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AR-V7 linked to treatment resistance in castration-resistant prostate cancer
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Detectable androgen receptor splice variant-7 messenger RNA in circulating tumor cells was associated with resistance to enzalutamide and abiraterone in men with castration-resistant prostate cancer, according to results of a prospective study.
Emmanuel S. Antonarakis, MD, of the department of oncology at Johns Hopkins University School of Medicine, and colleagues sought to evaluate resistance to enzalutamide (Xtandi, Astellas/Medivation) and abiraterone (Zytiga, Janssen) in 62 men with castration-resistant prostate cancer. Half the men received enzalutamide, an androgen receptor antagonist, and half received abiraterone, an oral androgen biosynthesis inhibitor.
Researchers used a quantitative reverse transcriptase polymerase chain reaction assay to detect androgen receptor splice variant-7 messenger RNA (AR-V7) — which lacks the ligand-binding domain targeted by hormonal therapy — in circulating tumor cells of the patients. Researchers detected AR-V7 in 39% of men treated with enzalutamide and 19% of men treated with abiraterone.
No men who expressed AR-V7 demonstrated a PSA response to enzalutamide, whereas 53% of AR-V7–negative men treated with enzalutamide demonstrated a response (
AR-V7–positive men who received abiraterone experienced significantly inferior response rates (0% vs. 68%;
AR-V7–positive men treated with enzalutamide or abiraterone had higher levels of full-length androgen receptor mRNA than AR-V7–negative men. However, in an analysis adjusted for expression of full-length androgen receptor messenger RNA, the association between AR-V7 positivity and treatment resistance persisted.
“If this finding is substantiated by others, it is possible that AR-V7 could be used as a biomarker to predict resistance to enzalutamide and abiraterone and to facilitate treatment selection,” Antonarakis and colleagues wrote. “However, our study does not prove a causal role for AR-V7 in mediating resistance to enzalutamide or abiraterone, and it remains possible that AR-V7 is a marker of more advanced disease or a higher disease burden.”
Although these data represent an advance in the treatment of prostate cancer, continued evaluation of the androgen receptor is necessary in this setting, Peter S. Nelson, MD, a member of the Program in Prostate Cancer Research at Fred Hutchinson Cancer Research Center and professor of oncology at University of Washington, wrote in an accompanying editorial.
“Fundamentally, the androgen receptor in its many permutations still represents the key target in prostate cancer,” Nelson wrote. “Continued efforts directed toward ablating androgen-receptor activity, particularly by interfering with the functions of the N-terminal domain of the androgen receptor, are likely to be fruitful. In the broader context, the study by Antonarakis and colleagues serves as a reminder that the ability to interrogate molecular features of a solid tumor in a longitudinal, iterative and relatively noninvasive manner opens up new opportunities for precision oncology.”
For more information:
Antonarakis ES.
Nelson PS.
Disclosure: Nelson reports personal fees from Medivation/Astellas and Janssen/Johnson & Johnson outside the submitted work. See the study for a full list of the researchers’ relevant financial disclosures.
Perspective
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Donald L. Trump, MD, FACP
The manuscript by Antonarakis and colleagues describes a straightforward but elegant analysis of the association between the detection — in circulating tumor cells (CTCs) — of AR-V7, of a variant of the androgen receptor (AR) predicted to be associated with resistance to AR-targeting agents (abiraterone or enzalutamide), and treatment success of either agent. AR-V7 is a truncated form of AR lacking the ligand-binding domain to which androgens — and enzalutamide — bind. One would predict that the presence of AR-V7 in prostate tumor cells would be associated with a reduced response to such agents. That is exactly what these investigators found; in fact, among patients with detectable AR-V7 in CTCs, no one responded to either enzalutamide (0 of 6) or abiraterone (0 of 12). If AR-V7 was not detected in CTCs, the response rate to either enzalutamide or abiraterone was 53%, substantially greater than the response rate of 30% to 35% seen in patients unselected for absence of AR-V7. In addition to PSA response rates, time to PSA, clinical and radiographic progression and OS were more favorable in AR-V7–negative patients.Although this was a relatively small study, the findings are entirely consistent with what one might expect based on our knowledge of prostate cancer biology. Intriguingly, and consistent with expectations (which doesn’t always happen!), the “pressure” of more prior therapy with AR-targeted agents appears to select for AR-V7–expressing cells. A challenging question not addressed by the authors is: Exactly how will these results be confirmed? What kind of trials?
It appears to this reviewer that replication of this result in one or two other similarly sized retrospective trials will “nail it.” The uniformly poor outcome of patients in whom CTCs express this level of AR-V7 is very compelling! Although it is also interesting to consider using absence of AR-V7 and expressing CTCs to choose patients who should receive enzalutamide or abiraterone, it may well be much more important to use the presence of AR-V7 cells to avoid these agents. The data are compelling (though this is a small study) that such patients do not benefit from treatment with abiraterone or enzalutamide. The icing on the cake would be to show that avoiding ineffective therapy guided by AR-V7 detection improves survival, as one might expect. That approach will require more work. Avoiding ineffective therapy also will have care-value consequences, because avoiding agents that have little to no benefit is good medicine, as well as good patient and “national” economics.
In a recent issue of JAMA, Peter B. Bach, MD, described such “indication-specific pricing for cancer drugs” (Bach PB. JAMA. 2014;312:1629-1630). If these data are confirmed, AR-V7 analysis would provide guidance to a defining a population of men with castration-resistant prostate cancer (CRPC) wherein the indication is clear: little to no benefit from use of expensive (about $7,000 per month) agents. Congratulations to the authors for an analysis that could substantially improve the value of therapy for men with CRPC.
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