Androgen Receptor Modulation Optimized for Response—Splice Variant: A Phase 3, Randomized Trial of Galeterone Versus Enzalutamide in Androgen Receptor Splice Variant-7–expressing Metastatic Castration-resistant Prostate Cancer

Abstract Background : Detection of androgen receptor (AR) splice variant-7 (AR-V7) messenger RNA (mRNA) in circulating tumor cells (CTCs) is associated with a suboptimal response to abiraterone and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). Galeterone inhibits CYP17 and AR, and induces AR protein degradation. We hypothesized that galeterone would be clinically superior to enzalutamide in AR-V7–positive (AR-V7+) mCRPC. Objective : To screen and characterize AR-V7+ mCRPC, and evaluate galeterone compared with enzalutamide. Design, setting, and participants : This was a multicenter randomized phase 3 trial; enzalutamide-, abiraterone-, and chemotherapy-naive mCRPC patients had AR-V7 prescreening using a CTC-based mRNA assay. Intervention : AR-V7+ patients were randomized (1:1) to open-label galeterone or enzalutamide; planned sample size was 148. Outcome measurements and statistical analysis : The primary endpoint was radiographic progression-free survival (rPFS). Baseline AR-V7 status was correlated with patient characteristics. Results and limitations : Overall, 953 men were prescreened for AR-V7; 323 (34%) had detectable CTCs, and 73/323 had AR-V7 mRNA. The AR-V7+ prevalence was 8% (73/953; 95% confidence interval [CI] 6–10%). AR-V7 was associated with indicators of advanced and high-volume disease at baseline, including higher prostate-specific antigen (PSA) level (p Conclusions : The prevalence of CTC mRNA AR-V7 in first-line mCRPC was 8% (95% CI 6–10%). AR-V7+ was associated with the characteristics of aggressive and advanced disease. These men had rapid disease progression. Development of galeterone will not be pursued. Patient summary : Of men with metastatic castration-resistant prostate cancer, 8% had the androgen receptor splice variant-7 (AR-V7) blood biomarker. The AR-V7+ patients had features of aggressive disease. Thirty-eight men were treated with either galeterone or enzalutamide; the trial was stopped early prior to determining efficacy because too many patients transitioned off the trial due to advancing cancer before having required radiographs.