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The Underlying Biology of Metastatic Prostate Cancer

Panelists: Joe OSullivan, MD, FRCPI, FFRRCSI, FRCR, The Northern Ireland Cancer Centre, Belfast City Hospital; Johann de Bono, PhD, MB, ChB, Institute of Cancer Research, Royal Marsden Hospital; Chris Parker, MD, FRCR, MRCP, Institute of Cancer Research, Royal Marsden Hospital; Bertrand Tombal, MD, PhD, Cliniques Universitaires Saint-Luc
Published Online: Thursday, Oct 12, 2017



Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Thank you for joining this OncLive® Peer Exchange® entitled, “Metastatic Prostate Cancer: A Practical Review of Therapy.” The treatment of prostate cancer has changed significantly in the last decade, owing to the introduction of several novel therapeutic strategies. Yet, challenges remain in selecting the optimal course of treatment for an individual patient with metastatic disease. There is a growing appreciation for the biologic heterogeneity of advanced prostate cancer and the need for more personalized approaches.

In this OncLive® Peer Exchange®, I’m joined by an international panel of experts in the field of prostate cancer research. Together, we will discuss the latest evidence surrounding the treatment of metastatic disease. We’ll focus on current approaches for therapeutic sequencing and combination therapy, strategies to manage resistance to androgen-targeted therapies, and treatment of prostate cancer associated with aberrant DNA repair.

I am professor Joe O'Sullivan. I am the clinical director of the Northern Ireland Cancer Centre of Belfast City Hospital, Northern Ireland. Joining me for this discussion are Dr. Johann de Bono, professor of cancer medicine at the Institute of Cancer Research and the Royal Marsden in Sutton, United Kingdom; Dr. Chris Parker, clinical oncologist at Royal Marsden Hospital and reader in prostate cancer oncology at the Institute of Cancer Research in Sutton, United Kingdom; and Dr. Bertrand Tombal, professor and chairman of urology at Cliniques Universitaires Saint-Luc in Brussels, Belgium.

Thank you for joining this discussion. Let’s begin. We’ll start with the biology of prostate cancer. Bertrand, I’m going to start with you. What is known about the differences in underlying biology between indolent and aggressive prostate cancers? What are the genetic drivers?

Bertrand Tombal, MD, PhD: It has been an important question for the last 10 years. Basically, you can look at 3 phases in the development. For 20 years, many people have been trying to look at a single individual genetic abnormality, if you think about PTEN loss, RB loss, or that there has been a lot of work on microRNA, like miR-21. Usually, regarding whether you had it or not, it conferred a higher aggressiveness, but the impact on clinical decisions was limited. The second part is all the work that has been done in CRPC as part of the dream teams. Work has been done, like in the Robinson paper, where in the end we came up with a list of what I call the usual suspects, meaning cell-cycle aberrations, AR mutations, AKT, PTEN pathways, and DNA repair mutations, but we’re going to speak about that later on.

Then the question is, and it’s a very important one, is this something you acquire through treatment or something that existed from the beginning? That’s where we have the latest update, that’s probably the case, and if you take work like that done by Rob Bristow in Toronto you can find that there’s not 1 suspect. But if you look at a patient who’s going to die from the disease, very often very early on you find a lot of genetic instability in many of these markers being expressed. Based on this, we come to question, what do we do with that in the clinics and does it impact treatment? Should you change your management based on this? That observation is the basis for new clinical trials.

Now, for a very, very basic questioning, we have commercial tests, and they usually use a panel of genetic abnormalities that have been chosen based on this theory. You’ve got Decipher, you’ve got Prolaris, and you’ve got Oncotype DX. My view on these is that they can’t help yet with really aggressive disease, but they can help you with telling who is not indolent, meaning they are most useful in telling that patients should not go on active surveillance. But for the real questioning, like what kind of high-risk localized disease needs escalation therapy versus standard therapy, there’s not 1 genetic abnormality. You find the usual suspects, such as PTEN, RB loss, and all the genetic instabilities, plus many others, such as c-MYC. That’s going to be moving toward a panel that covers more than 1 driver.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Johann, what do you think?

