title: Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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%; P = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7-positive and AR-V7-negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .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%; P < .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, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Changxue
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Brandon
authors.initials: B
authors.lastname: Luber
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mary
authors.initials: M
authors.lastname: Nakazawa
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Rosa
authors.initials: R
authors.lastname: Nadal
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.affiliation: Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
mesh_terms: D000046:Academic Medical Centers; D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015142:Baltimore; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D018572:Disease-Free Survival; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D009570:Nitriles; D018579:Patient Selection; D010641:Phenotype; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D011944:Receptors, Androgen / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D009570:Nitriles; D020033:Protein Isoforms; D012333:RNA, Messenger; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C540278:enzalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C089740:abiraterone