Anson Tharayanil: So you can re-challenge your patient with Xtandi and Zytiga after using chemotherapy to take care of the prostate cancer that has become resistant.




Joel Nowak: Recently, we've been blessed with a number of new drugs that have received FDA approval. These drugs are specifically designed to treat men with what is called castrate-resistant metastatic prostate cancer. Unfortunately, these new drugs don't always work for all men and for those men for which the drugs do work, they don't always continue to work or they work for a very limited period of time. 


There is a genetic test called the Oncotype DX ARV-7 Nucleus Detect Test that can help us predict if some of these new drugs specifically Xtandi also known as Enzalutamide and Zytiga known as abiraterone acetate will work for a specific man. The test will also help us know when these drugs have stopped working. 


To tell us about this genetic test we are going to be talking with Anson Tharayanil, who is a medical science liaison from Genomic Health Inc. He passionately believes that educating patients empowers them to be confident about and to make better treatment decisions. 


Welcome Anson.  Understanding and using this genetic test, Oncotype DX ARV- 7 Nucleus Detect Test fits squarely with your passion, empowering patients to be confident about their treatment decisions. 


However, before we discuss this test, I'm going to ask you a few basic questions, but they're very important background questions about castrate-resistant metastatic prostate cancer. First, Anson could you please tell us exactly what is castrate-resistant metastatic prostate cancer?


Anson: I think it's important to know that certain tumors are addicted to naturally occurring hormones in our bodies. For example, breast cancers are actually stimulated by the hormone estrogen and that the presence of that hormone causes cancer cells to divide and grow in the same way that cancer is fed by a class of hormones called androgens. The androgen that most people are commonly aware of is called testosterone. 


So whenever prostate cancer cells are exposed to androgens like testosterone, they begin to divide and therefore grow in size. This dependence on androgens is prostate cancer’s main weakness, and so physicians target that weakness by lowering the man's testosterone level either surgically or with various drugs ibn a process called castration. 


It's this strategy that is quite effective and it could be very effective for several years, but eventually, cancer learns to grow without androgens, so they became androgen independence. Another term for that is actually castration resistance. 


When cancer actually spreads outside of the prostate to nearby lymph nodes, bones or organs, it's called metastatic cancer. It was a symptom of prostate cancer.


Joel: That's quite interesting and certainly explains why men who have metastatic prostate cancer one of their first treatments is to make them castrate.  If a man has been castrated, either through a chemical means or through surgery, how does he know that he's now become castrate-resistant or hormone-independent?


Anson: When cancer actually becomes castrate-resistant the man's blood level of testosterone has dipped below 50 nanograms or ideally 20 nanograms, what happens is that cancer will eventually begin to grow and the signature of that growth has arrived in your PSA level which is also a blood test. As we see a rise in the PSA level, it's an indication to the physician that the patient is actually becoming castration resistance because the only reason the PSA would rise is that their prostate cancer cells that are present that are now growing again, without androgens. So, that's one of the definitions of or one of the indications rather of castration resistance, it could also be a progression of an existing disease or the appearance of new metastases.


Joel:  And that appearance would be found how?


Anson: That would be found usually on scans like a PET scan so you can see a lesion in the bone or an organ.


Joel: One of the things I mentioned in the introduction is that over the last say seven or approximately seven to 10 years we have a number of new drugs that are used to combat metastatic prostate cancer, specifically castrate-resistant metastatic prostate cancer.  Two of these commonly used drugs are enzalutamide also known as Xtandi and abiraterone acetate known as Zytiga. Unfortunately, these drugs don't always work and when they do work at some point they develop resistance or they stopped working.  At some point these drugs,  Enzalutamide or Xtandi and abiraterone        acetate, Zytiga develope this resistance. Can you actually explain to us what resistance is? And do we know how it develops?


Anson: Sure, so there' s Xtandi and Zytiga, and there's actually a newer drug called Erleada  its generic name is Apalutamide. These three drugs are classified as second-generation antiandrogens, and they're called that specifically because they attack the androgen signaling pathway, which is the pathway or the metabolic pathway that testosterone is included in. This pathway is a chemical pathway that the cell uses to trigger growth. We know that if you stop the androgen signaling pathway, various means you did reduce testosterone as was previously measured, putting the patient into the castration state, when you suppress the androgen signaling pathway, the signal telling the cell to divide and grow actually shut off. 


