PREMIERE

PLATO

UPWARD

ALLIANCE

PRESIDE: Continued enzalutamide treatment beyond progression in combination with docetaxel in

chemotherapy-naïve mCRPC

Planned evaluations•rPFS, time to PSA progression, PSA response, objective response, time to pain progression, time to first SRE, QoL

ADT=androgen-deprivation therapy; BID=twice daily; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; PSA=prostate-specific antigen; QD=once daily; QoL=quality of life; R=randomisation; rPFS=radiographic progression-free survival.

• A Phase 3b randomised, double-blind placebo-controlled study• Primary endpoint: PFS

25

n=500

Chemotherapy-naïve mCRPC after ADT

failure


Progressive disease with ongoing ADT

Asymptomatic/mildly symptomatic

ECOG PS 0–1

Open-label enzalutamide

160 mg QDSafety follow-up

Enzalutamide (160 mg QD) +

docetaxel 75 mg/m2/3 weeks + prednisone (5

mg BID)

Placebo QD + docetaxel 75 mg/m2/

3 weeks + prednisone (5 mg BID)

R1:1

PLATO: Continued enzalutamide treatment beyond progression in combination with abiraterone in

chemotherapy-naïve mCRPC

Planned evaluations•PFS, time to PSA progression, PSA response, safety

ADT=androgen-deprivation therapy; BID=twice daily; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; PFS=progression-free survival; PSA=prostate-specific antigen; QD=once daily; R=randomisation.NCT01995513. Available at http://clinicaltrials.gov. Last accessed: April 2014.

• A Phase 4 randomised, double-blind placebo-controlled study• Primary endpoint: PFS

26

Recruiting

n=500

Chemotherapy-naïve mCRPC

after ADT failure

ECOG PS 0–1

Estimated life expectancy >12 months

Open-label enzalutamide

160 mg QDSafety follow-up

Enzalutamide (160 mg QD) + abiraterone (1000

mg QD) + prednisone (5 mg BID)

Placebo (QD) + abiraterone

(1000 mg QD) + prednisone (5 mg BID)

PSA RISE

R1:1

PROGRESSION

Ongoing trials

ALLIANCE: Study on enzalutamide with or without abiraterone in mCRPC

Planned evaluations•OS•Safety, Grade ≥3 AEs•Decline in PSA•PFS•Objective response•rPFS•Tumour burden and bone activity

Timing•Estimated primary completion December 2019

ADT=androgen deprivation therapy; AE=adverse event; BID=twice daily; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen; QD=once daily; R=randomisation; rPFS=radiographic PFS.NCT01949337. Available at http://clinicaltrials.gov. Last accessed: April 2014.


Enzalutamide (160 mg QD) +

abiraterone (1000 mg QD) +

prednisone(5 mg BID)

R2:1

n=1224

Chemotherapy-naïve mCRPC

No prior ketoconazole

Progression after ADT

ECOG PS 0–1

• A Phase 3 randomised, double-blind, placebo-controlled trial

• Primary endpoint: Metastatic-free survival

27

Recruiting

Ongoing trials

Abiraterona + Enzalutamida

PEACE: EORTC: Comparing Radium-223 and Enzalutamide vs Enzalutamide

Abi=abiraterone; ADC=apparent diffusion coefficient; ADT=androgen-deprivation therapy; BPI=Brief Pain Inventory; CRPC=castration-resistant prostate cancer; ECOG=Eastern Cooperative Oncology Group; FPI=first patient in; ORR=overall response rate; P=prednisone; PFS=progression-free survival; QD=once daily; R=randomisation.

Planned evaluations•Primary endpoint: sPFS 1•Secondary endpoints:

– PFS 2– ORR T1, T2– Predictive value bone markers and

ADC (Diff coeff)

Safety analysis•At 25, 50, 100 patients•At least two cycles or end of treatment

Statistical analysis•233 events (Month 51)•90% power•9 month difference (17 vs. 26 months)•1-sided type 1 error 0.025

Ongoing trials


+ ADT

n=510

Asymptomatic/mildly symptomatic

Metastatic CRPC (≥2 bone mets)

Visceral mets –ve

Lymph node ±ve

Maximum one line of treatment (chemo-naïve)

BPI pain ≤4 (none to mild)

Schedule for docetaxel, abi/P, enzalutamide

ECOG 0–1

• A Phase 3 multicentre study• Primary endpoint: sPFS 1

Recruiting (subject to revision)FPI Q2/3 2014

Radium-223 50kBq/kg

monthly, for 6 months +

enzalutamide 160 mg QD

+ ADT

R



PSA

Metastatic

Symptoms


Non-Metastatic

Asymptomatic





castration


Localtherapy



nilutamide, etc.


