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ASCO 2016: Advanced Prostate Cancer Roundtable Discussion

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Published on June 7, 2016

What could developing research mean for advanced prostate cancer patients? Led by Dr. Tomasz Beer, an expert panel explores research discussed at the 2016 American Society of Clinical Oncology (ASCO) meeting in Chicago. The panel shares updates related to biomarkers, chemotherapy and hormonal approaches. Learn why Dr. Beer feels this year’s meeting is important in building “foundations for the future.”

Sponsored by the Patient Empowerment Network through educational grants from Sanofi Oncology and Astellas Pharma Inc.





Patient Empowerment Network

Transcript | ASCO 2016: Advanced Prostate Cancer Roundtable Discussion

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Dr. Beer:

Hello and welcome.  My name is Tom Beer, and I'm from the Knight Cancer Institute at Oregon Health & Science University in Portland, Oregon.  Today we're here in Chicago at the 2016 annual meeting of the American Society of Clinical Oncology.  Today with me is Dr. Emmanuel Antonarakis from Johns Hopkins University School of Medicine,  Dr. Russell Szmulewitz from the University of Chicago Medical Center, and joining us also is Joel Nowak, prostate cancer advocate and director of the advanced prostate cancer programs and advocacy at Malecare.  Welcome, everyone, and thank you for joining us. 

Today we're going to discuss the latest findings from the annual meeting at ASCO.  By way of introduction, I might offer a comment.  I think we've had a rich meeting with a lot of new data about biomarkers, predictors of outcome, new information about chemotherapy, and some additional information about local treatments and hormonal therapies in prostate cancer. 

I think we might describe this meeting as one that builds foundations for the future.  I'm not seeing major presentations that will dramatically change how we care for men with prostate cancer today, but a lot of the research that we're seeing at this meeting I think will serve as a basis for future changes in therapy that we expect to see in years to come. 

One of the major areas of interest at this meeting has been the affirmation and additional data about the new biomarkers that we're seeing that help us better understand the disease and potentially better select patients' treatments on an individual basis.  And no area is more compelling I think than the AR-V7 story that Dr. Antonarakis has played a key role.  There are a couple of important presentations on circulating tumor cells, AR-V7, circulating tumor cells heterogeneity at this meeting.  Emmanuel, would you like to comment on those? 

Dr. Antonarakis:

Sure.  So the AR-V7 story I think is expanding more and more each year, and I think the story broke about two years ago, so the AR-V7, an abnormal version of the androgen receptor that we think predicts resistance to the new hormone therapies like enzalutamide (Xtandi), abiraterone (Zytiga).  The interesting thing is that the data seems to hold up across a different variety of platforms for measuring circulating tumor cells, so the Hopkins group used one particular CTC assay, and another group led by Dr. Howard Scher at the Memorial Sloan Kettering used a different assay. 

The interesting and important thing is different assays measuring the same AR-V7 showing the same results, and that really speaks to the credibility and the importance of the biomarker.  The main findings, I would say to summarize them, are that patients that have AR-V7 in their circulating tumor cells appear to respond less well to drugs like enzalutamide and abiraterone, but they may still have some sensitivity to chemotherapy agents such as taxanes, docetaxel (Taxotere) and cabazitaxel (Jevtana).  And I think that data is beginning to accumulate and emerge.  And within the next six months, I think that there will be some commercially available biomarkers to test for this abnormality so that patients can be tested.  

Dr. Beer:

Joel, can I turn to you?  Why is this important for patients? 

Joel Nowak:

A lot of us are feeling frustrated, because we go into a treatment, and we're not aware if it's going to help us or not, have any effect.  We're pretty much sure that we're going to have some sort of side effect, and it's hard to pay the price of side effects without knowing there's going to be a positive flip on the other side. 

So having biomarkers that we're able to use to predict whether perhaps a treatment is going to be effective and also to know how long it's going to be effective, because right now we give somebody a treatment, and it's not always so clear as to when that treatment may have stopped working. And getting a better handle on when it's appropriate to move on to another treatment is really going to be important.  So this to me is one of the more exciting things that I've heard at the meeting. 

