GnRH antagonists have direct inhibitory effects on castration-resistant prostate cancer via intracrine androgen and AR-V7 expression.

Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer (PCa). Degarelix (Firmagon), a gonadotropin-releasing hormone (GnRH) receptor antagonist differs from luteinizing hormone-releasing hormone (LHRH) agonists by avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. The direct effect of degarelix and leuprolide on human prostate cancer cells was evaluated. In LNCaP, C4-2BMDVR and CWR22Rv1 cells, degarelix significantly reduced cell viability compared to the controls (p≤0.01). Leuprolide was stimulatory in the same cell lines. In C4-2B MDVR cells, degarelix alone or combined with abiraterone or enzalutamide reduced the AR-V7 protein expression compared to the control group. SCID mice bearing VCaP xenograft tumors were divided into four groups and treated with surgical castration, degarelix, leuprolide or buffer alone for 4 weeks. Leuprolide slightly suppressed tumor growth compared to the vehicle control group (p>0.05). Tumors in degarelix-treated mice were 67% of those in the leuprolide-treatment group but 170% larger than in surgically castrated ones. Measurements of intratumoral steroids in serum, tumor samples or treated cell pellets by LC-MS confirmed that degarelix better decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration; while leuprolide had no inhibitory effect. Collectively, our results suggested a selective mechanism of action of degarelix against androgen steroidogenesis and AR-variants. The present study provides additional molecular insights regarding the mechanism of degarelix compared to GnRH agonist therapy, which may have clincial implications.