So that's the whole point of these drugs is to shut off that growth pathway. What the cancer is eventually able to do is circumvent those drugs. Specifically, these drugs attack the androgen receptor protein, and it attacks a very specific spot of the protein which essentially acts as the on and off switch for that protein, the prostate cancer eventually adapts and the on and off switch essentially falls off and that protein is permanently stuck in the on position. 


So even in the presence of the drug, the protein still works and when the protein still works, it'll still triggers a growth signal. That's how the actual physical the reality of resistance occurs, it is because the tumors essentially been able to evade this classic drug by adapting this protein to operate independently of this on and off switch.


Joel:  Is there a way that we can actually reverse or turn this protein off?


Anson: Not directly, there's no way that we know of currently to reverse the actual resistance. What we do know and this is important to the utility the test is that once we know that resistance has developed, we can actually switch these AR-targeted therapies or androgen receptor-targeted therapies like Zytiga and Xtandi switch to another class of therapies like chemotherapy such as Docetaxel or Cabazitaxel and those drugs will actually kill the prostate cancer cells using different mechanisms that are outside of the androgen receptor. 


So, they can effectively kill off the resistant prostate cancer cells and at that point, you can actually, stop the therapy be and eventually, unfortunately, in a lot of cases, the cancer could come back but it can actually come back with a protein that is now normal and has an on and off switch. So you can reintroduce Xtandi and Zytiga at a later line.


Joel: What you're actually suggesting is that it would be possible to re-challenge the use of Xtandi or Zytiga after the introduction of another different type of pathway or a different therapy using a different pathway?


Anson: Correct. Yeah, you can re-challenge a patient with Xtandi and Zytiga after using chemotherapy to take care of the prostate cancer that has become resistant. Now, this isn't always the case it’s actually an active area of research and what we're looking into both our company as well as other research is how often does a switching occur between a mutated androgen receptor and the normal androgen receptor that you can then re challenge with extending Xtandi and Zytiga.


Joel: If I understand correctly, we're actually not directly changing them or turning the resistance off, what we're trying to do is kill those cells that have become resistant and then hopefully be able to go back and reuse that drug. Is that kind of a correct understanding?


Anson: Yes, that is correct. Right now, that is the best way to deal with the disease. But there's active research looking into drugs that actually you can turn off the resistance more directly and hopefully, those will come online in the next few years.


Joel: Your company Genomic Health has developed a test that is designed to evaluate the sensitivity a man's prostate cancer might have to either of these two drugs, Zytiga or Xtandi. The test is called the Oncotype DX ARV-7 Nucleus Detect Test, could you please tell us about this specific test?


Anson: The test is a blood draw. So, it's very simple to test actually to use and the blood draw is actually sent to our lab in San Diego. We'll use our technology to pull out the circulating tumor cells that happened to occur in the blood. So, normally, when a patient has metastatic prostate cancer, by definition, it's out in the body somewhere and typically, tumor cells are shed into the bloodstream. 


We can actually capture those tumor cells from the blood draw using our technology and then specifically, look for the presence or the absence of the ARV-7 protein. If ARV-7 protein is present, we know that patient is not going to respond to AR-targeted therapies like Xtandi and Zytiga, and that's a very clear indication for the physician to simply stop using those therapies and switch to another option, typically chemotherapy for perhaps radium or even a clinical trial. 


Now if the patient's negative, and they don't see the ARV-7 protein, and they actually have the option of switching from one drug to the other. So, specifically, if they started on Zytiga, they can consider switching to Xtandi and if they started on Xtandi, they can switch to Zytiga, because even though they're both the second-generation antiandrogen, they actually, have different mechanisms of action and there is data to suggest that you can actually do this switching strategy from one drug to another in ARV seven negative patients, and they will actually benefit from that.


Joel: So that situation you've described is for patients who are taking one of these two drugs, and we want to try to find out if, in fact, they will be able to continue the use of these drugs based on the circulating tumor cells.  It is also a way to predetermine whether a man may even be sensitive to these drugs by using this test. Is that correct? And is that a commonly a use?