Johann de Bono, PhD, MB, ChB: I would like to add to that. There is quite a lot of work indicating that the more indolent cancers have much fewer genomic aberrations, deleterious aberrations. For example, a paper in PNAS by Charles Sawyers’ group indicates that the less genomic aberration burden you have, the more indolent the disease. In fact, if you look at all the data emerging from ICGC, TCGA, and even other groups on the genomics, it’s quite apparent that the more indolent cancers have much, much less burden genomically. What’s also emerging is that if you have significant intra-patient, inter-tumor cell heterogeneity—that is the genomic instability that Bertrand mentioned—these cancers are much more likely to be lethal. This is going to be, probably, impactful overall with regards to selecting patients for more or less aggressive disease and maybe even different therapies.

Clearly, there’s evidence that, actually, DNA-repair defective cancers have a worse prognosis from diagnosis. I think there’s quite strong evidence for that, particularly BRCA2, and this may impact therapy. So, it is possible, although we haven’t got the data yet, that the local therapy we give in cancers that have, say, HRD defect or mismatch repair defect may need to be a different local therapy versus in cancers that don’t. But these are questions that need to be addressed in clinical trials, and I don’t think that today we can be making any recommendations about these data.

Chris Parker, MD, FRCR, MRCP: If we’re talking about men on active surveillance with localized disease, then the clinical decision is, do we treat them or not? I’m a bit skeptical about the value of these commercial genetic tests, because they’ve been developed in men who are not having MRI scans. The standard of care right now, especially in the United Kingdom, for active surveillance is to monitor with MRI. So, these commercial tests are only going to be helpful if they give added value over and above what we’re already getting from MRI.

Johann de Bono, PhD, MB, ChB: The concern is actually that with the lethal lesion, a small lesion that is perhaps not part of the main tumor mass and the MRI may even miss it, this is probably never going to be feasible with these assays.

Bertrand Tombal, MD, PhD: That’s where you see that actually, even if you take standard nomograms and are adding these genetic tests on top of that, you have an added value that remains modest. So, it really means that the sampling error and the intra-patient heterogeneity is not something these tests are capturing worldwide now.

Transcript Edited for Clarity 

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Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Thank you for joining this OncLive® Peer Exchange® entitled, “Metastatic Prostate Cancer: A Practical Review of Therapy.” The treatment of prostate cancer has changed significantly in the last decade, owing to the introduction of several novel therapeutic strategies. Yet, challenges remain in selecting the optimal course of treatment for an individual patient with metastatic disease. There is a growing appreciation for the biologic heterogeneity of advanced prostate cancer and the need for more personalized approaches.

In this OncLive® Peer Exchange®, I’m joined by an international panel of experts in the field of prostate cancer research. Together, we will discuss the latest evidence surrounding the treatment of metastatic disease. We’ll focus on current approaches for therapeutic sequencing and combination therapy, strategies to manage resistance to androgen-targeted therapies, and treatment of prostate cancer associated with aberrant DNA repair.

I am professor Joe O'Sullivan. I am the clinical director of the Northern Ireland Cancer Centre of Belfast City Hospital, Northern Ireland. Joining me for this discussion are Dr. Johann de Bono, professor of cancer medicine at the Institute of Cancer Research and the Royal Marsden in Sutton, United Kingdom; Dr. Chris Parker, clinical oncologist at Royal Marsden Hospital and reader in prostate cancer oncology at the Institute of Cancer Research in Sutton, United Kingdom; and Dr. Bertrand Tombal, professor and chairman of urology at Cliniques Universitaires Saint-Luc in Brussels, Belgium.

Thank you for joining this discussion. Let’s begin. We’ll start with the biology of prostate cancer. Bertrand, I’m going to start with you. What is known about the differences in underlying biology between indolent and aggressive prostate cancers? What are the genetic drivers?

