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.