Dr. Beer:

So another area that the field's very interested in is DNA repair defects.  Would you like to introduce the audience to the concept?  Why are we interested in this, and what's happened at this meeting?  

Dr. Szmulewitz:

Sure.  Well, let me start off by sort of giving a very top?line explanation of what it is, DNA repair and how it gets altered and what the implications of that are.  So as part of our—the cells process to make more cells, it's got to make more DNA. And in that process there are occasional errors that come up or breaks in the DNA that come up, and there are certain processes within all cells whose job it is to repair that damage. 

And there are hosts of enzymes, hosts of proteins or mechanisms that work together to make that possible within a cell, not just a cancer cell, any regular cell.  What we know is that cancer in general sometimes is predisposed to have mutations or changes in these DNA repair genes, and that allows them to then accumulate other mutations that make them more aggressive or grow and live despite other cues that tell them not to.  

However, what we are now learning is that in prostate cancer, these mutations, these DNA repair mutations, may also make them more sensitive to a specific type of therapy called PARP inhibitors.  You know, it's an exciting time in that field, and we've been talking about how do we make cancer care more precise for our men with prostate cancer, how do we refine and give the right therapy to the right patient. And I think that this development might be one of the first times in which we have more clear evidence of who might benefit from a very specific therapy. 

So to be more specific, a new drug called olaparib (Lynparza), which is a PARP inhibitor was recently shown and published in a large Phase II trial that in patients who have mutations and very specific DNA repair genes, some of those like BRCA1 and 2 we knew about and are very commonly known in the lay community.  Some of them, such ATM, are other enzymes in that pathway.  Regardless, patients who had a mutation in that had a very, very high, nearly 90 percent response rate. Whereas if you didn't, it was much lower.  So it offers the potential hope that if we detect these mutations, we might be able to target that biology and create lethality with this medication.  

Dr. Beer:

Emmanuel, can I follow up on that?  So a paper from Peter Nelson presented at this meeting reported that more than 11 percent of men with advanced prostate cancer carry inherited mutations that are associated with a defect in these DNA repair pathways.  The most famous of these are the so-called BRACA genes, BRCA1, BRCA2.  Many people are aware of these genes.  They are associated with an increased risk of breast and ovarian cancer—11 percent, that's a surprise.  Should we be offering testing for these inherited defects to our patients with advanced prostate cancer, and what does that mean for their families? 

Dr. Antonarakis:

So I think we need to make a distinction here and maybe also educate the audience.  So when we're talking about these mutations for men, there are two different types.  The first type is the one that you're born with.  We call that a germline.  It's just a jargon.  It means it's just the one you're inherited with, and you can pass on to your kids and your family. 

The second type of mutation is called somatic.  Somatic mutations are only found within the tumor but not necessarily the ones that you were born with, and you can't really inherit and pass on a somatic mutation.  

So here what we're talking about is germline mutations, these mutations that you were born with, that you can also pass off to your offspring.  And we thought that these mutations existed in 2 to 3 percent of men.  Now we think it's remarkably higher, maybe up to 11, 12 percent.  And, yes, Tom, I do think that that's a bit of a game-changer, because now it's not really as rare as we once thought. And, as was mentioned by Russell, we now might have a therapy, these PARP inhibitors, such as olaparib, which could provide clinical benefits to those patients. 

So I think there's a lot of hope there, but there are also implications for family counselling.  If a man has one of these mutations, let's say BRCA2, then that person's sister or daughter may have to be screened for breast cancer or ovarian cancer.  So there are other implications beyond the prostate cancer diagnosis itself.  

Joel Nowak:

And I also think that there's an implication for children of men who are diagnosed with prostate cancer and grandchildren and so forth and so on.  We've known that there's some sort of genetic relationship in a small number of men, but understanding how much larger it is than we actually thought, really it means that it's more important for anyone who has had prostate cancer or a family first-degree relative who's had prostate cancer that they really do make sure they speak to their doctor about finding out where their PSA pass is, doing some prework, and also looking at ways they may be able to do to help prevent the development of disease.  And I also want to thank you so much for your excellent explanation of germline, okay, for a lot of people who don't understand that. 

