[Prognostic factors and response predictors in castration resistant prostate cancer.] / Factores pronósticos y predictores de respuesta en cáncer de próstata resistente a la castración.

Prostate cancer is a health problem in many Countries worldwide. Understanding the essential function of androgens in the prostate physiology led to the development of hormonal blockade as a therapeutic option in advanced disease, with limited response with time and development of resistance. In this stage, where castration resistant prostate cancer (CRPC) is defined, it is associated with poor prognosis because survival varies between 18 and 24 months. Even with castration levels, tumors are dependent on the functional androgen receptor (AR). In this paper, we analyze pretreatment clinical parameters such as prognostic or progression-predictive biomarkers, castration resistance mechanisms, the development of new technologies for the use of the so called liquid biopsies from biological ayufluids and the identification of circulating tumor cells as CRPC response and progression biomarkers. Currently ongoing clinical trials are partially oriented to the search of new prognostic and predictive biomarkers, that will enable to open up precision medicine and so to improve oncological patient's quality of life with it.

[Immunotherapy in castration resistant prostate cancer.] / Inmunoterapia en cáncer de próstata resistente a la castración.

We review the role of immunotherapy in castration resistant prostate cancer. Two immunotherapeutic strategies have been applied, isolated or in combination, either with each other or with other agents with demonstrated efficacy in this scenario that would play a role as immunomodulators: vaccines or monoclonal antibodies aimed to block immune response checkpoint inhibitors. Although CRPC presents, a priori, characteristics suggesting that immunotherapy may play a relevant role as a therapeutic strategy, its clinical application has demonstrated a limited and heterogeneous activity, in terms of proportion of responders and response intensity. Generally, the objective response rate is very low, although, in patients who have response it is possible to detect a clear, long-lasting benefit. Only the autologous vaccine Sipuleucel T has demonstrated an overall survival increase in patients with good prognosis criteria. In these treatments, it is characteristic that no progression free survival increase is visible due to its action mechanism. PSA evolution may not be considered a surrogate variable of radiological response or clinical benefit in this environment either. It is necessary to identify what patient's or tumor's characteristics are able to maximize the response. An important limitation is the absence of response predictive biomarkers that serve for patient preselection. As a general rule, the best responses with isolated immunotherapeutic treatments have been observed in patients with low tumor load, which may suggest that their optimal application could be in earlier phases of the disease (high risk localized, biochemical failure, etc) Combination strategy, without doubt the one with best future, is based on additional treatments increasing cell lysis with the subsequent antigen exposure and/ or producing an immunomodulatory effect that can surmount tumor induced immunologic tolerance. The results obtained suggest that immunotherapy may be more effective in combined therapy with other active therapies (abiraterone, enzalutamide, Radium 223, docetaxel) in a fight to achieve disease chronification.

Inmunoterapia en cáncer de próstata resistente a la castración / Immunotherapy in castration resistant prostate cancer

Revisamos el papel de la inmunoterapia en el cáncer de próstata resistente a castración. Se han aplicado dos estrategias inmunoterápicas, de forma aislada o en combinación, bien entre ellas o bien con otros agentes de eficacia demostrada en este escenario y que ejercerían un papel inmunomodulador: vacunas o anticuerpos monoclonales destinados al bloqueo de puntos de control inhibidores de la respuesta inmune. Aunque a priori el CPRC presenta características que sugieren que la inmunoterapia podría jugar un papel relevante como estrategia terapéutica, su aplicación clínica ha demostrado una actividad limitada y heterogénea, en cuanto a la proporción de respondedores e intensidad de respuesta. En términos generales, la tasa de respuestas objetivas es muy baja, aunque, en los pacientes que responden, es posible detectar un beneficio claro y duradero. Sólo la vacuna autóloga Sipuleucel T ha demostrado un aumento de la supervivencia global en pacientes con criterios de buen pronóstico. Es característico en estos tratamientos que no se observe un incremento en la supervivencia libre de progresión debido a su propio mecanismo de acción. Tampoco la evolución del PSA puede considerarse una variante subrogada de respuesta radiológica o beneficio clínico en este entorno. Se hace necesario identificar qué características de los pacientes o del tumor son capaces de maximizar la respuesta. Una limitación importante es la ausencia de biomarcadores predictores de respuesta que sirvan para la preselección de pacientes. Como norma general, las mejores respuestas con tratamientos inmunoterápicos aislados se han observado en pacientes con baja carga tumoral, lo cual puede sugerir que su aplicación óptima podría ser en fases más precoces de la enfermedad (localizado de alto riesgo, fracaso bioquímico, etc.). La estrategia de combinación, sin lugar a dudas la de más futuro, se fundamenta en que los tratamientos adicionales incrementan la lisis celular con la consiguiente exposición antigénica y/o ejercen un efecto inmunomodulador capaz de vencer la tolerancia inmunológica inducida por el tumor. Los resultados obtenidos sugieren que la inmunoterapia puede ser más efectiva en modo tratamiento combinado con otros tratamientos activos (abiraterona, enzalutamida, Radio 223, docetaxel) en la lucha por lograr cronificar la enfermedad