Enzalutamide


Sipuleucel-T


Neoadjuvant†

TERRAIN†

Monotherapy†

STRIVE†

M0 CRPC ‡

PREVAIL


AFFIRM

PRESIDE

PROSPER

PLATO

UPWARD

ALLIANCE

STRIVE: A study of Enzalutamide vs Bicalutamide in men with prostate cancer that failed primary ADT

Planned evaluations•Biochemical or radiographic PFS •Time to PSA progression•PSA response (≥50% decline from baseline)•Time to radiographic progression•QoL (FACT-P)•Safety

Timing•Estimated study completion June 2015

ADT=androgen-deprivation therapy; FACT-P=Functional Assessment of Cancer Therapy-Prostate; PFS=progression-free survival; PSA=prostate-specific antigen; PSADT=PSA doubling time; QD=once daily; QoL=quality of life; R=randomisation.NCT01664923. Available at http://clinicaltrials.gov. Last accessed: April 2014.

n=400Progressive

prostate cancer on first-line ADT*

PSA ≥5 ng/mL or PSADT

≤10 months if PSA 2 to <5 ng/mL

R1:1

Enzalutamide

160 mg QD

Bicalutamide 50 mg QD

Enrolment complete

• STRIVE is a Phase 2, randomised, double-blind, active-controlled trial

• Stratified by stage: M0N0, M0N1, or M1• Primary endpoint: PFS (biochemical or

radiographic)

32

Ongoing trials

TERRAIN: A study of Enzalutamide vs Bicalutamide in castrate men with metastatic prostate cancer

Planned evaluations•Radiographic PFS•Time to first SRE•Initiation of cytotoxic chemotherapy•QoL (FACT-P, EQ-5D)•PSA progression•Pain palliation (BPI-SF)•Safety (AEs, vital signs, physical exam, lab evaluations, ECG)•PKs

Timing•Estimated study completion December 2014

• TERRAIN is a Phase 2, randomised, double-blind, active-controlled trial

• Primary endpoint: PFS

n=370 mCRPC

Asymptomatic or mildly symptomatic

Progression after first-line ADT

Enzalutamide 160 mg QD

Bicalutamide 50 mg QD

R1:1

Enrolment complete

PROSPER: An efficacy and safety study of Enzalutamide in patients with non-metastatic CRPC

Planned evaluations•Metastatic-free survival•OS•Time to pain progression•Time to opiate use for prostate cancer pain•Time to first use of cytotoxic chemotherapy•Time to first use of new antineoplastic therapy•Time to PSA progression•PSA response rates•QoLTiming•Estimated study completion August 2017

ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer; EORTC=European Organisation for Research and Treatment of Cancer; FACT-P=Functional Assessment of Cancer Therapy-Prostate; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen; PSADT=PSA doubling time; QD=once daily; QLQ=Quality of Life Questionnaire; QoL=quality of life; R=randomisation.NCT02003924. Available at http://clinicaltrials.gov. Last accessed: April 2014.


Placebo QD

R2:1

n=1560

Non-metastatic (M0) CRPC


Progressive disease with ongoing ADT

Asymptomatic

PSADT ≤10 months

• M0 CRPC is a Phase 3, randomised, double-blind, placebo-controlled trial

• Primary endpoint: Metastatic-free survival

34

Recruiting

Enzalutamida en pacientes con cáncer de próstata sin tratamiento hormonal previo1,2

• Estudio fase 2 que evalua la eficacia y seguridad de enzalutamida en monoterapia en pacientes con cáncer de próstata localizado, localmente avanzado o mestastásico que no hayan recibido previamente tratamientos hormonales o quimioterapia.