Dr. Beer:

I do want to highlight for the audience that this high rate of inherited mutations is being found in men with metastatic advanced prostate cancer, and we think there is a distinction between localized and advanced. And so I'm not sure that all men with prostate cancer need to be concerned that they have a high risk of having these mutations.  But those men who have metastatic disease probably should be talking to their doctors about that. 

Russ, do you have an additional comment on this? 

Dr. Szmulewitz:

I would just add that we're talking about this testing for these genes, the germline, the inherited risk we can do with a blood test.  The mutations that are somatic, that you get in perhaps in a tumor over time, they have to be assayed.  You have to actually test the tumor material.  And what papers have now shown us is that the rate of those aberrations, those abnormalities, might be as high as 25 or 30 percent in advanced prostate cancer tumors. 

So in my practice we're looking in the upcoming months how you might triage this and how you might proceed with a patient in your office. We might start with family counselling in genetic risks and a blood test. And if they have a mutation there, that gives us hope that this medication might help.  And otherwise we might be doing more biopsies sequentially as the disease progresses to look for some of these mutations. 

Dr. Beer:

That's a tremendous change I think…

Dr. Szmulewitz:

Tremendous change. 

Dr. Beer:

…for patients out there.  I would say we're working on it, trying to sort this out.  We haven't implemented biopsies for everybody of metastatic disease and practices yet, but I think we're going to either do that or look to assays that try to detect circulating tumor DNA and perhaps get around the need for a biopsy.  

Let's move on to some treatment developments.  So in localized disease one abstract caught my eye, a randomized study of standard-length radiation and so-called hypo-fractionated or shorter radiation.  Joel, let me turn to you and have you comment on is duration of radiation a significant issue?  Is this something that patients will care about? 

Joel Nowak:

Yeah, absolutely they will.  Normally, radiation takes a piece of your life.  Granted, it's only for a few minutes, but it's every day for any X number of weeks, and men want to live their life.  They want to go to work.  They want to play golf or go to the baseball game, and it's very difficult when you have to go to the clinic on a daily basis for a long period of time.  It definitely interferes with quality of life, and one of the things with all cancers—I mean we're always very concerned, certainly patients are, about the quality of life.  

Dr. Beer:

So that study in a randomized fashion showed that the outcomes with a shorter course of radiation where higher doses are used every day are about the same as with standard.  So I think we're going to see more and more shorter-course radiation regimens being offered to men with localized prostate cancer. 

A lot's happened in advanced disease.  I'm going to turn to Russ and ask him to comment a little bit on developments with cabazitaxel (Jevtana).  Cabazitaxel is a novel taxane which is currently approved as a second-line chemotherapeutic.  There were some hopes that it might move up front, but the results of this meeting suggest that it's going to stay where it's currently used.  

Russ, do you want to comment on what we learned? 

Dr. Szmulewitz:

Sure.  So cabazitaxel was a designed therapy that was hoped to overcome certain resistance mechanisms with the initial drug, docetaxel.  The company that makes both of them conducted a randomized study comparing one to the other for patients with advanced prostate cancer in whom initial hormone therapy is no longer effective with the hope that—it should be noted that cabazitaxel does improve survival in patients who have already received docetaxel and had progression with docetaxel.  The question was if we move it forward, does that improvement persist up front?

And I was not entirely surprised by these data.  The cabazitaxel was sort of designed to overcome resistance to docetaxel, and perhaps the men who receive docetaxel, get it and then progress are the ones that are inherently going to derive the most benefit from cabazitaxel.  

So I would add that we are moving docetaxel even more forward into the hormone-sensitive setting, meaning that patients who haven't yet had their hormone therapy fail them are receiving docetaxel up front.  So we might, in fact, be still using cabazitaxel in the castrate-resistant setting first.  And this study doesn't really answer that question. 

