Antonarakis Discusses AR-V7 and Response to Taxanes in mCRPC

Emmanuel S. Antonarakis, MBBCh

Androgen receptor splice variant-7 (AR-V7) is a truncated form of the AR that does not have the ligand-binding domain. Detection of AR-V7 in circulating tumor cells (CTCs) can be used to predict resistance to AR-targeting agents, such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi).

At the 2015 Genitourinary Cancers Symposium, Emmanuel S. Antonarakis, MBBCh, presented new data looking at AR-V7 and response to taxane therapy in men with metastatic castration-resistant prostate cancer (mCRPC). To gain further insight into this research, OncLive interviewed Antonarakis, who is an assistant professor at Johns Hopkins Medicine.

Please discuss the study with AR-V7 in mCRPC that you presented at the 2015 Genitourinary Cancers Symposium.

We had previously reported that if a patient has AR-V7 in their circulating tumor cells, they generally did not respond at all to abiraterone or enzalutamide. We wondered, “If those patients are resistant to abiraterone and enzalutamide, could they potentially respond to other drugs?”

We decided to investigate whether the presence or absence of AR-V7 in CTCs from these patients predicted response or resistance to taxane chemotherapies— docetaxel and cabazitaxel.

The bottom line was that the presence of AR-V7 did not cause primary resistance to chemotherapy. In other words, those patients did retain at least some level of sensitivity to docetaxel and cabazitaxel.

This is important because it means that if a patient is diagnosed with the AR-V7 splice variant in their tumors, although we know that they may not respond to abiraterone or enzalutamide, they have a decent chance of responding to the chemotherapy agents.

What is the current role of chemotherapy in the management of prostate cancer, and how might this study affect that role?

The question of chemotherapy in prostate cancer has become a lot more relevant recently. We’ve seen that if you use chemotherapy upfront in patients with metastatic hormone-sensitive disease, you can achieve a huge overall survival advantage. Two to three years ago, chemotherapy was often used as a very last resort. Today, we're beginning to see a resurgence of chemotherapy use.

If you're a patient and given a choice to either take a pill or come for an IV chemotherapy—the vast majority of patients would pick the pill. What if you had a biomarker that predicted that the pill wouldn't work? In that situation, you’d have stronger leverage to advise that patient to undergo chemotherapy.

We believe AR-V7 might be one of the first treatment selection markers. If a patient comes into the clinic and their AR-V7 marker is negative, treatment with abiraterone or enzalutamide would be very reasonable and would have a fairly high chance of success. On the other hand, if you have a patient who has an AR-V7 splice variant detected, that patient may not wish to waste time, so to speak, with oral abiraterone or enzalutamide. That patient might be convinced to go straight to chemotherapy upfront.

We have to acknowledge that the AR-V7 biomarker test is done only under the auspices of research. There is no commercially available test in this country and no test that is being performed in a CLIA-certified laboratory. As physicians, we should not be using these results to make treatment decisions.

However, it is my belief that within the next 6 to 12 months, we will have a CLIA-certified test at least at one institution, and we may even have a commercially available test for AR-V7. If that is the case, this will be a very useful treatment selection marker in the future.

A lot of work has to be done until the point where a patient can just walk into their physician's office and order this type of test. What are the challenges with this 6- to 12-month timeline?

I'm very optimistic about the timeline for this test. When you have a biomarker that has the potential to alter treatment choices, the industry moves on it very quickly.

I don't necessarily need Johns Hopkins to be the first to reach the finish line, I just want that to happen so it can be available for our patients and so that it can inform our clinical trials.

That’s the other half — once we have a marker that we know is robust, we can begin designing trials to test whether a new drug might have clinical activity in patients that do have the AR-V7 splice variance.

What’s the take-home message for community oncologists?

The take-home message for a community oncologist right now is that, at this point in time, the test is only being offered at Johns Hopkins. Within a few months, it's going to be offered on a research study at four more institutions: Memorial Sloan Kettering, Duke University, Cornell University, and Dana-Farber Cancer Institute.

In the next 2 to 3 months, we will be launching a prospective study. Patients can then get tested as part of a research study at those sites.

What is the test like? Will a practicing oncologist need any special training?

It's a blood test, so it can be done very easily through the clinic and won't require a needle biopsy or invasive procedure. One of the caveats, though, is that we have to be able to identify circulating tumor cells in the blood in order to perform the test.

If circulating tumor cells are found in the blood, which are present in at least 50% of metastatic prostate cancer patients using our platform, that patient would be able to have a result in about 5 working days. That's my vision.