*Patients must have an ECOG performance status of 0, life expectancy of >1 year. †If patients exhibited clinical benefit at Week 25, enzalutamide treatment was continued until disease progression or unacceptable toxicity.ADT=androgen-deprivation therapy; ECOG=Eastern Cooperative Oncology Group; mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetics; PSA=prostate-specific antigen; QD=once daily; QoL=quality of life. 1.Tombal B, et al. ASCO-GU 2013; Poster presentation 18.2.Smith MR, et al. ECC 2013; Oral presentation 2852.

Patient population

Patients with hormone-naïve prostate cancer (all

stages)

Non-castrate levels of testosterone (≥230 ng/dL)

PSA ≥2 ng/mL

Rising PSA requiring ADT

ECOG performance status 0 at screening

Life expectancy ≥12 months

(N=67)*


for 25 weeks†

Primary endpoint:

PSA response (≥80% decline) at Week 52

Secondary endpoints:

Enzalutamide PK

PSA kinetics

Changes in hormone levels

Metabolic changes

QoL

Safety/tolerability

Respuesta PSA semana 25

*Analysis was restricted to patients who completed the 25-week study period. Four patients who discontinued before Week 25 (for any reason) were considered non-responders; †≥80% decrease in PSA level. PSA=prostate-specific antigen.Tombal B, et al. ASCO-GU 2013; Poster presentation 18.

• 92.5% of patients (n=62*) experienced a PSA response†

(95% CI: 86.2%–98.8%)• Median decrease in PSA was 99.6% (range: –100 to –86.5%)

36

Max

imu

m d

ecli

ne

in

PS

A a

s p

erc

enta

ge

chan

ge

fro

m b

asel

ine

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58Observations

10080604020

0–20–40–60–80

–10061 64 67

Cinética de la Respuesta por PSA

Cinética de las concetraciones séricas de LH y testosterona durante Enzalutamida

• Aumento medio de 185% en LH desde el basal a la semana 25• Aumento medio de 114% en la testosterona desde basal a la semana 25

LH=luteinising hormone.Tombal B, et al. ASCO-GU 2013; Poster presentation 18.

185%(n=58)

114%(n=63)

450

400

350

300

250

200

150

100

50

0

Co

nce

ntr

atio

n (

%)

1 2 5 9 13 17 21 25Time (weeks)

LHTestosterone

Neoadjuvant study: A study of Enzalutamide as a neoadjuvant therapy for patients undergoing

prostatectomy for localised PC

Planned evaluations•Pathological CR•Downstage/surgical margins•PSA, DHT, testosterone nadir, time to and duration of nadir•Pharmacodynamic markers (proliferative index, apoptotic index, tumoural DHT, AR signalling markers, etc.)•Safety and tolerability

Timing•Study completed

*Intermediate risk: T2b or T2c clinical stage or PSA at screening 10–20 ng/mL or Gleason Score of 7; high risk: T3 clinical stage or PSA at screening >20 ng/mL or Gleason Score 8–10 AR=androgen receptor; CR=complete response; DHT=dihydrotestosterone; ECOG PS=Eastern Cooperative Oncology Group performance status; PSA=prostate-specific antigen; QD=once daily; Q3MOS=once every three months; R=randomisation; SC=subcutaneous.NCT01547299. Available at http://clinicaltrials.gov. Last accessed: April 2014.

n=52

Intermediate to high risk prostate

cancer*

≥3 positive cores

ECOG PS 0–1

R1:1

6 months ofenzalutamide 160 mg

QD + dutasteride 0.5 mg QD + leuprolide

22.5 mg SC Q3MOS prior to radical prostatectomy

6 months of enzalutamide 160 mg QD

prior to radical prostatectomy

• Phase 2, open-label, randomised study• Stratified based on intermediate and high risk*• Primary endpoint: Pathological CR rate

39

Completed

RESISTENCIA A ENZALUTAMIDA: LIGADA O NO AL RA

RESISTENCIA A ENZALUTAMIDA: LIGADA O NO AL RA

Conclusiones

• Enzalutamida es hoy una parte fundamental en el manejo del CPRC

• Enzalutamida, por su perfil de toxicidad, mínimo, lo hace idóneo para su aplicación en fases precoces de la enfermedad y en combinación

• Además de su incorporación a fases precoces de la enfermedad, optimizar la duración del

tratamiento profundizando en los mecanismos de resistencia

| Presentation Title | Presenter Name | Date | Subject | Business Use Only

Gracias!!

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Experiencia y Futuro del tratamiento con Enzalutamida