AR-V7 Not Predictive of Chemo Outcomes in mCRPC, But May Still Have Prognostic Value

Emmanuel Antonarakis, MD

The spliced androgen receptor (AR) variant AR-V7 was not shown to be a biomarker for chemotherapy efficacy in advanced prostate cancer, according to a small prospective study presented in a presscast held ahead of the 2015 Genitourinary Cancers Symposium. However, previously reported data have shown that AR-V7 might have value as an indicator of patient response to the AR-targeted agents enzalutamide (Xtandi) and abiraterone acetate (Zytiga).

The data presented during the presscast included 37 patients with metastatic castration-resistant prostate cancer (mCRPC) who were starting taxane chemotherapy with cabazitaxel or docetaxel. The researchers found that regardless of AR-V7 status, there was not a significant difference in PSA response or in progression-free survival (PFS).

“Detection of AR-V7...in men with metastatic castration-resistant prostate cancer is not associated with primary resistance to taxane therapy, as we previously showed in the context of AR-directed therapy,” said lead author Emmanuel S. Antonarakis, MBBCh.

AR-V7 is a spliced form of AR that lacks the ligand-binding domain that is the target of enzalutamide and abiraterone. Despite the absence of this domain, AR-V7 is still constitutively active.

Antonarakis, who is an assistant professor at Johns Hopkins Medicine, and colleagues assessed 17 patients with AR-V7—positive mCRPC and 20 patients with AR-V7–negative disease. AR-V7 status was determined by the presence or lack of AR-V7 in circulating tumor cells (CTCs), as determined by the qRT-PCR assay.

Association between baseline AR-V7 status and PSA response was the primary endpoint, with the link between AR-V7 status and PFS as a secondary measure. Multivariable regression models were used to adjust for AR-V7 status, AR-FL expression level, and abiraterone/enzalutamide use.

There was a nonsignificant difference in PSA response rate between the two cohorts at 41% in AR-V7—positive patients and 65% in AR-V7–negative patients (P = .19). The variation in PFS was also nonsignificant at 5.1 versus 6.9 months, respectively (HR = 2.65; P = .11).

Unlike with these outcomes, Antonarakis presented data at the 2014 ESMO Congress in which AR-V7 was shown to have a prognostic value for outcomes in mCRPC with abiraterone and enzalutamide. That study included 31 patients treated with enzalutamide and 31 patients who received abiraterone. There were 12 and 6 AR-V7—positive patients in the two arms, respectively, as detected by qRT-PCR analysis of CTCs.

The outcomes showed that AR-V7 was linked with resistance to the two targeted therapies. Inferior overall survival (OS) was observed in AR-V7—positive patients in both the enzalutamide (HR = 6.9; 95% CI, 1.7–28.1; P = .002) and abiraterone (HR = 12.7; 95% CI 1.3-125.3; P = .006) cohorts. Antonarakis et al noted that the negative prognostic impact of AR-V7 was upheld in the combined analysis (HR = 8.3; 95% CI 2.5-27.4; P <.001).

For further insight, Antonarakis et al combined the data from both the current taxane analysis and the earlier study with targeted agents presented at ESMO.

“What we aimed to do was to determine whether the AR-V7 biomarker behaves differently in the setting of AR-directed therapies…and the setting of taxane chemotherapy.”

Antonarakis said the analysis showed that “If a patient is AR-V7 positive, they have a greater [likelihood] of clinical or radiographic progression with enzalutamide or abiraterone compared to a taxane.” The HR for this comparison was 0.21 (95% CI 0.07-0.59; P = .003).

Conversely, for AR-V7—negative patients, the PFS outcomes appeared to be comparable in the two populations with an HR for the comparison of 1.02 (95% CI, 0.46-2.25; P = .959).

Assessing the totality of the combined study analysis data, Antonarakis said, “In the AR-V7—positive men, it is possible that taxanes may be more efficacious than AR-directed therapies in this setting. In the AR-V7–negative men, taxanes appear to have comparable efficacy to AR-directed therapy.”

Before altering clinical practice based on these data, Antonarakis said, “We need to prospectively validate these findings in at least one multicenter clinical trial.”

References

1. Antonarakis ES, Lu C, Yan Chen Y, et al. AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant prostate cancer (mCRPC). 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 138.
2. Antonarakis ES, Lu C, Wang H, et al. Annals of Oncology (2014)25(5):1-41.

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