Abstract 2605: Androgen receptor (AR) anomalies and efficacy of apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the phase 3 SPARTAN study
Authors: Smith Matthew R. , Thomas Shibu , Chowdhury Simon , Olmos David , Li Jinhui , Mainwaring Paul N. , Oudard Stéphane , Feng Felix Y. , Gormley Michael , Ricci Deborah S. , Rooney Brendan , Lopez-Gitlitz Angela , Yu Margaret K. , Small Eric J. 
Published: August 2018

Abstract
Introduction The next-generation AR inhibitor APA improves median metastasis-free survival by 2 yrs and second progression-free survival (PFS2; time from randomization to progression during the first mCRPC therapy or death) in men with nmCRPC and prostate-specific antigen doubling time ≤ 10 mos. AR anomalies (splice variants, ligand binding mutations, amplification) have been linked to AR signaling-targeted therapy resistance in mCRPC, but their relevance in nmCRPC is unknown. We assessed the frequency of AR anomalies after APA ± androgen deprivation therapy (ADT) and their effect on PFS2.
Methods Pts received APA (240 mg QD) or placebo (PBO), with continuous ADT. ARv7 expression was tested using real-time PCR in 200 whole blood samples (end of treatment [EOT], first progression). Next-generation sequencing was performed on 240 EOT plasma samples to detect 5 clinically relevant AR mutations (L702H, W742C, H875Y, F877L, T878A) and AR amplification. Kaplan-Meier methods were used to estimate median PFS2, and Cox proportional hazard models to estimate HR and 95% CI.
Results At EOT, 9.4% (9/96) of pts in the APA group and 12.5% (13/104) in the PBO group expressed ARv7. AR mutations were seen in 8.4% (10/118) and 6.5% (8/122) of pts in the APA and PBO groups, respectively. AR amplification occurred in 15.2% (18/118) and 14.7% (18/122) of pts in the APA and PBO groups, respectively. Although AR anomaly positivity had minimal impact on PFS2 with respect to APA, shorter median PFS2 was observed in AR anomaly-positive vs -negative pts, irrespective of treatment (Table).
Conclusions APA treatment in nmCRPC pts did not increase the frequency of AR anomalies common in AR signaling-targeted therapy-resistant mCRPC. AR anomaly positivity was associated with shorter median PFS2 in the PBO group but not in the APA group. These preliminary findings suggest adding APA may circumvent mechanisms of resistance to standard ADT.
Median PFS2, mos*Events*GroupAR anomaly positiveAR anomaly negativeHR (95% CI)P valueAR anomaly positiveAR anomaly negativeOverall23.327.11.57 (0.94-2.61)0.08023/4342/116APA19.725.41.17 (0.54-2.51)0.69310/1920/49PBO23.329.71.99 (1.0-3.97)0.04613/2422/67*Includes only pts who received abiraterone acetate plus prednisone or enzalutamide as the first mCRPC therapy.
Citation Format: Matthew R. Smith, Shibu Thomas, Simon Chowdhury, David Olmos, Jinhui Li, Paul N. Mainwaring, Stéphane Oudard, Felix Y. Feng, Michael Gormley, Deborah S. Ricci, Brendan Rooney, Angela Lopez-Gitlitz, Margaret K. Yu, Eric J. Small. Androgen receptor (AR) anomalies and efficacy of apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the phase 3 SPARTAN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2605.