Anson: What we know is that the vast majority of men do not have this mutation from the start. What happens is that this mutation actually becomes present because of exposure to Xtandi or Zytiga. It's actually an adaption or an evolution of the tumor in what this encounter to treatment. 


What happens is that typically, when a patient is considered to be metastatic and have metastatic castrate-resistant prostate cancer, they'll be exposed or excuse me, given Xtandi or Zytiga and they don't necessarily need to test the assumptions that they're negative and as the patients eventually fail, and usually these drugs will last about two or three years before you start to see a rise in PSA. At that point, a physician can take the blood draw and determine whether or not they're actually have acquired resistance or they're actually ARV-7 negative and can simply switch therapies.


Joel: The right place for a man to consider having this test would be when their PSA is rising, and they are castrate and they are also taking either Zytiga or Xtandi. The goal would be to determine whether or not they have circulating tumor cells in their blood and if they do have them, then they would probably need to move on to an alternative treatment and if they don't, they could consider switching to the other drug or perhaps staying with the drug they're taking; is that kind of sum up what you're saying?


Anson: Yes, correct. If the patient has a circulating tumor cell that's positive for ARV-7 protein meaning that any ARV-7 protein is detected, then they should consider switching to a different class of drugs like chemotherapy, if they're negative, they can simply stay within that class of drugs and switch from Xtandi to Zytiga or Zytiga to Xtandi. 


Joel: As you said, the test is a simple blood drawer that doctor either could do at his office or at a lab? 


Anson: Correct, Yes. 


Joel: How long does it usually take for these results to be delivered back to the doctor or the patient? And what form are they delivered?


Anson: So, our typical turnaround time is seven to 10 calendar days. What happened after the blood draw is that the samples are overnighted to our laboratory, and we'll do the analysis at our laboratory in San Diego. Once the analysis complete, the physician will either get a fax copy or a digital report through our secure online portal and it'll be as simple, actually very simple, one-page report and it will say either positive or negative. This test in and of itself is actually very straightforward to understand and interpret. If you have a positive result, you know what to do if you have a negative result that you know what to do as well.


Joel:  What determines a positive or a negative result?


Anson: During our analysis, we will look for the presence of circulating tumor cells on top of that will isolate those tumor cells and specifically look for the ARV-7protein using the special digital imaging platform that was created. If we see the ARV-7 protein in the cell, and specifically in the nucleus of the cell where the DNA is and where all the growth signals go to actually become active. If we see that protein in that specific location will call the patient positive, you only need to have one cell to be considered positive. Because if there's one cell in the blood sample, there are likely thousands if not millions more in the actual body. As long as we see one cell that's positive, the patient's considered positive. If we don't see any cells or we don't see anything positive cells and the patients considered negative.


Joel: How accurate is the test? How often do you get false negatives or false positives?


Anson: So, this is a very interesting question. So far, in our studies, every single patient that has been called ARV-7 positive by our test, we have shown that they have absolutely no response to AR-targeted therapies. So, I hesitate to say that we're 100% accurate in every single case, but so far, our data suggest that this test is highly accurate and with a high level of competence, if you got an ARV-7 positive result, that definitely means or you can be at least highly confident that that result means that you will not respond to further AR-targeted therapy like Zytiga and Xtandi.


Joel: You had discussed earlier the possibility that if a man is ARV positive, that they go on to an alternative treatment, either chemotherapy or radium and you also mentioned that it might be possible to re-challenge that man going back to Xtandi or Zytiga, because you hopefully have killed the cells that are positive are ARV positive. 


I'm just curious, has anybody or have you done any work to take men who are positive, give them an alternative treatment and then after that treatment, look to see if they are positive or negative prior to introducing or reintroducing or re-challenging with Zytiga or Enzalutamide?


Anson: We're actually in the process of conducting that study right now. So, we're presently developing the study and recruiting sites and patients to look into that very question. There have been other research groups that have also looked at this question and we do see that in a subset of cases, the ARV-7 status can convert back and forth from positive to negative and negative to positive, I'm hesitant to give any specific percentages because those studies that I've mentioned from other groups are relatively small, we know that it's not going to be every single a patient whose status will switch back and forth. But it's a significant number of patients that make this question worthwhile to investigate in our study, and I'm sure other groups are also looking at this quite diligently.


