Background: Galeterone is an oral small molecule that disrupts androgen receptor (AR) signaling via multiple pathways: AR degradation, CYP17 inhibition, and AR antagonism. Immunofluorescent staining of circulating tumor cells (CTCs) is used to measure N-terminal and C-terminal (C-term) AR immunoreactivity. Reduced C-term immunoreactivity is indicative of CTCs that express AR splice variants with C-term loss, of which AR-V7 is the most common form. C-term loss is associated with abiraterone and enzalutamide resistance in patients with castration-resistant prostate cancer (CRPC) (Scher 2015). Methods: ARMOR 2 is a phase II study in 121 total patients; 107 patients with CRPC received the recommended phase II dose of 2550 mg in 4 cohorts: treatment-naïve (never treated with abiraterone/enzalutamide) non-metastatic (M0), treatment-naïve metastatic (M1), abiraterone-refractory, and enzalutamide-refractory. Endpoints included prostate-specific antigen (PSA) response and changes in CTC enumeration and AR expression. C-term AR expression was evaluated in patients with >4 N-terminal AR+ CTCs/mL. C-term loss status, PSA response, and percent change from baseline were evaluated for 61 treatment-naïve patients. Results: Seven patients (M0=1; M1=6) were identified as C-term loss positive; 54 patients (M0=22; M1=32) had C-term loss status of negative/unknown. PSA decline of ≥50% was achieved across groups, including 6 C-term loss patients. Conclusions: Patients with CRPC with C-term loss experienced meaningful benefit with galeterone, as assessed by decline in PSA. PSA response was similar between patients with C-term loss and those without. These data support the rationale for further development of galeterone for mCRPC, both with and without AR splice variant expression. Clinical trial information: NCT01709734

CI = confidence interval