Abstract CT134: Androgen receptor (AR) mutations in patients (pts) with castration-resistant prostate cancer (CRPC) with and without prior abiraterone acetate (AA) treatment
Authors: Rathkopf Dana E. , Smith Matthew R. , Antonarakis Emmanuel S. , Ryan Charles J. , Berry William R. , Shore Neal D. , Liu Glenn , Higano Celestia , Alumkal Joshi J. , Hauke Ralph , Tutrone Ronald , Saleh Mansoor , Chow Maneval Edna , Thomas Shibu , Ricci Deborah , Yu Margaret K. , de Boer Carla J. , Trinh Angela , Kheoh Thian , Bandekar Rajesh , Scher Howard I. 
Published: August 2015

Abstract
Background: ARN-509 is a second-generation antiandrogen with antitumor activity in CRPC. Activating mutations in the AR ligand-binding domain (LBD) have been associated with resistance to first- (T877A) and second- (F876L) generation antiandrogens. We evaluated the type and frequency of relevant AR LBD mutations in ARN-509-treated CRPC pts at baseline (BL) and disease progression (PD).
Methods: ARN-509-001 was a phase I/II study that evaluated ARN-509 activity in nonmetastatic (M0), chemotherapy-naïve, and post-AA CRPC. Of the 97 pts enrolled in phase II at a dose of 240 mg/d, 92 were evaluable for the mutation analysis at BL and 82 at PD. Relevant mutations in circulating tumor DNA were detected using a digital PCR method called BEAMing (Beads, Emulsification, Amplification, and Magnetics) (Richardson AL. Clin Cancer Res. 2012).
Results: Median duration of therapy was ∼16 months. One pt in the M0 cohort and one in the chemotherapy-naïve cohort had the F876L mutation at BL. Two pts in the chemotherapy-naïve cohort and one in the post-AA cohort acquired the AR F876L mutation during treatment. Pts with M0 CRPC did not acquire a mutation (Table 1). Three pts in the post-AA cohort had the T877A mutation at BL; the T877A mutation was not detected in any other cohort at BL. In the post-AA cohort, one pt acquired the T877A mutation during treatment while another lost the mutation (Table). The two pts with detectable F876L at BL developed prostate-specific antigen (PSA) progression at 4 and 6 months, respectively, compared with a median time to PSA progression of 16.4 months in the remainder of pts.
Conclusions: Pts with metastatic CRPC who were treated with ARN-509 had a low rate of acquisition of the AR F876L (3/82 = 4%) and AR T877A (1/82 = 1%) mutations. These results suggest that ARN-509 may be continued in the setting of a rising PSA. Larger studies are needed to confirm the prevalence of F876L, T877A, and the conversion rate.
AR F876LAR T877AEvaluableBLPDAcquiredBLPDAcquiredpatientsn/Nn/Nn/Nn/NTotal922/925/823/823/923/821/82M0491/491/470/470/500/470/47Chemotherapy-naïve241/243/202/200/200/200/20Post-AA190/191/151/153/193/151/15
Citation Format: Dana E. Rathkopf, Matthew R. Smith, Emmanuel S. Antonarakis, Charles J. Ryan, William R. Berry, Neal D. Shore, Glenn Liu, Celestia Higano, Joshi J. Alumkal, Ralph Hauke, Ronald Tutrone, Mansoor Saleh, Edna Chow Maneval, Shibu Thomas, Deborah Ricci, Margaret K. Yu, Carla J. de Boer, Angela Trinh, Thian Kheoh, Rajesh Bandekar, Howard I. Scher. Androgen receptor (AR) mutations in patients (pts) with castration-resistant prostate cancer (CRPC) with and without prior abiraterone acetate (AA) treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT134. doi:10.1158/1538-7445.AM2015-CT134