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Prostate Cancer: Mortality and Impact of Second-Generation Androgen-Receptor Inhibitors

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Universitat de Barcelona. Facultat de Medicina

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[eng] Prostate cancer is the second most frequently diagnosed cancer worldwide and the ﬁfth leading cause of cancer death in men. Despite, the above mentioned incidence and mortality, the existence of a small proportion of patients who have indolent prostate cancers has led to the widely held belief that prostate cancer has low lethality. The widespread use of PSA screening in asymptomatic patients in some countries might partially explain this belief. Overdiagnosis of indolent prostate cancers with PSA screening might have diluted the real mortality rates of more aggressive and advanced prostate cancers. Epidemiological studies analyzing real prostate cancer mortality and causes of death in countries were early PSA screening is uncommon are therefore urgently needed to provide a real picture of the impact of prostate cancer on mortality. Several second-generation androgen receptor pathway inhibitors such as enzalutamide or abiraterone have been successfully tested in patients with metastatic castration-resistant prostate cancer (CRPC). Although the individual efficacy of abiraterone and enzalutamide in prostate cancer is well established, the therapeutic benefit of targeting AR signaling axis by sequential administration of these agents is not clear, since cross-resistance could occur. Similarly, while an antiandrogen withdrawal syndrome (AAWS) has been reported for almost all first-generation antiandrogens such as bicalutamide, there is no evidence of any withdrawal effect with second-generation antiandrogen enzalutamida.
The main objectives of this thesis was to investigate mortality and causes of death in men with prostate cancer diagnosed in London (UK) where routine screening testing for PSA amongst asymptomatic men is low; to analyze the antitumour activity of enzalutamide in metastatic castration-resistant prostate cancer patients previously treated with abiraterone and to examine PSA levels following enzalutamide discontinuation in metastatic castration-resistant prostate cancer patients, in order to assess whether an AAWS exists with enzalutamida. 
As main methods, we analyzed prostate cancer mortality on 53.081 men diagnosed with prostate cancer between January 1st 1997 and December 31st 2006 extracted from death certificates from the Thames Cancer Registry (TCR) database. The TCR is a population-based epidemiological registry, covering around 12 million people resident in an area of South East England. The enzalutamida cross-resistance and potential AAWS was analyzed retrospectively in patients with metastatic CRPC treated with enzalutamide in the UK between 2012 and 2013. For the Enzalutamide Cross-Resistance study, we identified 39 patients previously treated with both abiraterone and docetaxel and subsequently treated with enzalutamida. For the Enzalutamide Withdrawal study, we identified patients with evidence of disease progression on enzalutamide for whom at least 1 available PSA post-enzalutamide discontinuation was available. 30 patients were initially identified. A subsequent updated analysis increased the patient sample to 49 patients.
The main results of this thesis are that the mortality of prostate cancer remains significant, challenging the traditional belief that prostate cancer is an indolent disease and is not an important cause of death in men. We showed that prostate cancer was the most frequent cause of death in the whole study population as well as in all the subgroups, regardless of age, stage of disease and treatment received. We also showed that the antitumour activity of enzalutamide is significantly reduced when it is given to heavily pre-treated metastatic CRPC patients previously treated with abiraterone acetate. All the efficacy endpoints analyzed in our cohort were significantly poorer compared to the data reported in the AFFIRM pivotal study in abiraterone-naïve patients, including PSA response rates, radiological response rates and survival. This indicates a phenomenon of cross-resistance between these 2 hormonal drugs targeting the AR signaling pathway. Our results also showed for the first time that enzalutamide is associated with an antiandrogen withdrawal syndrome in a minority of patients (2%).

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[spa]  El cáncer de próstata es el segundo cáncer diagnosticado con mayor frecuencia en todo el mundo y la quinta causa de muerte por cáncer en varones. Cuando la enfermedad se halla en fase metastásica no existen tratamientos curativos y la supervivencia de los pacientes es limitada. Los objetivos principales de esta tesis eran investigar la mortalidad y las causas de muerte en varones con cáncer de próstata diagnosticado en Londres (Reino Unido), así como analizar la posible existencia de resistencia cruzada entre los inhibidores del receptor de andrógenos enzalutamida y abiraterona en pacientes con cáncer de próstata resistente a castración y la posible existencia de un síndrome de retirada del antiandrógeno con enzalutamida. Los principales resultados de la tesis son, en primer lugar, que la mortalidad debida al cáncer de próstata en nuestro estudio fue significativa, independientemente de los factores basales y que, en un entorno epidemiológico donde la detección precoz del PSA es bajo, como es el caso del Reino Unido, nuestros resultados desafían la creencia de que el cáncer de próstata no es una causa importante de muerte en varones. En segundo lugar, vimos que la actividad antitumoral de enzalutamida de nuestro estudio en paciente previamente pretratados con abiraterona es significativamente inferior a los publicados en los ensayos aleatorizados de enzalutamida en pacientes no previamente tratados con abiraterona. Estos datos sugieren una actividad antitumoral reducida de enzalutamida en los pacientes previamente tratados con abiraterona, indicando una posible resistencia cruzada entre dichos fármacos que comparten un similar mecanismo de acción. Finalmente, nuestro estudio proporcionó la primera evidencia de que enzalutamida puede tener un síndrome de retirada del antiandrógeno en una minoría de pacientes con cáncer de próstata metastásico resistente a la castración.

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Prostate Cancer: Mortality and Impact of Second-Generation Androgen-Receptor Inhibitors