Dr. Beer:

Yeah.  So in another study, two doses of cabazitaxel were compared to one another, and those showed by and large that we have the option of using a slightly lower dose of cabazitaxel with a similar result, a little bit less toxicity.  So I think cabazitaxel is here to stay.  It's likely to be a second-line drug after docetaxel. But as Russ alluded to, we're using docetaxel earlier. 

And, Emmanuel, maybe you could comment.  The study that established docetaxel early first was the so-called CHAARTED study.  In that study, men were treated for metastatic prostate cancer with standard hormonal therapy and six cycles of docetaxel right away, and that study showed a significant survival advantage to moving chemotherapy up early.  That's why we're doing that work. 

At this meeting, we heard about some of the quality-of-life results from that trial.  Would you want to put that in context for us? 

Dr. Antonarakis:

So two groups of men—the one had the hormone therapy alone up front.  That's what we were doing for many years.  The other group of men had the hormone therapy plus six cycles of the docetaxel given every three weeks.  So the quality-of-life study was basically showing the three-month quality-of-life data, and then the subsequent long-term quality-of-life data after the chemotherapy actually had ended. 

And perhaps not surprisingly at the three-month time point the patients that were receiving of chemotherapy and the hormone therapy had a slightly lower quality of life per the—on the report.  However, the interesting thing, and I think the take-home message is in the long term, several months after the chemotherapy had ended the quality of life in those patients who had received the double therapy, the chemo and the hormones, was actually improved. 

So, of course, our goal is sort of the long-term horizon for these patients and not just the immediate toxicity of the therapy.  And again, in experienced centers, I think the short-term toxicity can be well managed. So I think the lesson there is, you know, patients should sort of try to get through it and with the help of their oncologist and their family members and their peers try to sort of stick with it, and in the long-term that their quality of life will actually go up rather than go down, having had that chemo early. 

Dr. Beer:

Joel, let me turn to you with a specific question.  I must say when chemotherapy came along for this earlier use, I think some of us thought patients wouldn't want it.  You know, chemotherapy has a bad name, if you will.  But in our practice, our patients really have embraced it.  I think they've seen—when they hear about the survival advantage they're in favor of being quite aggressive.  Is that what you're hearing?  Or how do people feel about this?  

Joel Nowak:

I don't have a statistic, but I will say that I think a fair number of people, probably is a majority of people do feel the way you've just indicated that you've seen in your practice.  However, there's still this significant smaller number who think of chemotherapy and all the negative effects.  I mean, it's not the chemotherapy that Aunt Edna had 25 years ago, and that's the reputation that chemotherapy still has, and it takes a fair amount of work to get people, to get the men to understand that it's worth—it's worth the risk, reminding them that you can start. And if it's really something you can't tolerate, you can stop.  There's no rule that says you can't stop.  You need to discuss that with your doctor. 

And I think that this study is really going to give us a lot of conversation, an opportunity, because I think, if I remember correctly from the study that a year after the therapy, the chemotherapy that the quality of life were actually being reported as being better.  And I think that that is really important, and it's something that I will continue to really stress with men who are having that I don't know if I really want it.  

Dr. Beer:

Emmanuel, I'm going to come back to you.  You were involved in a trial called TAXYNERGY.  It's going to be a real challenge to explain that trial to our audience, but we'll give you a crack at it.  It's an interesting study. 

Dr. Antonarakis:

It's an interesting study.  The usual way that we prescribe chemotherapy is we start the drug, either cabazitaxel or docetaxel, and we either continue that until the patient can't take the side effects anymore, or their cancer continues to grow despite the chemotherapy.  So we call that treat until progression or toxicity. 

So in this case, we try to see whether switching the chemotherapy from one drug to another by some early indicator of response might be better than just sticking with the drug until the end.  So what we did was we randomized patients, so they either started off with cabazitaxel or docetaxel.  After four cycles of therapy, they had a PSA check.  And if the PSA had dropped by 30 percent or more, we said, hey, listen, these guys are having a good response.  They should remain on the same drug that they started with. 

