Valor presente y futuro de la inmunoterapia en

Valor presente y futuro de la inmunoterapia en el CPRC Nuria Romero Laorden Investigador Juan Rodés - Oncología Médica Hospital Universitario La Princesa

DISCLOSURE INFORMATION ● Employment: ● Consultant or Advisory Role: Bayer ● Stock Ownership: ● Research Funding: Bayer, Astellas, Janssen, Sanofi-Aventis ● Speaking: MSD, Sanofi-Aventis, Astellas, Janssen-Cilag ● Grant support: ● Other:

ESTRATEGIAS 1. Vacunas

N Engl J Med 2010; 363: 411 -22.

IMPACT STUDY: Sipuleucel T vs placebo ü Diferencias en SG (HR 0. 78, p=0. 03) ü Sin diferencias en tiempo a la progresión ü Casi un 40% de pacientes tratados con quimioterapia 25. 8 months 21. 7 months Kantoff et al, NEJM 2010

Vacunas: ensayos clínicos ü En enfermedad localizada ü En recaída bioquímica ü En CP metastásico hormonosensible Patel A, Fong L. Oncology 2018

ü En CP resistente a la castración M 0, asintomático Patel A, Fong L. Oncology 2018

ü En CP resistente a la castración metastásico Patel A, Fong L. Oncology Jun 2018 Patel A, Fong L. Oncology 2018

Gulley et al. JCO 2010. Randomized phase II trial suggested OS prolongation

Gulley et al. Oral Presentation. ASCO 2018

Gulley et al. Oral Presentation. ASCO 2018

ESTRATEGIAS 2. Checkpoint inhibitors

Schepisi et al, Int Journal Mol Sci 2017

11% respuestas bioquímicas 10% respuestas radiológicas

Antonarakis KN 199. ASCO GU 2019

Fase 2 multi-cohorte en pacientes politratados • En la cohorte A no se realizó selección de pacientes por presencia o no de defectos de la reparación • N= 42 pacientes, 4 ongoing • Follow-up 11. 4 meses (5. 5 -15 meses)

12% respuestas bioquímicas 7% respuestas radiológicas • Las toxicidades grado 3 -4 más frecuentes fueron anemia (27%), fatiga (7%), astenia (7%), y neutropenia (7%) • Respecto a la toxicidad inmuno-mediada todas las toxicidades fueron grado 1 -2, la más frecuente hipotiroidismo. Yu EY, KN 365. ASCO GU 2019

Yu EY, KN 365. ASCO GU 2019

31% respuestas bioquímicas 14% respuestas radiológicas Fase 2 multi-cohorte • N= 72 pacientes, 18 ongoing • Tras progresión a enza/abi • Follow-up 10. 1 meses (7. 9 -12. 4 meses) • Expresión de PDL 1 +29%

26% respuestas bioquímicas 20% respuestas radiológicas Fase 2 multi-cohorte • N= 70 pacientes, 22 ongoing • Tras progresión a abiraterona • Follow-up 8. 9 meses (6. 5 -13 meses) • Expresión de PDL 1 +30%

Havel JJ Nature 2019

ESTRATEGIAS 3. Búsqueda de biomarcadores

1551 tumors from 1346 patients with prostate cancer at MSKCC were prospectively analyzed. Tumor mutation burden and MSIsensor score, a quantitative measure, were calculated. • • • 32 (3. 1%) d. MMR prostate cancer (7 germ) 23 (2. 2%) high MSIsensor scores. 11 patients with MSI-H/d. MMR CRPC received anti–PD-1/PD-L 1 therapy. o 6 biochemical response (≥ 50%) o 4 radiological response o As of May 2018, 5/6 responders were still on therapy for as long as 89 weeks Abida et al, Jama Oncol 2018

• • N= 17 Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i. v. every 28 days and olaparib 300 mg tablets p. o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. The most common treatment-related grade 3 or 4 adverse events were • anemia (4/17; 24%), • lymphopenia (2/ 17; 12%), • infection (2/17; 12%), • nausea (2/17; 12%) Karzai et al, Journal Immunot Cancer 2018

• • Patients with fewer peripheral myeloid derived suppressor cells and with alterations in DDR genes were more likely to respond Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response Karzai et al, Journal Immunot Cancer 2018

POOR PROGNOSIS PATIENTS: Median age of participants was 65, median PSA was 115 ng/m. L, 67% had visceral metastases, and 60% had ≥ 4 prior systemic therapies. • • • Preliminary evidence suggests that AR-V 7 -positive tumors may be enriched for DNA-repair defects Prospective phase 2 trial n=15 AR-V 7 metastatic prostate cancer patients nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks 4 DOSES MANTEINANCE nivolumab 3 mg/kg every 2 weeks Outcomes included PSA response rate, ORR, PSA PFS, clinical/radiographic PFS and OS Targeted NGS was performed to determine DNArepair defects -> 40% (6/15) DRD mutations (3 in BRCA 2, 2 in ATM) Boudadi K, et al. Oncotarget 2018

Overall PSA response rate was 2/15 (13%), ORR was 2/8 (25%). Responses appeared better in DRD+ § § PSA-PFS (HR 0. 19; P<0. 01, significant), PFS (HR 0. 31; P=0. 01, significant), and OS (HR 0. 41; P=0. 11, nonsignificant). There were no new safety concerns. Boudadi K, et al. Oncotarget 2018

BEYOND THAT WE KNOW • Sequence variants in the ATR gene (a DNA damage sensor) as well as the BRIP 1, CHEK 2, and RAD 50 genes (all of which are considered to be HR genes). • Missense mutations observed in the BRIP 1 and CHEK 2 genes both involve functional domains of the corresponding protein products. Therefore, it is possible that one or both of these mutations may result in loss of function of the BRIP 1 and/or CHEK 2 genes, which could lead to HR deficiency Dib E, et al. Clin Genit Cancer Dec 2018

ESTRATEGIAS 4. Futuro

• • Reactivación de retrovirus endógenos mediante tratamientos que actúan a nivel epigenético Activación de la vía IFN Jones PA, et al. Nature Rev 2019

Jones PA, et al. Nature Rev 2019

INDUCCIÓN DE UN AMBIENTE INMUNE ADECUADO Más allá de la combinación terapéutica… ¿Secuenciación de tratamiento?

CONCLUSIONES La inmunoterapia no forma parte actualmente del presente del tratamiento convencional del cáncer de próstata Pendientes de resultados de múltiples ensayos en marcha, en combinación y secuenciación terapéutica - Prometedores datos en subgrupos específicos de pacientes - Necesidad de biomarcadores

Gracias nuriaromerolaorden@gmail. com