Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer

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

Research output: Contribution to journalArticlepeer-review

Abstract

Importance: 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. Design, setting, and participants: 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. Main outcomes and measures: 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 responseswere 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 interactionwas observed between AR-V7 status and treatment type (P < .001). Clinical outcomeswere 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 responseswere higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFSwere 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 and relevance: 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.

Original languageEnglish (US)
Pages (from-to)582-591
Number of pages10
JournalJAMA Oncology
Volume1
Issue number5
DOIs
StatePublished - Aug 2015
Externally publishedYes

Bibliographical note

Funding Information:
Funding/Support: This research was supported by the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program grant W81XWH-12-1-0605, the Patrick C. Walsh Fund, the Johns Hopkins Prostate SPORE grant P50 CA058236, and National Institutes of Health grant P30 CA006973.

Publisher Copyright:
© 2015 American Medical Association.

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