Circulating Tumor Cells as Possible Clinical Endpoint in Prostate Cancer Trials
Published Online:2:40 PM, Tue December 6, 2016
Mark Stein, MD
“One thing that investigators have been looking at is if we can use this decrease in circulating tumor cells as a clinical endpoint in a trial,” said Stein. “So, rather than, say, looking at something like survival, do changes in circulating tumor cells correlate so tightly with survival that you can therefore use it as a substitute or surrogate?”
By embedding these biomarkers into clinical studies, he said, trials may be able to move more quickly through development, and answer more lingering questions regarding androgen receptor (AR)–resistance in prostate cancer.
In an interview with Targeted Oncology at the 2016 Chemotherapy Foundation Symposium, Stein, a medical oncologist at Rutgers Cancer Institute of New Jersey, discussed the emergence of circulating biomarkers in clinical practice and how they can be used to combat AR-resistance.
TARGETED ONCOLOGY: Please discuss where we’re at with circulating biomarkers in prostate cancer.
Stein: This is certainly an emerging area in prostate cancer, although we are not routinely using circulating biomarkers in clinical care. With advances in technology, the ability to sample cells, blood, and DNA that is in circulation—these are all going to be integrated into routine care over the coming months and years.
Right now, 1 of the main questions is, when a drug stops working, why does it stop working? Can we figure out who’s going to benefit and who’s not going to benefit? When looking at some of the hormonal therapies, are there predictors of response that we could sample beforehand?
Really, the first use of circulating biomarkers in prostate cancer was just to understand what we call prognostic factors. If somebody has a lot of circulating tumor cells, that is considered a rather poor prognosis factor. Conversely, what’s been shown, if you can decrease the number of circulating tumor cells, patients who respond well seem to do better, and that is an early indicator of having a good response to treatment.
People have looked to see if these markers add anything to traditional markers like CAT scans, or PSA, and they do, which is very exciting. But that’s really focusing mainly on counting the number of cells, and these are papers that go back now about a few years. Some of the new technology is even moving beyond that and looking at specific characteristics of the DNA in circulation.
TARGETED ONCOLOGY: Are there any specific ongoing trials that are looking to identify biomarkers?
Stein: Getting back to this whole idea of counting, and trying to figure out if there’s a decrease in the amount of circulating tumor cells, there is 1 important question that needs further validation. Typically, the way a trial is done, we follow patients for survival, but that takes a long time. It slows trials down, and it makes it much harder to get answers to our questions.
One thing that investigators have been looking at is if we can use this decrease in circulating tumor cells as a clinical endpoint in a trial. So, rather than, say, looking at something like survival, do changes in circulating tumor cells correlate so tightly with survival that you can therefore use it as a substitute or surrogate?
One trial that was done retrospectively showed that it can be used as a surrogate. There are going to be additional trials going forward, with circulating tumor cells embedded into the trials, to definitively establish that those changes can be used as a surrogate for overall survival, and therefore expedite trial development.
Another exciting area of development has been using changes in the AR to understand if tumors will still respond to hormonal therapies. Specifically, drugs like enzalutamide (Xtandi) or abiraterone acetate (Zytiga) have really become routine parts of practice with castration-resistant prostate cancer.
What’s been shown very elegantly now is that the response rate, although perhaps not zero, but close to it, is present when patients have a mutation in the AR. In other words, cells with a mutation in the AR don’t respond to hormonal therapy. That would be an important thing to know right upfront, and it is also potentially an important mechanism of resistance. Therefore, you’d want to go ahead and, for instance, use another form of treatment, such as chemotherapy.
The first generation of those studies has been completed, but now there are additional confirmatory studies going on to really understand how useful this marker is and the best way of assessing it across different platforms.
TARGETED ONCOLOGY: In terms of the AR-resistance we've witnessed, do we understand the prevalence of it and why this occurs?
Stein: It’s really a selective pressure. There are some questions, such as, do these splice variants always exist at low levels? The answer is that they’re there, though we don’t completely understand why they’re there. The full-length AR is the majority of the AR in the cell, but not all of it, and then under selective pressure, cells probably proliferate that are able to adapt to the presence of an AR inhibitor, such as enzalutamide.
What’s also interesting is that, if you then give another treatment afterward, like chemotherapy, you’ll actually see levels of the AR variants decrease, suggesting that, once the selective pressure is removed, that variant goes away.
TARGETED ONCOLOGY: Will these developments in biomarker research open any doors for immunotherapy agents?
Stein: Sure. Obviously, once you have this biomarker, then you have to decide what you’re going to do with it. You certainly want to direct additional therapies toward patients who may be in the most need for additional treatment. Drugs are now being developed that will target different areas of the AR that still remain intact even when the splice variant is present.
TARGETED ONCOLOGY: What would you like the community oncologist to take away from all of this?
Stein: I think there are tests that are commercially available looking at splice variants, and that’s certainly something that could be useful, particularly if it becomes very difficult to understand if a patient should go on a particular therapy or not. It’s also important to have a working knowledge of the trials coming along. This technology is moving quickly, and the platforms are changing quickly. It’s vital to have this framework for understanding where the technology will fit in, and to be aware of clinical trials addressing this—such as clinical trials that may look at a particular biomarker. This could be an important way of deciding where you’re going to put a patient on a particular trial.