Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Emmanuel S. Antonarakis, Changxue Lu, Brandon Luber, Hao Wang, Yan Chen, Mary Nakazawa, Rosa Nadal, Channing J. Paller, Samuel R. Denmeade, Michael A. Carducci, Mario A. Eisenberger, Jun Luo
Journal: JAMA Oncology (2015)

<h3>Importance</h3> We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. <h3>Objective</h3> To investigate whether AR-V7–positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. <h3>Design, Setting, and Participants</h3> We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. <h3>Main Outcomes and Measures</h3> We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). <h3>Results</h3> Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7–positive and AR-V7–negative men (41% vs 65%;<i>P</i> = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0;<i>P</i> = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8;<i>P</i> = .11) were comparable in AR-V7–positive and AR-V7–negative patients. A significant interaction was observed between AR-V7 status and treatment type (<i>P</i> &lt; .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7–positive men, whereas outcomes did not differ by treatment type in AR-V7–negative men. In AR-V7–positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%;<i>P</i> &lt; .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS,<i>P</i> = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS,<i>P</i> = .003). <h3>Conclusions and Relevance</h3> Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7–positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7–negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell–based AR-V7 detection may serve as a treatment selection biomarker in CRPC.