Nuevos conceptos y alternativas en el tratamiento hormonal para la enfermedad avanzada María J. Ribal Servicio de Urología. Hospital Clínic. Universitat de Barcelona

El tratamiento hormonal no está exento de efectos secundarios, debemos tener en cuenta la calidad de vida de nuestros pacientes. Podemos retrasar la castración-resistencia? –Tratamiento hormonal intermitente –Tratamiento hormonal diferido Los mecanismos moleculares de desarrollo del CPCR han abierto las puertas a nuevas alternativas terapéuticas. –El RA es uno de los efectivos en el desarrollo del CPCR. –Las maniobras hormonales siguen siendo vigentes en el CPCR.

We performed a matched cohort study using linked administrative data at the Institute for Clinical Evaluative Sciences (ICES) in Ontario, Canada (population of approximately 11,000,000). Men with prostate cancer were identified using the Ontario Cancer Registry (OCR). The OCR is a comprehensive provincial registry that captures more than 95% of cancer cases

Tratamiento inmediato o diferido

Selection Criteria

Results Intermittent versus Continous AD

(ASCO#4558) Prospective study, N = 48 PCa pts treated with intermittent ADT for biochemical relapse after RP or RT Dynamics of bone mineral density (BMD) during intermittent ADT ADT-induced loss of BMD was attenuated during the ‘off treatment’ period of an intermittent ADT regimen, suggesting less net BMD loss than during continuous ADT

Castración resistencia

Rising PSA Hormone Naive Monotherapy Rising PSA CRPC Locally Advanced Mets CRPC Symptomatic Mets Asymptomatic Hormone Naive Mets Asymptomatic CRPC CRPC Post-Docetaxel Death From CRPC Multimodality NCCN, Prostate Cancer Continuum

Análisis secundario de la rama placebo de un estudio RCT (atrasentran vs placebo) N = 470 pts afectos CPRC M0 Análisis multivariante: Predictive factors for outcome* Factor not predictive for outcome* PSABMI PSA velocity Time (mo) Median time to disease progression22.4 Median time to first bone metastasis25.2 Median overall survival46.8

Charles B. Huggins “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.”

CRPC: Adaptation or selection? Androgen-sensitive tumour cells Androgen-independent tumour cells Tumour hormone- dependent Tumour hormone- independent Adaptation theory: genetic changes provide survival mechanisms that allow the cells to continue growing in the androgen depleted environment Regression of tumour Hormone withdrawal Clonal selection pathway, androgen withdrawal allows for the selection of androgen- independent cells to proliferate that existed at the time of initiation of therapy Hormone- withdrawal

Testosterone DHT 5a-R RA (Inactive) AR with DHT Ligand (Dimers) Activated AR gets in the nucleus and binds DNA Androgen Response Element (ARE) Gene expression Hsp 90 Hsp 70