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Practical Implications of AR-V7 Testing in Prostate

Insights From: Emmanuel S. Antonarakis, MBBCh, Johns Hopkins Medicine; Andrew J. Armstrong, MD, MSc, Duke Cancer Center; Howard I. Scher, MD, Memorial Sloan Kettering Cancer Center
Published Online: Tuesday, Aug 29, 2017



Transcript:

Andrew J. Armstrong, MD, MSc: The test becomes increasingly prevalent as the disease progresses. So, it goes from about 10% to 12% in the frontline setting to about twice that in the post-abiraterone/enzalutamide setting. This is really where the test probably has the greatest utility in preventing the switch from abiraterone to enzalutamide and from enzalutamide to abiraterone. In the frontline setting, most patients actually do respond to this therapy, meaning that there’s less clinical utility for doing a test before a patient has ever had abiraterone or enzalutamide.

The same would be true of the Hopkins QIAGEN assay where the prevalence seems to increase over time and with disease progression. And so, if you’re a clinician faced with a patient who’s progressing on abiraterone and the choice is between enzalutamide and another alternative therapy, such as a taxane or radium, this test may help—along with other clinical features of that patient—to decide what the next appropriate step may be.

The groups of patients have right now only castration-resistant disease. We tend not to see AR-V7 as a positive test in hormone-sensitive disease, and we tend not to see certain circulating tumor cells very much in patients without metastatic disease. So, it’s really only going to be indicated for patients with metastatic disease, in patients who have failed frontline hormonal therapy, and that’s where the clinical decision really has an unmet need. We’re trying to develop novel agents that may benefit these patients directly, whether that’s in immune therapy or a DNA repair agent or a combination approach. This is where the field is moving.

Howard I. Scher, MD: When we were looking at the AR-V7 in the first-line setting, in patients who were just progressing, the frequency was very low, under 5%. So, there’s no point really in ordering a test when you have a high–response rate drug and a low frequency in the alteration. Get into the second-line, you’ve got about a 20% rate, and we were able to show that in patients. In our first trial, we didn’t use the test result, we didn’t know the test result. We didn’t use the test result to make a decision; it was basically the physician’s choice, and we found, using a protein test, that when the AR-V7 was in the nucleus of the cell, those patients did not respond to our hormonal agents.

In contrast, they did respond to a taxane, docetaxel or cabazitaxel. And then ultimately, when we completed the analysis and looked at other factors that might influence survival, we were able to show what’s called a therapy interaction and that those patients had an improved survival by getting a taxane at that point in time if the AR-V7 was identified.

It’s more than a preliminary result, but it has to be validated, which means it has to be shown independently in other tests. I believe Dr. Antonarakis did speak about it in a study that’s being conducted by Dr. Armstrong from Duke University, where he’s comparing different AR-V7 tests in that context—the context of first decision, second decision, and third decision. Those results will hopefully be available within the next year.

Andrew J. Armstrong, MD, MSc: Right now, a patient would still get frontline abiraterone or enzalutamide irrespective of the results of this test. So, it’s generally not going to be recommended to do this test before a patient has ever seen those drugs. However, many patients will then progress on these drugs within 1 to 3 years of their therapy being started. In those patients, many physicians right now in the United States are switching from one to the other. However, those patients are most unlikely to benefit. So, trying to find a test that will allow the patient more optimal care to get a taxane, to get a clinical trial, to get some combination approach, and maybe a novel hormonal therapy and a novel immunotherapy radium-223 if they have bone predominant disease, this is where the test can be useful, basically in preventing the use of ineffective therapies.

Transcript Edited for Clarity
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Transcript:

Andrew J. Armstrong, MD, MSc: The test becomes increasingly prevalent as the disease progresses. So, it goes from about 10% to 12% in the frontline setting to about twice that in the post-abiraterone/enzalutamide setting. This is really where the test probably has the greatest utility in preventing the switch from abiraterone to enzalutamide and from enzalutamide to abiraterone. In the frontline setting, most patients actually do respond to this therapy, meaning that there’s less clinical utility for doing a test before a patient has ever had abiraterone or enzalutamide.

The same would be true of the Hopkins QIAGEN assay where the prevalence seems to increase over time and with disease progression. And so, if you’re a clinician faced with a patient who’s progressing on abiraterone and the choice is between enzalutamide and another alternative therapy, such as a taxane or radium, this test may help—along with other clinical features of that patient—to decide what the next appropriate step may be.

The groups of patients have right now only castration-resistant disease. We tend not to see AR-V7 as a positive test in hormone-sensitive disease, and we tend not to see certain circulating tumor cells very much in patients without metastatic disease. So, it’s really only going to be indicated for patients with metastatic disease, in patients who have failed frontline hormonal therapy, and that’s where the clinical decision really has an unmet need. We’re trying to develop novel agents that may benefit these patients directly, whether that’s in immune therapy or a DNA repair agent or a combination approach. This is where the field is moving.

Howard I. Scher, MD: When we were looking at the AR-V7 in the first-line setting, in patients who were just progressing, the frequency was very low, under 5%. So, there’s no point really in ordering a test when you have a high–response rate drug and a low frequency in the alteration. Get into the second-line, you’ve got about a 20% rate, and we were able to show that in patients. In our first trial, we didn’t use the test result, we didn’t know the test result. We didn’t use the test result to make a decision; it was basically the physician’s choice, and we found, using a protein test, that when the AR-V7 was in the nucleus of the cell, those patients did not respond to our hormonal agents.

In contrast, they did respond to a taxane, docetaxel or cabazitaxel. And then ultimately, when we completed the analysis and looked at other factors that might influence survival, we were able to show what’s called a therapy interaction and that those patients had an improved survival by getting a taxane at that point in time if the AR-V7 was identified.

It’s more than a preliminary result, but it has to be validated, which means it has to be shown independently in other tests. I believe Dr. Antonarakis did speak about it in a study that’s being conducted by Dr. Armstrong from Duke University, where he’s comparing different AR-V7 tests in that context—the context of first decision, second decision, and third decision. Those results will hopefully be available within the next year.

Andrew J. Armstrong, MD, MSc: Right now, a patient would still get frontline abiraterone or enzalutamide irrespective of the results of this test. So, it’s generally not going to be recommended to do this test before a patient has ever seen those drugs. However, many patients will then progress on these drugs within 1 to 3 years of their therapy being started. In those patients, many physicians right now in the United States are switching from one to the other. However, those patients are most unlikely to benefit. So, trying to find a test that will allow the patient more optimal care to get a taxane, to get a clinical trial, to get some combination approach, and maybe a novel hormonal therapy and a novel immunotherapy radium-223 if they have bone predominant disease, this is where the test can be useful, basically in preventing the use of ineffective therapies.

Transcript Edited for Clarity
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