Assay predicts outcomes in men taking mCRPC agent

June 1, 2016

Expression of androgen receptor splice variant 7 (AR-V7) in whole blood predicts worse cancer-related outcomes in patients with metastatic castration-resistant prostate cancer who are treated with abiraterone acetate (ZYTIGA).

San Francisco-Expression of androgen receptor splice variant 7 (AR-V7) in whole blood predicts worse cancer-related outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who are treated with abiraterone acetate (ZYTIGA). 

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Using a real-time polymerase chain reaction (RT-PCR) assay, detection of AR-V7 transcripts in whole blood was associated with a 0% PSA response rate and significantly inferior progression-free survival and overall survival in patients treated with abiraterone, Australian researchers reported at the Genitourinary Cancers Symposium in San Francisco.

AR-V7, a truncated form of the androgen receptor that lacks the ligand-binding domain, is relatively common among men with mCRPC. The missing C-terminal of AR-V7 is important because it’s the part of the androgen receptor that androgen receptor inhibitors bind. Previous work at Johns Hopkins University, Baltimore has shown that AR-V7 expression in circulating tumor cells was associated with resistance to abiraterone and enzalutamide (XTANDI) (N Engl J Med 2014; 371:1028-38). In this study, PSA response rates were also 0% in AR-V7-positive patients who were treated with either abiraterone or enzalutamide.

“Ours is a small cohort at only 37 patients, but in our patients who have AR-V7-positive disease, we’re seeing similar results in terms of no PSA response rate and poorer survival,” said co-author Arun Azad, MD, a medical oncologist at Monash University, Melbourne, Australia.

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“You might ask what’s the benefit of our study on top of what we already know from the Johns Hopkins study,” he said. “The difference here is the assay. This is a whole blood RNA assay using PAXgene tubes, which are not time sensitive, unlike the AdnaGen test that was used in the Johns Hopkins study, which also requires collection of circulating tumor cells.”

PAXgene RNA tubes are collected using 2.5 mL of whole blood. The tube is inverted eight to 10 times and then placed into a –70ºC freezer, after which it can be analyzed at any time up to 7 years later.

Next: 'A very user-friendly assay'

 

‘A very user-friendly assay’

“It’s a very user-friendly assay, unlike the AdnaGen, which needs to be done within 4 hours and has a lot of other steps in terms of processing,” said Dr. Azad.

Using this assay, while at the British Columbia Cancer Agency in Vancouver, BC, he and colleagues including Tilman Todenhöfer, MD (who led development of the assay), sought to correlate AR-V7 expression with outcomes in 37 patients with mCRPC treated with abiraterone acetate. RT-PCR was performed for the following genes: AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3, and TMPRSS2:ERG. For each gene, the highest computed tomography value among 20 normal controls was set as the threshold for a positive test.

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Median patient age was 70 years and 59% had received prior docetaxel (Taxotere). None had received abiraterone or enzalutamide previously. Four patients (11%) were AR-V7-positive. AR-V7-positive patients were more likely to have high levels of alkaline phosphatase (p=.04) and lactate dehydrogenase (p=.07) and more often had Eastern Cooperative Oncology Group Performance Status ≥2 (p=.052) than those who were AR-V7-negative.

The PSA50 response rate, defined as PSA decline ≥50% confirmed ≥3 weeks later, was 0% in AR-V7-positive patients compared with 41.9% in AR-V7-negative patients (p=.04). PSA30 response rates were 0% and 52% (p=.051) in the AR-V7-positive and AR-V7-negative patients, respectively.

Median progression-free survival was 0.7 months in AR-V7-positive patients and 4 months in AR-V7-negative patients (p<.001). Median overall survival was 6.6 months in the AR-V7-positive patients and 22.1 months in the AR-V7-negative patients (p=.0004).

Significant predictors of worse overall survival were AR-V7-positive status (p=.007), an increased level of ALP (p=.02), ≤36 months on primary hormone therapy (p=.03), >2 markers that were positive (p=0.03), and HOXB13 positivity (p=.02).

“It’s reassuring that the PAXgene tubes assay is showing similar results to what has been seen with the AdnaGen assay, but it’s potentially more user friendly and therefore more useful as a companion diagnostic down the line,” said Dr. Azad.

Dr. Azad has received honoraria from Janssen-Cilag and is a consultant/adviser for Astellas Pharma. Several of his co-authors have a financial or other relationship with Astellas Pharma, Janssen Pharmaceuticals, Janssen Oncology, and/or other pharmaceutical companies.

 

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