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. 2014 Sep 11;371(11):1028-38.
doi: 10.1056/NEJMoa1315815. Epub 2014 Sep 3.

AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer

Emmanuel S Antonarakis  1 , Changxue Lu, Hao Wang, Brandon Luber, Mary Nakazawa, Jeffrey C Roeser, Yan Chen, Tabrez A Mohammad, Yidong Chen, Helen L Fedor, Tamara L Lotan, Qizhi Zheng, Angelo M De Marzo, John T Isaacs, William B Isaacs, Rosa Nadal, Channing J Paller, Samuel R Denmeade, Michael A Carducci, Mario A Eisenberger, Jun Luo
Affiliations

AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer

Emmanuel S Antonarakis et al. N Engl J Med. .

Abstract

Background: The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.

Methods: We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.

Results: A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.

Conclusions: Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).

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Figures

Figure 1
Figure 1. Transcript Levels of Full-Length Androgen Receptor mRNA and AR-V7 in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer
Absolute transcript copy numbers of full-length androgen receptor messenger RNA (mRNA) and androgen-receptor splice variant 7 mRNA (AR-V7) detected in circulating tumor cells are shown for the 6 abiraterone-treated patients (Panel A) and the 12 enzalutamide-treated patients (Panel B) who were positive for AR-V7 at baseline (i.e., in pretreatment samples of circulating tumor cells). Ratios of AR-V7 to full-length androgen receptor mRNA are expressed as percentages. Levels of full-length androgen receptor mRNA are also shown for AR-V7–negative samples. Eight abiraterone-treated patients who were negative for full-length androgen receptor mRNA (not shown) were also negative for AR-V7. One enzalutamide-treated patient was negative for both full-length androgen receptor mRNA and AR-V7 (not shown).
Figure 2
Figure 2. Waterifall Plots of Best Prostate-Specific Antigen (PSA) Responses According to AR-V7 Status
Panel A shows the 31 enzalutamide-treated patients, and Panel B the 31 abiraterone-treated patients. The dotted line shows the threshold for defining a PSA response (≥50% reduction in PSA level from baseline). Asterisks indicate an increase of more than 100% in best PSA response. Daggers indicate patients in the enzalutamide cohort who had previously received abiraterone and patients in the abiraterone cohort who had previously received enzalutamide.
Figure 3
Figure 3. Kaplan–Meier Analysis of PSA Progression–free Survival and Clinical or Radiographic Progression–free Survival According to AR-V7 Status
The median PSA progression–free survival in enzalutamide-treated patients (Panel A) was 1.4 months (95% CI, 0.9 to not reached) in AR-V7–positive patients and 6.0 months (95% CI, 3.8 to not reached) in AR-V7–negative patients (hazard ratio for PSA progression with AR-V7 positivity, 7.4; 95% CI, 2.7 to 20.6; P<0.001 by the log-rank test). The median PSA progression–free survival in abiraterone-treated patients (Panel B) was 1.3 months (95% CI, 0.9 to not reached) in AR-V7–positive patients and more than 5.3 months (95% CI, 5.3 to not reached) in AR-V7–negative patients (hazard ratio for PSA progression with AR-V7 positivity, 16.1; 95% CI, 3.9 to 66.0; P<0.001 by the log-rank test). The median clinical or radiographic progression–free survival in enzalutamide-treated patients (Panel C) was 2.1 months (95% CI, 2.0 to not reached) in AR-V7–positive patients and 6.1 months (95% CI, 4.7 to not reached) in AR-V7–negative patients (hazard ratio for clinical or radiographic progression with AR-V7 positivity, 8.5; 95% CI, 2.8 to 25.5; P<0.001 by the log-rank test). The median clinical or radiographic progression–free survival in abiraterone-treated patients (Panel D) was 2.3 months (95% CI, 1.4 to not reached) in AR-V7–positive patients and more than 6.3 months (95% CI, 6.3 to not reached) in AR-V7–negative patients (hazard ratio for clinical or radiographic progression with AR-V7 positivity, 16.5; 95% CI, 3.3 to 82.9; P<0.001 by the log-rank test).
Figure 4
Figure 4. Detection of Full-Length Androgen Receptor mRNA and AR-V7 in Metastatic Prostate-Cancer Tissue
In situ detection of full-length androgen receptor mRNA and AR-V7 in prostate-cancer tumor specimens was performed with the use of RNA in situ hybridization analysis. The tumor-tissue specimens shown are a radical-prostatectomy (RP) specimen that lacks AR-V7 expression from a patient (not enrolled in this study) who had not received hormonal treatment, an autopsy-derived specimen of a liver metastasis from a patient whose circulating tumor cells were shown to express AR-V7 (Autopsy), and core-needle biopsy specimens from a patient in whom AR-V7 was not detected (Biopsy 1) and a patient in whom AR-V7 was detected (Biopsy 2) in circulating tumor cells. All the tumor specimens show expression of full-length androgen receptor mRNA. The prostate-cancer cell lines that served as positive and negative controls for AR-V7 detection by means of RNA in situ hybridization are shown in Figure S6 in the Supplementary Appendix.
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