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Nuevas alternativas terapéuticas

en cáncer de próstata

Maria José Méndez Vidal

HU Reina Sofía

29 de Junio de 2018

Evolución del tratamiento del CP

• Enfermedad incurable, • Aparición de resistencias • Necesidad de nuevos

tratamientos

• Nuevos Agentes hormonales • Inhibidores PARP • Combinaciones con nuevos agentes

(inh AKT) • Inmunoterapia • Radiofármacos

• Nuevos Agentes hormonales • Inhibidores PARP • Combinaciones con nuevos agentes

(inh AKT) • Inmunoterapia • Radiofármacos

Fármaco Mecanismo Fase

ARN 509 Apalutamida

Antiandrógeno, Bloqueo transl.

III en CPRC M0 y CPHS finalizado

ODM-201 Antiandrógeno Menor paso barrera HE.

III finalizado M0, en marcha HS

EPI-001 Inhibición N terminal

I/II

Orteronel Inh. 17-20 liasa, menos efectos secundarios.

Fase III finalizado negativo

Galeterona Inh CYP 17 antiandrógeno

Fase III suspendido

Mifepristona Inh.receptor glucocorticoide

Fase I/II

Onapristona Inh. Receptor progesterona

Fase I/II

Desarrollo Fase III Apalutamida Población Brazos Objetivo

ATLAS n=1500

CP localizado o alto riesgo con RT

apalutamide (240 mg) 30m, + bicalutamide placebo 4m +(GnRH) agonist for 30 RT about 8 weeks after randomization

Apalutamide placebo+ bicalutamida 4m +(GnRH) agonist for 30 RT about 8 weeks after randomization

SLP metastasica MFS

SPARTAN n=1200

CPRCM0 PSADT <10 meses

ARN 240 + ADT vs placebo + ADT

SLP metastasica

TITAN n=1000

CP HS metastasico

ARN +ADT vs placebo ADT

SLP SG

NCT02257736 N=986

CPRCm ARN+ abi + PDN vs Abi+pl+ PDN

rSLP

Desarrollo Fase III ODM

Población Brazos Objetivo

ARAMIS 1500

CPRCM0 PSADT <10 meses

ODM 600 C 12h + ADT vs placebo + ADT

SLP metastasica

ARASENS 1300

CP HS metastasico

ODM+ADT+ docetaxel vs placebo+ ADT+docetaxel

SLP SG

• Nuevos Agentes hormonales • Combinaciones con nuevos agentes

hormonales. • Inhibidores PARP • Inmunoterapia • Radiofármacos

Combinaciones agentes hormonales

Brazos

Ipatasertib Inh AKT Abiraterona+ PDN+ipatasertib vs abiraterona placebo+PDN

Estratificación por estatus PTEN Fase III

AZD5363

Inh AKT

Combinación con enzalutamida

Fase II

LY3023414

Inh PI3K mTOR Enza + LY302vs enza placebo

Fase II aleatorizado

Abiraterona + Ipatasertib

Diferencias en subgrupos expresión PTEN

• Nuevos Agentes hormonales • Inhibidores PI3K-Akt-mTOR • Inhibidores PARP • Inmunoterapia • Radiofármacos

DNA repair and PARP inhibitors

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

iPARP+ terapia hormonal

Mayor tasa de respuesta en mutados

Slide 17

Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

Trial design

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Olaparib + abiraterona

Baseline characteristics

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Primary endpoint: Investigator-assessed rPFS

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

rPFS by DNA Repair mutation status

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Response rates

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Overall Survival

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Is this practice changing?

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Inhibidores PARP desarrollo clínico FARMACO POBLACION

TRITON 2 Fase II

RUCAPARIB brazo único Postabi/enza en pacientes con mutaciones

TRITON 3 Fase III

RUCAPARIB vs estandar Abi/Enza o QT

en pacientes con mutaciones

GALAHAD Fase II

NIRAPARIB monoterapia Postabi/enza en pacientes con mutaciones

TALAZOPARIB Postabi/enza en pacientes con mutaciones

• Nuevos Agentes hormonales • Inhibidores PI3K-Akt-mTOR • Inhibidores PARP • Inmunoterapia • Radiofármacos

PROSTVAC-VF

Vacuna Proteina PSA acoplada a vectores víricos (vaccinina, Fowlpox) +molec coestimuladoras(B7.1, ICAM-1,LFA-3) Dosis inicial vaccinina, adicionales fowlpox.

PROSPECT Phase 3 Design

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Overall Survival ITT

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

IMbassador250 Phase III Design: Enzalutamide +/-

Atezolizumab

Primary Endpoint: Overall survival

Key Secondary Endpoint: rPFS, Time to PSA

progression, PSA response, Time to SSE, ORR

in evaluable patients (RECIST and mRECIST),

DoR, PRO

Phase III, multicenter, randomized, open-label study designed to evaluate the safety and

efficacy of atezolizumab + enzalutamide vs. enzalutamide alone in patients with mCRPC after

failure of an androgen synthesis inhibitor (e.g., abiraterone) and failure of, ineligibility for, or

refusal of a taxane regimen.

Enzalutamide

160mg qd

Atezolizumab

1200 mg q3w

+

Enzalutamide

160mg qd

Key Eligibility (n = 730)

• mCRPC

• ECOG PS 0-1

• Progression on a prior androgen

synthesis inhibitor (e.g. abiraterone)

for prostate cancer

• Failed one prior taxane-containing

regimen or refused / ineligible for

taxane

Stratification Factors

• Prior taxane (≥2 cycles for mCRPC)

yes / no

• Liver metastasis (yes / no)

• LDH ≤ ULN vs > ULN

• Brief Pain Inventory Q3 (<4 versus

≥4)

1:1

Ran

do

miz

atio

n

(n=

~7

20

)

Safety Run-In (n=10)

Atezolizumab 1200 mg iv q3w +

Enzalutamide 160mg po qd

KEYNOTE-199: Pembrolizumab <br />For Post-Docetaxel Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Study Design

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Baseline Characteristics

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Best Response by RECIST 1.1 (Central Review)

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Is this practice changing?

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

¿cómo seleccionar pacientes?

Cortesía David Lorente

• Nuevos Agentes hormonales • Inhibidores PI3K-Akt-mTOR • Inhibidores PARP • Inmunoterapia • Radiofármacos

PSMA-directed radioligand therapy

PSMA-directed radioligand therapy (RLT) emerged as therapeutic option for mCRPC. PSMA-directed RLT advantage of potentially addressing both visceral and bony micro- and macroscopic disease.

177 Lu-PSMA is the most commonly used PSMA-specific RPT in the clinic

DOTA-conjugated radioligand, 177 Lu-PSMA-617, has demonstrated favorable biodistribution and pharmacokinetic properties high target affinity, prolonged intratumoral retention and minimal renal uptake

68Ga-PSMA11 PET/CT localizes recurrent prostate cancer with high accuracy

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Study Design

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Detection Rate and Location

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Primary Endpoint (PPV)

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Primary Endpoint (pos. predictive value, PPV)

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Example: distant recurrence

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Is this practice changing?

Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

Conclusiones

● A pesar de los avances es necesario seguir desarrollando nuevos fármacos.

● Es esencial seleccionar a los pacientes con los biomarcadores adecuados (alteraciones vías reparación DNA, pérdida de PTEN, inestabilidad).

● Necesario selección de pacientes y adecuado diseño de estudios.