We review the role of immunotherapy in castration resistant prostate cancer. Two immunotherapeutic strategies have been applied, isolated or in combination, either with each other or with other agents with demonstrated efficacy in this scenario that would play a role as immunomodulators: vaccines or monoclonal antibodies aimed to block immune response checkpoint inhibitors. Although CRPC presents, a priori, characteristics suggesting that immunotherapy may play a relevant role as a therapeutic strategy, its clinical application has demonstrated a limited and heterogeneous activity, in terms of proportion of responders and response intensity. Generally, the objective response rate is very low, although, in patients who have response it is possible to detect a clear, long-lasting benefit. Only the autologous vaccine Sipuleucel T has demonstrated an overall survival increase in patients with good prognosis criteria. In these treatments, it is characteristic that no progression free survival increase is visible due to its action mechanism. PSA evolution may not be considered a surrogate variable of radiological response or clinical benefit in this environment either. It is necessary to identify what patient`s or tumor's characteristics are able to maximize the response. An important limitation is the absence of response predictive biomarkers that serve for patient preselection. As a general rule, the best responses with isolated immunotherapeutic treatments have been observed in patients with low tumor load, which may suggest that their optimal application could be in earlier phases of the disease (high risk localized, biochemical failure, etc) Combination strategy, without doubt the one with best future, is based on additional treatments increasing cell lysis with the subsequent antigen exposure and/ or producing an immunomodulatory effect that can surmount tumor induced immunologic tolerance. The results obtained suggest that immunotherapy may be more effective in combined therapy with other active therapies (abiraterone, enzalutamide, Radium 223, docetaxel) in a fight to achieve disease chronification

Factores pronósticos y predictores de respuesta en cáncer de próstata resistente a la castración / Prognostic factors and response predictors in castration resistant prostate cancer

El cáncer de próstata es un problema de salud en muchos países a nivel mundial. La comprensión de la función esencial que los andrógenos tienen en la fisiología de la próstata condujo al desarrollo del bloqueo hormonal como opción de tratamiento en la enfermedad avanzada, con respuesta limitada en el tiempo y desarrollo de resistencia. Es en esta etapa donde se define el cáncer de próstata resistente a la castración (CPRC) y se asocia con mal pronóstico ya que la supervivencia oscila entre 18 y 24 meses a partir de ese momento. Aún con niveles de castración, los tumores son dependientes del receptor androgénico (RA) funcional. En el presente trabajo analizamos los parámetros clínicos pre-tratamiento como biomarcadores pronósticos o predictivos de progresión, los mecanismos de resistencia a la castración, el desarrollo de nuevas tecnologías para el uso de las denominadas biopsias líquidas a partir de fluidos biológicos y la identificación de células tumorales circulantes como biomarcadores de respuesta y progresión en CPRC. Los ensayos clínicos actualmente en marcha están en parte orientados hacia la búsqueda de nuevos biomarcadores pronósticos y predictivos, lo que permitirá abrir las puertas a la medicina de precisión y con ello mejorar la calidad de vida del paciente oncológico

Prostate cancer is a health problem in many Countries worldwide. Understanding the essential function of androgens in the prostate physiology led to the development of hormonal blockade as a therapeutic option in advanced disease, with limited response with time and development of resistance. In this stage, where castration resistant prostate cancer (CRPC) is defined, it is associated with poor prognosis because survival varies between 18 and 24 months. Even with castration levels, tumors are dependent on the functional androgen receptor (AR). In this paper, we analyze pretreatment clinical parameters such as prognostic or progression-predictive biomarkers, castration resistance mechanisms, the development of new technologies for the use of the so called liquid biopsies from biological ayufluids and the identification of circulating tumor cells as CRPC response and progression biomarkers. Currently ongoing clinical trials are partially oriented to the search of new prognostic and predictive biomarkers, that will enable to open up precision medicine and so to improve oncological patient's quality of life with it