Joel: If in fact, you are able to show that a significant number of patients do convert from positive to negative would it be worth a man investing or having an ARV-7 tests done after that new therapy that we've used after they've been positive, as opposed to perhaps just going on and trying one of these drugs?


Anson: The short answer is yes, with the caveat that as long as AR targeted therapy is still on the table really becomes a very specific clinical question for a particular patient. The whole point of the ARV-7 test is to say, Do I continue with an AR-targeted therapy? Or do I go in another direction? So if the new challenge or the new if there's a new line of therapy and the physician is saying, maybe I can consider AR target therapy one more time, then it's a good position, or it's a good idea to do another test.


Joel: Given the economic toxicity of having cancer? What is it going to cost them? And I guess the first question is for those men who do have insurance, is this test covered by insurance?


Anson: Yes, so Medicare, actually just earlier this year in 2019, has started covering the cost of the test and once Medicare starts to cover the cost of the test, a lot of the private payers will start doing so as well. 


So currently, Medicare does cover the cost of tests and we're in the process of contracting with a lot of the major payers in the country for coverage of the test. In terms of what an individual patient will see in terms of costs, luckily, the company has a really generous Patient Assistance Program. So, in the process of getting the test ordered, the patient can actually contact our billing department who will go over our patient assistance program to get them a better idea of what sort of costs they'll likely have. Typically, unfortunately, I can't give you an exact number because it depends on the insurance. But typically, it's not an onerous cost for the patient, if they even see a cost at all.


Joel:  How would they go about finding how to reach out to the company? Is there a phone number that you may have or place that they can find it?


Anson: Yes, there are two ways to contact the company one through the website, which is, So O, N, C, O, T, Y, P, E, I, Q .com and then also our customer service line, and they're a fantastic group. They're very knowledgeable about the tests that can answer a lot of technical questions, as well as any logistics for billing questions. If you call 866-662-6897, again, 866-662-6897. That's our Customer Service Group and they can answer any questions, the technical questions about the test or billing questions as well.


Joel:  Terrific. That's really nice to hear. Now, I have private insurance and I'm told that my private insurance is not going to cover me. So, I would have to make an appeal of that decision. Is the company able to provide help in making that request or asking the insurance company to reconsider?


Anson: Yes, I believe our processes is that we will continue to appeal to the patients' insurance to get reimbursement and make sure the test is covered for them.


Joel:  I do know or I have heard that there is another ARV-7 test available or being used, but I understand that it's not currently commercially available. Is that the case?


Anson: Yes, that's the case. That's actually the test out of Johns Hopkins called the ADNA test. 



Before I talk about the test, I just want to point out that a lot of groups have looked at the ARV-7 protein using a different methodology. So, we look for the presence of the protein, Johns Hopkins looks  for the presence of the RNA, which is a molecule that creates the protein, for lack of a better word. 


Both companies, both methodologies show that ARV-7 is clearly an important biomarker. So, as a general census it’s really good, in terms of confidence that what we're seeing is a real effect. 


The Johns Hopkins test right now, it's rated for research use only. So, it's not necessarily scaled-up to deal with receiving samples from across the country. Whereas for our test, it's been developed so that we can receive samples from around the country, if not around the world, and have a reliable result. When you commercialize the test and make it available to the public it requires a whole other layer of quality control that research use only test doesn't necessarily need to implement. 


Now, that's not to say that it's necessarily a worse test. However, there's a lot of safeguards and quality control metrics and regulatory requirements that are required for a test to become commercialized.  That's from a logistics point of view. 


In terms of the actual data, it's interesting to show that in the recent Prophecy Study, which was published earlier in 2019, the two tests were compared head to head and what we found is that when our platform, the Oncotype DX-7 Nucleus Detect Test looked for the protein and called a patient, ARV-7 positive, all of those patients did not respond to AR-targeted therapy whatsoever. 


On the flip side, however, with the Johns Hopkins test, a couple of those patients that were called ARV-7 positive still responded to AR-targeted therapy. In other words, AR-targeted therapy worked in those patients, despite being called quote unquote "ARV-7 positive" and so there is a belief that because Hopkins test is not looking at the location of the protein, it's just looking for the presence or absence of it. That's what's leading to these potential false positives. Our test, however, is looking both for the presence of the protein and whether or not it's specifically in the nucleus of itself. If it's in other parts of the cell, we actually don't call it positive it has to be specified in the nucleus of the cell. We know that what it is in the nucleus of the cell, that's when the patient was actually fully resistant to AR-targeted therapies.


