AR-V7 Validated as a Predictive Biomarker to Guide Treatment Selection for Men with Metastatic Castration-Resistant Prostate Cancer

Thursday, June 28, 2018

Bottom Line:

An international team of researchers led by Howard Scher, MD, Co-Chair of the Center for Mechanism Based Therapy and Head of the Biomarker Development Initiative at Memorial Sloan Kettering Cancer Center (MSK), has validated a biomarker that can predict whether people with metastatic castration-resistant prostate cancer (mCRPC) may live longer if they are treated with a taxane-based chemotherapy instead of a second targeted androgen receptor–signaling inhibitor (ARSi). These findings, from an independent, multicenter, blinded study, confirmed a previous finding that the presence of a nuclear-localized, androgen receptor–positive splice variant (AR-V7) protein in circulating tumor cells (CTC) can predict therapeutic response and demonstrate a survival benefit.

Implications:

A blood test to determine whether to treat people with progressing mCRPC using an ARSi or a taxane-based chemotherapy is currently an unmet medical need. A liquid biopsy could extend life through improved clinical decision-making by identifying people who need to switch from targeted hormonal therapy to chemotherapy.

Author Comment:

“These confirmatory findings will enable more informed and reliable therapy-guiding decisions for an individual on the most appropriate treatments for his prostate cancer at critical decision points in management,” explained Dr. Scher. “By validating the AR-V7 biomarker, we can predict which therapy is most likely to offer an overall survival benefit. Armed with this knowledge, physicians and patients will feel more confident knowing that each individual is receiving the best treatment for them.”

Background:

ARSi therapy, such as abiraterone (Zytiga®) and enzalutamide (Xtandi®), and taxanes, such as docetaxel (Docefrez®, Taxotere®) and cabazitaxel (Jevtana®), are the most widely used drug classes for progressing mCRPC. ARSi therapy is the preferred choice at the first-line decision point in the management of disease in people with mCRPC. However, as response or failure on one ARSi does not uniformly predict response to a second, there are no formal guidelines on how to best sequence these drugs.

Preliminary findings showing the CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker were published in JAMA Oncology in November 2016.

Method and Findings:

The researchers set out to determine whether a validated assay from Epic Sciences for AR-V7 protein in CTCs localized to the nucleus can predict differential overall survival in people with mCRPC treated with taxanes versus ARSi therapy.

This multi-institutional, correlative study followed 142 people with mCRPC for 4.3 years. They were treated at outpatient clinics at MSK; the Institute for Cancer Research, London (in the United Kingdom); and the London Health Sciences Centre (in Canada). Blood samples were obtained prior to treatment with ARSi therapy or chemotherapy and tested with a validated assay for the AR-V7 protein in CTCs.

Those who tested positive for AR-V7 and were treated with taxane-based chemotherapy showed greater overall survival relative to those who were treated with ARSi therapy (14.3 versus 7.3 months, respectively). Those who tested negative for AR-V7 who were treated with ARSi therapy had improved overall survival relative to those treated with taxanes (median overall survival was 19.8 versus 12.8 months, respectively). The authors validated the test with a prognostic risk group to ensure that the biomarker effect was due to the biomarker rather than other clinical variables.

Journal:

“Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer” was published in JAMA Oncology on June 28, 2018.

Authors:

Howard Scher, MD, Co-Chair of the Center for Mechanism Based Therapy and Head of the Biomarker Development Initiative, served as corresponding author.