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

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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 1 2015

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Castration
Androgen Receptors
Prostatic Neoplasms
Drug Therapy
Prostate-Specific Antigen
Circulating Neoplastic Cells
Disease-Free Survival
Taxoids
taxane
docetaxel
Therapeutics
abiraterone
MDV 3100

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{a8efbe4b9f0e4cb885d3842adbd48483,
title = "Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer",
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.",
author = "Emmanuel Antonarakis and Changxue Lu and Brandon Luber and Hao Wang and Yan Chen and Mary Nakazawa and Rosa Nadal and Channing Paller and Denmeade, {Samuel R} and Carducci, {Michael A} and Mario Eisenberger and Jun Luo",
year = "2015",
month = "8",
day = "1",
doi = "10.1001/jamaoncol.2015.1341",
language = "English (US)",
volume = "1",
pages = "582--591",
journal = "JAMA oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "5",

}

TY - JOUR

T1 - Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer

AU - Antonarakis, Emmanuel

AU - Lu, Changxue

AU - Luber, Brandon

AU - Wang, Hao

AU - Chen, Yan

AU - Nakazawa, Mary

AU - Nadal, Rosa

AU - Paller, Channing

AU - Denmeade, Samuel R

AU - Carducci, Michael A

AU - Eisenberger, Mario

AU - Luo, Jun

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

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U2 - 10.1001/jamaoncol.2015.1341

DO - 10.1001/jamaoncol.2015.1341

M3 - Article

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EP - 591

JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

IS - 5

ER -