Joel:  Interesting. I didn't know any of that, really good, I'm glad you shared that. Earlier on the podcast, you mentioned a newer drug Erleada or Apalutamide. Apalutamide is relatively similar to Xtandi. Have you looked at whether or not Apalutamide develops resistance, the way Xtandi does? Is the resistance similar because of having the ARV-7 protein? Would this test also be useful for men who are on Apalutamide and trying to understand if they have become resistant to it?


Anson: Yes, it would be. Apalutamide is specifically in the pre-metastatic or M 0 space. It's technically also considered a second-generation anti-androgen. It works the same way as Zytiga and Xtandi work. For that reason, we actually expect the resistance pathways to be very similar. In practice, if a man was to be exposed to Erleada or Apalutamide in the M 0 space, and then later have progressive disease, where the diseases getting worse, at that point, they'd be considered metastatic and they would be eligible for Oncotype testing because they may have the ARV-7 protein resistance and so those patients are actually eligible for testing.


Joel: Not only are they eligible, would Medicare or, and Medicaid cover that I know as you mentioned earlier, but it would also for men who are on Xtandi or Zytiga, is the same in this case for Apalutamide?


Anson: Yes, it is because for Medicare's acceptance criteria, or excuse me, billing criteria, the patient needs to be metastatic and would have had to already failed an AR-targeted therapy.  So, patients would also be qualified for it.


Joel: That's something that a patient on Apalutamide definitely needs to make sure their doctor knows because I have a feeling that a lot of doctors don't necessarily associate the use of this test with Apalutamide. I think that's really important to take home for a lot of men.


Anson: And we actually expect a higher rate of positivity going forward because these drugs are being used earlier and earlier in the cancer progression pathway. As patients get exposed to these drugs at an early level, we actually expect to see higher rates of AR-7 positivity.


Joel: I really want to thank you very much for sharing this important information about the Oncotype DX ARV-7test.  It's a test that every man who is progressed, who is castrate resistant and maybe I should now say not only castrate-resistant given the Apalutamide approvals, any man who has metastatic disease and considering a second line hormone therapy needs to know about the test and needs to make sure that they discuss it with their doctor, if I'm at my doctor's, and I am on one of these drugs, and my PSA is rising despite being on these drugs, and I'm not being offered the ARV-7 test. 


Obviously, I would need to say something to my doctor, but how do I actually find out about it myself so that I can actually give this information to my doctor so that they can go ahead and follow up on it and arrange for it?


Anson: The best resource that we have both for patients and physicians outside of reaching out to the company directly is through our website. The Oncotype DX or excuse me, website is our best place. We have a great section built for patients and physicians specifically, that gives a brief summary of the utility of the test and that's really helpful for both physicians and patients that aren't even aware of what the whole biomarker ARV-7 biomarkers is about and then also more details on how to order the test and when it's appropriate to order the test.


Joel: Thank you, again. It is really exciting to see that we have all these new treatments that are being developed for metastatic prostate cancer, as well as the tools like the Oncotype the DX ARV-7 test that really will allow us to better utilize these new second-line drugs. As patients, we really would like to thank the company for spending the time and the money to develop them. I wanted to ask before we leave if you have anything you would like to share related to the test or not with men who are suffering from metastatic prostate cancer.


Anson: I think it's important to know that this is a very difficult time in a lot of men's lives. And it's important to ask questions and it's important to seek out support. A lot of guys don't do that we're really not built or trained to do such a thing. But this is the one time if no other time in your life that you should ask the help of your friends, help of your families the help of your physicians, they have resources as well that they can provide for you because it's a stressful time. It's good, stay engaged and stay educated, and that'll help take the edge off of the difficult journey.


Joel: Thank you so much for what I would say are very wise words. This has been Joel Nowak from Cancer ABC's along with Mr. Anson Tharayanil from Genomic Health. We have been talking about this new test the Oncotype DX ARV-7 Nucleus Detect Test, a test that you need to learn more about and consider using as you move through your prostate cancer journey. Thank you for joining us and until the next podcast.