AR-V7 mRNA level testing predicts mCRPC Tx response

Androgen receptor splice variant 7 (AR-V7) mRNA level testing in whole blood is a simple and promising “liquid biopsy” approach for predicting a poor treatment outcome in patients with metastatic castrate-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone (ZYTIGA) or enzalutamide (XTANDI), said senior author Matthias Heck, MD, at the AUA annual meeting in San Francisco.

“A study published in 2014 showed that AR-V7 expression in circulating tumor cells predicted treatment resistance to abiraterone and enzalutamide in men with mCRPC. However, the detection of CTCs is complicated and involves a sophisticated work-up,” said Dr. Heck, of Technical University of Munich, Munich, Germany.

“Tumor-specific RNA can also be detected in blood fractions other than CTCs. We sought to develop a practical and robust liquid biopsy approach for the direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture.”

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Absolute quantification of the AR-V7 transcripts is performed using droplet digital polymerase chain reaction. Evaluation of the method’s performance for predicting treatment resistance in mCRPC patients was done in a study that included 85 patients with mCRPC who were scheduled to begin a new line of treatment with abiraterone (56 patients) or enzalutamide (29 patients); prior systemic treatment for mCRPC included abiraterone or enzalutamide in 24 (28%) patients. Twenty-eight healthy males age <40 years were included as a control group to determine background levels of the AR-V7 and AR full length transcripts in peripheral whole blood.

After adjustment for the finding that AR-V7 was detectable in 18 control subjects, the mCRPC patients were divided into two groups for having low (70 patients, 82%) or high (15 patients, 18%) AR-V7 expression.

PSA response, defined as a ≥50% decline, was analyzed as the main marker for categorizing patients as being responsive or resistant to abiraterone/enzalutamide treatment. None of 12 evaluable mCRPC patients in the low AR-V7 group achieved a PSA response compared with 31 (49%) of the 63 evaluable men with low AR-V7 expression in whole blood.

“A multivariable analysis confirmed that AR-V7 status independently predicted PSA response,” Dr. Heck reported.

Next:PSA PFS, clinical PFS, and OS also examinedAdditional analyses considered associations between AR-V7 status and PSA progression-free survival, clinical progression-free survival, and overall survival. For all three endpoints, the results showed that high AR-V7 status was significantly associated with a worse outcome, and in a multivariable analysis, high AR-V7 status was consistently found to be an independent outcome predictor.

Dr. Heck noted that in addition to analyzing RNA expression in CTCs and whole blood, other liquid biopsy methods for determining AR-V7 status have analyzed RNA expression in exosomes and protein expression in CTCs.

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“Depending on the method used, the rate of AR-V7 positivity in patients with mCRPC has been reported to vary considerably, with a range between 11% and 68%. Moreover, there are conflicting data on the true predictive value of AR-V7. Various studies have reported that up to 19% of AR-V7 positive patients achieve a PSA decline ≥50%,” he said.

“Therefore, further prospective studies are needed to identify the optimum method for determining AR-V7 positivity and its value as a resistance marker to next-generation AR-directed therapy.”

The findings were published in European Urology (2017; 72:828-34).

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