Bertrand Tombal, MD, PhD: It has been an important question for the last 10 years. Basically, you can look at 3 phases in the development. For 20 years, many people have been trying to look at a single individual genetic abnormality, if you think about PTEN loss, RB loss, or that there has been a lot of work on microRNA, like miR-21. Usually, regarding whether you had it or not, it conferred a higher aggressiveness, but the impact on clinical decisions was limited. The second part is all the work that has been done in CRPC as part of the dream teams. Work has been done, like in the Robinson paper, where in the end we came up with a list of what I call the usual suspects, meaning cell-cycle aberrations, AR mutations, AKT, PTEN pathways, and DNA repair mutations, but we’re going to speak about that later on.

Then the question is, and it’s a very important one, is this something you acquire through treatment or something that existed from the beginning? That’s where we have the latest update, that’s probably the case, and if you take work like that done by Rob Bristow in Toronto you can find that there’s not 1 suspect. But if you look at a patient who’s going to die from the disease, very often very early on you find a lot of genetic instability in many of these markers being expressed. Based on this, we come to question, what do we do with that in the clinics and does it impact treatment? Should you change your management based on this? That observation is the basis for new clinical trials.

Now, for a very, very basic questioning, we have commercial tests, and they usually use a panel of genetic abnormalities that have been chosen based on this theory. You’ve got Decipher, you’ve got Prolaris, and you’ve got Oncotype DX. My view on these is that they can’t help yet with really aggressive disease, but they can help you with telling who is not indolent, meaning they are most useful in telling that patients should not go on active surveillance. But for the real questioning, like what kind of high-risk localized disease needs escalation therapy versus standard therapy, there’s not 1 genetic abnormality. You find the usual suspects, such as PTEN, RB loss, and all the genetic instabilities, plus many others, such as c-MYC. That’s going to be moving toward a panel that covers more than 1 driver.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Johann, what do you think?

Johann de Bono, PhD, MB, ChB: I would like to add to that. There is quite a lot of work indicating that the more indolent cancers have much fewer genomic aberrations, deleterious aberrations. For example, a paper in PNAS by Charles Sawyers’ group indicates that the less genomic aberration burden you have, the more indolent the disease. In fact, if you look at all the data emerging from ICGC, TCGA, and even other groups on the genomics, it’s quite apparent that the more indolent cancers have much, much less burden genomically. What’s also emerging is that if you have significant intra-patient, inter-tumor cell heterogeneity—that is the genomic instability that Bertrand mentioned—these cancers are much more likely to be lethal. This is going to be, probably, impactful overall with regards to selecting patients for more or less aggressive disease and maybe even different therapies.

Clearly, there’s evidence that, actually, DNA-repair defective cancers have a worse prognosis from diagnosis. I think there’s quite strong evidence for that, particularly BRCA2, and this may impact therapy. So, it is possible, although we haven’t got the data yet, that the local therapy we give in cancers that have, say, HRD defect or mismatch repair defect may need to be a different local therapy versus in cancers that don’t. But these are questions that need to be addressed in clinical trials, and I don’t think that today we can be making any recommendations about these data.

Chris Parker, MD, FRCR, MRCP: If we’re talking about men on active surveillance with localized disease, then the clinical decision is, do we treat them or not? I’m a bit skeptical about the value of these commercial genetic tests, because they’ve been developed in men who are not having MRI scans. The standard of care right now, especially in the United Kingdom, for active surveillance is to monitor with MRI. So, these commercial tests are only going to be helpful if they give added value over and above what we’re already getting from MRI.

Johann de Bono, PhD, MB, ChB: The concern is actually that with the lethal lesion, a small lesion that is perhaps not part of the main tumor mass and the MRI may even miss it, this is probably never going to be feasible with these assays.

Bertrand Tombal, MD, PhD: That’s where you see that actually, even if you take standard nomograms and are adding these genetic tests on top of that, you have an added value that remains modest. So, it really means that the sampling error and the intra-patient heterogeneity is not something these tests are capturing worldwide now.

Transcript Edited for Clarity 
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