Futuro del tratamiento con Radium 223 en el carcinoma. Jose Pablo Maroto

Transcripción

1 Futuro del tratamiento con Radium 223 en el carcinoma de próstata metastásico Jose Pablo Maroto

2 Introducción: Por qué funcionaría una terapia dirigida al hueso en CPRC? > 90% de los pacientes con CPRC: evidencia radiológica de metástasis óseas 1 >80% de pacientes: única manifestación de enfermedad metastática Metástasis óseas: Riesgo de eventos óseos sintomáticos (SSEs): compresión medular, fractura patológica, cirugía ósea, radioterapia 2 Tratamientos dirigidos al hueso: Reducen SSEs y ofrecen un mejor control del dolor (Denosumab) PERO NO PROLONGAN SUPERVIVENCIA 1. Tannock et al. N Engl J Med. 2004;351: Lipton. Semin Oncol. 2010;37:S15-S29.

3 Supervivencia Global: Denosumab vs Zoledrónico: No diferencias 1.00 (proportion) Overall survival Denosumab Zoledronic acid HR = 1.03 (95% CI, ) P = Patients at risk: Zoledronic acid Denosumab HR = 1.03 (95% CI, ) P = Study month Fizazi K et al. Lancet 2011;377:

4 Fase III ALSYMPCA: Supervivencia Global Median OS (months) Radium Ra 223 (n = 614) Placebo (n = 307) Hazard ratio % CI P < Median OS : 3.6 months Radium Ra 223 Placebo Month Parker et al. J Clin Oncol 2012;30(suppl.):abstr LBA4512. Presented at ASCO NCT

5 FDA Indication: Radio-223 es un agente terapéutico radioactivo emisor alfa, indicado para el tratamiento de los pacientes con cáncer de prostata resistente a castración, con metásasis óseas sintomáticas y ausencia de metástasis viscerales conocidas 1. 1 Food and Drugs Administration. Xofigo Highlights of prescribing information.

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8 Cuál es el futuro en CaP- del Radium-223? 1. Optimizar 2. Adelantar 3. Combinar

9 1. Optimizar PHASE RADIUM 223 CLINICAL TRIALS CLINICALTRIALS.GO V IDENTIFIER STATUS I/II A re-treatment safety study of Ra 223 in subjects with CRPC with bone metastases who received an initial course of six doses of Ra kbq/kg every four weeks NCT Completed; data in Q1/16 II A three arm randomized open-label Phase II study of Ra kbq/kg vs 80 kbq/kg, and vs 50kBq/kg in an extended dosing schedule in subjects with castration-resistant prostate cancer metastatic to the bone NCT Enrollment completed III II

10 AAA 89 años en la actualidad Sin antecedentes de interés CPRC, Gleason 4+3 Docetaxel x 6 ciclos Enzalutamida Sólo metástasis óseas, ligeramente sintomáticas, analgesia primer escalón

11 PHASE RADIUM 223 CLINICAL TRIALS CLINICALTRIALS.GO V IDENTIFIER STATUS I/II A re-treatment safety study of Ra 223 in subjects with CRPC with bone metastases who received an initial course of six doses of Ra kbq/kg every four weeks NCT Completed; data in Q1/16 II A three arm randomized open-label Phase II study of Ra kbq/kg vs 80 kbq/kg, and vs 50kBq/kg in an extended dosing schedule in subjects with castration-resistant prostate cancer metastatic to the bone NCT Enrollment completed III II Randomizado a la rama de extensión de tratamiento Excelente tolerancia sin toxicidad añadida Completó 10 ciclos: Stop por astenia y adelgazamiento No hemos diagnosticado metástasis extra-óseas

12 PSA Docetaxel Enzalutamida Radium-223

13 FFAA Docetaxel Enzalutamida Radium-223

14 Con Radium Cuál es la duración óptima del tratamiento? Cómo sabemos que está funcionando?

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17 Valor de la normalización de FFAA con Radium-223

18 NaF/FDG PET/MRI in Measuring Response to Radium Ra 223 Dichloride in Patients With Metastatic Hormone-Resistant Prostate Cancer Stanford: Evaluación de NaF/FDG PET/MRI como predictor de respuesta PET: Captación a las 12 y 24 semanas RMN: Variación en tamaño a las 12 y 24 sem Correlación con variación en FFAA Detección de Metástasis Extraóseas

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20 2. Adelantar Radium-223 Evitamos SREs Más fácil llegar a >4 ciclos Perfil toxicidades idóneo Podemos combinar Dolor no es tan importante en esta fase inicial Miedo a impacto sobre reserva medular Segundas neoplasias Coste

21 Phase III ALSYMPCA: Time To First SRE Survival Pro obability, % 100 Radium Ra 223 (n = 614) Placebo (n = 307) Median OS (months) Hazard ratio % CI P Radium Ra 223 Placebo 0 Month Parker et al. J Clin Oncol 2012;30(suppl.):abstr LBA4512.