If their PSA had not dropped by 30 percent or more or even if it had increased, in those patients we would switch them.  After the fourth dose, then their fifth drug would be the alternative drug.  So, for example, a patient receiving docetaxel for four doses whose PSA doesn't go down adequately after the fourth dose, you will be switched to cabazitaxel rather than waiting for the docetaxel to stop working. 

And what we found was in about half of patients who did not have that adequate PSA response with the first four doses, if you switch them to the alternative drug, you could salvage some of those patients.  In other words, you could get them to respond to the second agent.  And that was true in both directions.  So in some patients, docetaxel was not as effective up front, but then cabazitaxel can salvage them, and the inverse was also true.  Some men who started with cabazitaxel may not have had appropriate response but then would be salvaged by the older taxane, docetaxel.  So I think—I'm not sure if that's ready for clinical practice, but it really does provide some interesting hypotheses that could be tested in other studies. 

Dr. Beer:

Yeah.  So I think at this ASCO we're learning that chemotherapy continues to have an important role in the management of prostate cancer.  Docetaxel is an important component of the initial treatment of metastatic disease, and we have some good data to suggest that the quality-of-life penalty that men pay in the first three months goes away, and, in fact, in the long term there are gains to doing that. 

We've learned that cabazitaxel is going to stay as a second-line treatment, but we're learning how to refine it.  There are studies of a lower dose.  There are studies that Emmanuel pointed out where we may be able to switch into cabazitaxel therapy a little earlier in the appropriate patients.  So the work continues to make the chemotherapy as tolerable and as effective as it can be for our patients. 

Now, an area that we heard less about at this meeting than maybe a year or two ago are hormonal agents.  A couple of years ago, enzalutamide and abiraterone were really at front and center at the meeting and have now become standards of care for men with metastatic disease.  But there was one study for us out of MD Anderson that looked at preoperative use of these agents and showed that combining everything, standard hormonal therapy, abiraterone, enzalutamide, didn't really seem to add to just abiraterone and standard hormonal therapy.  Is that a bit of a cautionary note that we shouldn't assume that more is always better?  What do you think? 

Dr. Szmulewitz:

Yeah.  It's a great question.  I think that kitchen-sink approach is sort of our instinct.  You know, if one thing is good and two things are good independently, then we should put them all together, and that will achieve the best result.  And I think the only way that we can know that is through studies like this one in which patients were given before surgery different combinations or given all three or just two, and it didn't show that the addition of enzalutamide to abiraterone was—was beneficial. 

And I think that some of this we have to think about the biology a little bit more.  And we have to think of how the cancer cell is going to adapt to the therapy that we're giving it.  And so abiraterone, for example, eliminates the production of hormones in the tumor and in the body, and enzalutamide blocks the hormone receptor.  The end result of both is to stop the hormones from working. 

What this tells us at least in a short period of time that perhaps the adaptation isn't necessarily to, for example, keep the hormone receptor active without the normal amounts of hormones there.  So I think what this study will also provide is a lot of material to study from these patients so that we can figure out how was the—were the tumors adapting and how can we for the next study refine on that knowledge. 

Dr. Beer:

It seems to me it's a reminder that we need to stay humble and do the studies.  There are many good ideas in oncology, and those of us who have been in the field for some time have seen many great ideas fail, some great ideas succeed, some ideas that we thought were mediocre succeed widely.  Like CHAARTED, many of us really didn't think that chemotherapy would have such a big impact in early disease, but evidence really is king. And until we know, we ought to stay humble and make sure that we recognize that things don't always turn out the way we think they might. 

I think I'd like to close this discussion with a question to all three of you guys.  All of the progress that we see here at ASCO is largely a result of patients who were courageous enough to volunteer for clinical studies, whether it's clinical trials with a new therapy or outcome studies where they contribute information or a blood sample.  Why should a patient with prostate cancer consider a clinical trial in their care?  Let me start with Joel. 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

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