Blood Tests Predict Effectiveness of Hormonal Therapies

A multi-institutional group of clinical researchers, led by the Duke Cancer Institute’s Andrew Armstrong, MD, McS, FACP, published a new report this month in the Journal of Clinical Oncology, that describes results from the PROPHECY study, which prospectively compared two blood tests to assess how well they predicted the effectiveness of hormonal therapy in men with metastatic prostate cancer.

The blood tests, which are called “liquid biopsies,” detect androgen receptor splice variant-7 (AR-V7) in circulating prostate cancer cells.  The circulating tumor cell (CTC) tests are simple, non-invasive blood draws, and provide results in just a few days, identifying cells that shed from the tumor or metastasis into circulation.

The PROPHECY study, presented at the American Society of Clinical Oncology Annual Meeting in 2018, was a multicenter, prospective study of 118 men across five medical centers with metastatic prostate cancer who had disease progression despite hormonal therapy and who were starting abiraterone acetate or enzalutamide treatment. It compared two current assays in a blinded fashion, in which investigators were blinded to the CTC results and laboratories were blinded to the clinical results.  The two tests are called the EPIC AR-V7 Nuclear Protein CTC assay (now called the Oncotype DX® AR-V7 Nucleus Detect™ test), and the Johns Hopkins AR-V7 Adnatest assay. Both tests measure AR-V7 in different ways using either protein or mRNA, and neither has yet been approved by the FDA.

“We have therapies to treat recurrent, metastatic prostate cancer, but they don’t work on everyone, and cross-resistance between newer hormonal therapies is a major emerging problem in our field,” explained Armstrong. “It’s important to know which men are more likely to benefit from further hormonal therapies as well as to identify those men with little chance of benefiting in order to rapidly provide alternative, more effective therapies and or to develop new therapies for these men.”

Results proved both tests showed AR-V7 detection correlated with worse progression-free survival (PFS) — the length of time during or after treatment without disease progression — and overall survival (OS) during treatment with abiraterone or enzalutamide.  Men with AR-V7 positivity have a very low chance of benefitting from abiraterone or enzalutamide and if a patient is progressing on either therapy with a positive test, it would be sensible to switch to an alternative non-hormonal type of therapy, such as docetaxel, cabazitaxel, radium-223, or a clinical trial.  This study confirms the results of initial development efforts published in the NEJM and JAMA Oncology, and represents the first positive multicenter, blinded, prospective study of a circulating tumor cell predictive biomarker. These results may contribute to the USFDA approval of these CTC-based assays in the future.

“Men with AR-V7–positive CTCs have a very low probability of benefit from abiraterone or enzalutamide, ranging from 0% to 11%,” said Armstrong. “Moving forward, having this predictive power could spare many men from undergoing therapies that would not benefit them. For this subset of men, we can get them started on different therapies or enroll them in clinical trials for immunotherapy, targeted therapies, or combination approaches.”

Beyond AR-V7, the PROPHECY study is focused on developing new biomarkers and liquid biopsy tests using CTCs and cell free DNA and RNA to determine additional mechanisms of resistance that may lead to better therapies for these patients. A critical component of this multicenter collaborative work, which includes Duke, Weill Cornell Medical Center, Johns Hopkins University, Memorial Sloan Kettering Cancer Center, and the University of Chicago, is discovery, and already investigators are identifying new genetic targets important to hormone therapy resistance. Such findings should help improve treatment selection and spur innovative drug discovery efforts. However, in the meantime, the AR-V7 test can provide one such predictive medicine approach that is available today at Duke and nationally.