Blood tests that examine circulating tumor cells, CTC’s, (cells that shed from the tumor or metastasis into circulation), for the presence of a mutated AR-V7 protein, could help determine if a patient with advanced prostate cancer would fare better with chemotherapy or with medicines such as enzalutamide (Xtandi) or abiraterone (Zytiga) that target the androgen receptor (a cellular protein that binds male hormones). But as happens with many medications, tumors often develop a resistance to such therapies that target the androgen receptor. Resistance develops because the medicines target a domain of the receptor that is missing in the AR-V7 version.
When a patient is first diagnosed with metastatic hormone-resistant prostate cancer, the preferred treatment involves androgen receptor inhibitors like Xtandi or Zytiga. But if a patient fails a first-line treatment with these inhibitors, there is no guarantee he’ll respond to a second inhibitor. In such cases, researchers need biomarkers that help them select which patients should receive a second androgen receptor inhibitor, and which should switch to chemotherapy.
One international team of researchers tested whether AR-V7, measured by a blood test in circulating tumor cells could predict the best treatment approach for each patient. The test they used, called Oncotype DX AR-V7 CTC nuclear protein test, was developed by Epic Sciences and Genomic Health. (A similar test has been developed at Johns Hopkins University and is called CTC AR-V7 RNA test.)
In one study of 142 patients at three institutions, all had been treated with one of the androgen receptor inhibitors (Xtandi or Zytiga) without success. Seventy patients were then moved to another round of treatment with an androgen receptor inhibitor, while 72 patients were treated with taxane-based chemotherapy — Taxotere (docetaxel) or Jevtana (cabazitaxel). Patients were followed for up to 4.3 years.
As expected, researchers found that patients who were negative for AR-V7 survived significantly longer with an androgen receptor inhibitor (19.8 months) than with chemotherapy (12.8 months). Conversely, chemotherapy was a better approach for patients who were positive for AR-V7, nearly doubling survival times compared to the androgen receptor inhibitor — 14.3 vs. 7.3 months. Overall, these results suggest that assessing AR-V7 levels in circulating tumor cells through a blood test may help identify the best second-line therapy for patients with metastatic hormone-resistant prostate cancer. These results were published in an issue of JAMA Oncology.
Meanwhile, in a second study, investigators at the Duke Cancer Institute designed a multi-center study — called PROPHECY (NCT02269982) – to evaluate how well both blood tests above predict the effectiveness of these hormone therapies.
A total of 118 men were enrolled at five medical centers to provide external validation for the two tests. For both tests, 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). While the Johns Hopkins test appeared to be more sensitive and flagged more non-responding patients, the Epic test seemed to be more specific, leading to no false-positive data.
“We have therapies to treat recurrent, metastatic prostate cancer, but they don’t work on everyone, and cross-resistance is a major emerging problem in our field. It’s important to know who will be more likely to respond and who has little chance of benefiting in order to rapidly provide alternative, more effective therapies or to develop new therapies for these men,” said Andrew Armstrong, MD, associate director for clinical research in the Duke Prostate and Urologic Cancer Center. “Having this predictive power could spare many men from undergoing therapies that would simply not benefit them, saving time, money and a great deal of emotional distress,” Armstrong said. “The results of this study are clinically useful in guiding care, particularly in men with high-risk disease and those who have already tried enzalutamide or abiraterone.”
Both of the studies were summarized in articles published online in Prostate Cancer News Today, August 8th and June 18th, 2018 respectively.