Improved Androgen Receptor Splice Variant 7 Detection Using a Highly Sensitive Assay to Predict Resistance to Abiraterone or Enzalutamide in Metastatic Prostate Cancer Patients

Abstract

BackgroundIn metastatic castration-resistant prostate cancer (mCRPC), androgen receptor splice variant 7 (AR-V7) expression is associated with a low response to androgen receptor signaling (ARS) inhibitors such as abiraterone or enzalutamide. ObjectiveTo perform a highly sensitive assay for detecting AR-V7 (hsAR-V7) in circulating tumor cells (CTCs) and evaluate its ability to predict response to ARS inhibitors. Design, setting, and participantsFrom 41 mCRPC patients, CTCs were prospectively enriched using AdnaTest platform and analyzed for AR-V7 with and without the highly sensitive assay. Outcome measurements and statistical analysisThe first objective of the study was to compare AR-V7 detection rates with and without the highly sensitive assay. Next, we investigated how AR-V7 (detected without the highly sensitive assay) and hsAR-V7 status influenced prostate-specific antigen (PSA) response and long-term clinical outcomes (PSA progression-free survival [PFS] and radiological PFS) after ARS-inhibitor treatment. Finally, discriminatory abilities of the assays were assessed by C-index to compare their impact on long-term clinical outcomes. Results and limitationsAR-V7 detection rates increased from 22% to 56% when the highly sensitive assay was used. The discriminatory abilities of hsAR-V7 for PSA PFS (C-index, 0.74; 95% confidence interval [CI], 0.60–0.88) and radiological PFS (0.70; 95% CI, 0.55–0.85) were higher than those of AR-V7 detected without the highly sensitive assay (0.60, 0.51–0.72, and 0.56, 0.44–0.67, respectively). After ARS-inhibitor treatment, PSA response was lower in hsAR-V7+ (53%) than in hsAR-V7– (93%) patients (p = 0.016). AR-V7+ patients had shorter median PSA PFS (3.0 vs 10.6 mo, p = 0.032) and nonsignificantly shorter median radiological PFS (6.0 vs 14.8 mo, p = 0.24) compared with AR-V7– patients. The hsAR-V7+ status was associated with shorter median PSA PFS (3.0 mo vs not reached, p = 0.0001) and radiological PFS (median, 6.0 mo vs not reached, p = 0.0026). ConclusionsThe hsAR-V7 assay achieved the highest AR-V7 detection rates among those reported in mCRPC. Discriminatory abilities for long-term clinical outcomes were better with hsAR-V7 assay. Patient summaryWe prospectively analyzed circulating tumor cells from men with metastatic castration-resistant prostate cancer for androgen receptor splice variant 7 (AR-V7) status using a highly sensitive assay. It yielded higher AR-V7 detection rates and predicted resistance to androgen receptor signaling inhibitors with better discriminatory abilities for long-term clinical outcomes.