Nuevas alternativas terapéuticas en cáncer de próstata Maria José Méndez Vidal HU Reina Sofía 29 de Junio de 2018

Transcripción

1 Nuevas alternativas terapéuticas en cáncer de próstata Maria José Méndez Vidal HU Reina Sofía 29 de Junio de 2018

2 Evolución del tratamiento del CP Enfermedad incurable, Aparición de resistencias Necesidad de nuevos tratamientos

3 Nuevos Agentes hormonales Inhibidores PARP Combinaciones con nuevos agentes (inh AKT) Inmunoterapia Radiofármacos

4 Nuevos Agentes hormonales Inhibidores PARP Combinaciones con nuevos agentes (inh AKT) Inmunoterapia Radiofármacos

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6 Fármaco Mecanismo Fase ARN 509 Apalutamida ODM-201 EPI-001 Orteronel Antiandrógeno, Bloqueo transl. Antiandrógeno Menor paso barrera HE. Inhibición N terminal Inh liasa, menos efectos secundarios. III en CPRC M0 y CPHS finalizado III finalizado M0, en marcha HS I/II Fase III finalizado negativo Galeterona Inh CYP 17 antiandrógeno Fase III suspendido Mifepristona Onapristona Inh.receptor glucocorticoide Inh. Receptor progesterona Fase I/II Fase I/II

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8 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 ADT vs placebo + ADT SLP metastasica TITAN n=1000 CP HS metastasico ARN +ADT vs placebo ADT SLP SG NCT N=986 CPRCm ARN+ abi + PDN vs Abi+pl+ PDN rslp

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10 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+docetaxe l SLP SG

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13 Nuevos Agentes hormonales Combinaciones con nuevos agentes hormonales. Inhibidores PARP Inmunoterapia Radiofármacos

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15 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 LY Inh PI3K mtor Enza + LY302vs enza placebo Fase II aleatorizado

16 Abiraterona + Ipatasertib

17 Diferencias en subgrupos expresión PTEN

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

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20 DNA repair and PARP inhibitors Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

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23 iparp+ terapia hormonal

24 Mayor tasa de respuesta en mutados

25 Slide 17 Presented By Carmel Pezaro at 2018 ASCO Annual Meeting

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27 Olaparib + abiraterona Trial design Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

28 Baseline characteristics Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

29 Primary endpoint: Investigator-assessed rpfs Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

30 rpfs by DNA Repair mutation status Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

31 Response rates Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

32 Overall Survival Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

33 Is this practice changing? Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

34 Inhibidores PARP desarrollo clínico TRITON 2 Fase II FARMACO POBLACION 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

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

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37 Vacuna Proteina PSA acoplada a vectores víricos (vaccinina, Fowlpox) +molec coestimuladoras(b 7.1, ICAM-1,LFA-3) Dosis inicial vaccinina, adicionales fowlpox. PROSTVAC-VF

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39 PROSPECT Phase 3 Design Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

40 Overall Survival ITT Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

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43 IMbassador250 Phase III Design: Enzalutamide +/- Atezolizumab 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. 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) 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 Safety Run-In (n=10) Atezolizumab 1200 mg iv q3w + Enzalutamide 160mg po qd 1:1 Randomization (n=~720) Atezolizumab 1200 mg q3w + Enzalutamide 160mg qd Enzalutamide 160mg qd

44 KEYNOTE-199: Pembrolizumab <br />For Post-Docetaxel Metastatic Castration-Resistant Prostate Cancer (mcrpc) Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

45 Study Design Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

46 Baseline Characteristics Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

47 Best Response by RECIST 1.1 (Central Review) Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

48 Is this practice changing? Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

49 cómo seleccionar pacientes?

50 Cortesía David Lorente

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

52 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.

53 177 Lu-PSMA is the most commonly used PSMA-specific RPT in the clinic

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

55 68Ga-PSMA11 PET/CT localizes recurrent prostate cancer with high accuracy Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

56 Study Design Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

57 Detection Rate and Location Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

58 Primary Endpoint (PPV) Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

59 Primary Endpoint (pos. predictive value, PPV) Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

60 Example: distant recurrence Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

61 Is this practice changing? Presented By Rahul Aggarwal at 2018 ASCO Annual Meeting

62 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.