Background
Castration-resistant prostate cancer (CRPC) is currently incurable. A feature of progressive CRPC is the sustained activity of the androgen receptor (AR) by mechanisms including AR gene overexpression/amplification, compensatory feedback mechanisms e.g. activation of PI3K pathway, AR gene abnormalities and glucocorticoid receptor (GR) signalling. Despite novel agents like abiraterone acetate (AA) (androgen biosynthesis inhibitor) and Enzalutamide (novel second-generation anti-androgen) progressive disease still develops.
Objective and Aims:
Our goal is to elucidate the resistant mechanisms to current novel treatments resulting in development of disease progression in castration-resistant prostate cancer (CRPC). We plan to elucidate this through the identification of androgen-receptor (AR) mutations, reactivation of the glucocorticoid pathway and compensatory feedback mechanisms between androgen biosynthesis and AR expression.
Design and Research Methodology:
We designed a phase III randomized control trial to address resistance secondary to compensatory feedback mechanisms. Enzalutamide will be given in combination with AA in progressive CRPC on previous enzalutamide. In addition, to identify the development of functionally relevant AR mutations, we will be looking for circulating tumour DNA in patients progressing on both abiraterone and enzalutamide.
We plan to evaluate the reversal of resistance secondary to glucocorticoid pathway reactivation by discontinuing concomitant steroids given with AA through a phase II trial. Here we will also examine expression of both the GR and AR in these patients to better elucidate resistance secondary to glucocorticoid pathway reactivation.