22 Safety of Cytotoxic Chemotherapy Following Radium-223 Chloride Therapy in the Phase III ALSYMPCA Study in Patients with CRPC with Bone Metastases Parameter Radium-223 (n=93) Placebo (n=54) During Chemotherapy Administration Deaths on chemotherapy, % Causality: PC and skeletal mets (± other mets) PC with other mets (or mets not specified) Cerebral hemorrhage due to trauma Cardiopulmonary failure 30 Days After Chemotherapy Administration Deaths within 30 days after chemotherapy, n % 6 4 Causality: PC and skeletal mets (± other mets) Bronchopneumonia Respiratory failure + pulmonary edema Mets, metastases; PC, prostate cancer Sartor O, et al. Presented at: ESMO, Sept. 28 Oct 2, 2012, Vienna; Poster 936P.

23 Problemas a largo plazo con Radium-223?

24 3. Combinar

25 Secuencia o Combinación? Combinación: Posibilidad de Radium-223 en pacientes con extensión extra-ósea Heterogeneidad del CaP Retrasar el desarrollo de resistencias Más caro Secuencia: Más barato NO HAY RESISTENCIA CRUZADA

26 Conversiones ARv7 según tipo de tratamiento Nakazawa M Ann Oncol,00:1-7, 2015

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28 American EAP. Concomitant use Abi/Enza plus Radium in first line therapy

29 PHASE RADIUM 223 CLINICAL TRIALS CLINICALTRIALS.GOV IDENTIFIER STATUS III A phase III randomized, double blind, placebo controlled trial of Ra 223 in combination with Enzalutamide in asymptomatic or mildly symptomatic chemo naïve patients with bone predominate disease NCT Now Enrolling III II A phase III randomized, double blind, placebo controlled trial of Ra 223 in combination with Abiraterone in asymptomatic or mildly symptomatic chemo naïve patients with bone predominate disease A phase III randomized, double blind, placebo controlled trial of Ra 223 in combination with Docetaxel in asymptomatic or mildly symptomatic chemo naïve patients with bone predominate disease NCT NCT Now enrolling Now Enrolling II II A phase III randomized, double blind, placebo controlled trial of Ra 223 in combination with Sorafenib or Pazopanib in asymptomatic or mildly symptomatic chemo naïve patients with bone predominate disease NCT Now enrolling II

30 Fase I: Docetaxel + Radium-223

31 Further Study of Radium-223 Plus Docetaxel: Expanded Safety Cohort Study Design and Schedule of Evaluations The dose regimen currently being explored in a randomized 2:1 open-label expanded safety cohort treated with radium kbq/kg + docetaxel 60 mg/m 2 compared to docetaxel 75 mg/m 2. TREATMENT (30 WEEKS) PATIENTS (N=46) Progressive mcrpc >2 bone metastases R >2 lung and/or liver 2:1 (>2 cm) metastases were not permitted. No symptomatic nodal disease or other primary tumors n=33 n=13 Radium kbq/kg bw q 6 wk 5 + docetaxel 60 mg/m 2 q 3 wk mg prednisone bid Docetaxel 75 mg/m 2 q 3 wk 10 (option of step-down to 60 mg/m 2 ) + 5 mg prednisone bid FOLLOW-UP q 3 months until 12 months after first injection PRIMARY END POINT: Safety EXPLORATORY EFFICACY ENDPOINTS: Biochemical and bone markers; radiologic and soft tissue imaging; and patient-reported outcomes (expanded safety cohort) SOURCE: Morris MJ, et al. Ann Oncol. 2014;25 (Suppl 4): iv1 - mdu abstr 765PD. 31

32 PSA and Bone ALP Dynamics RADIUM kbq/kg IV q 6 wk 5 + DOCETAXEL 60 mg/m 2 IV q 3 wk 10 N= DOCETAXEL 75 mg/m 2 IV q 3 wk 10 N=13* Change of PSA, % Change of PSA, % Change of ALP, % RADIUM kbq/kg IV q 6 wk 5 + DOCETAXEL 60 mg/m 2 IV q 3 wk 10 N=28 Change of ALP, % DOCETAXEL 75 mg/m 2 IV q 3 wk 10 N=13* ALP, alkaline phosphatase. *5 docetaxel patients received the step-down dose of 60 mg/m 2. SOURCE: Morris MJ, et al. Ann Oncol. 2014;25 (Suppl 4): iv1 - mdu abstr 765PD. 32

33 Mensajes para casa Todo paciente con metástasis óseas sintomáticas y sin enfermedad extraósea significativa visceral- puede beneficiarse de Radium-223 Mejora dolor, calidad de vida: PROLONGA SUPERVIVENCIA Aún podemos optimizar Tratamiento eficaz y poco tóxica en pacientes con enfermedad predominantemente ósea

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