In May, Prostatepedia asks doctors, advocates, and patients why men with prostate cancer should consider joining clinical trials. Chances are you’ve never thought about entering a clinical trial. You and your doctor have hammered out a prostate cancer treatment plan that takes into account your particular cancer and which side effects you’re willing to live with and which you’re not. But a clinical trial? Most men never really think about joining a trial unless their own doctor brings it up—if he or she does at all.
But there are clinical trials available to men at every stage of the prostate cancer journey from new diagnosis to active surveillance to monitoring for potential recurrence to advanced disease. Some trials offer men access to a drug or therapy that they might not otherwise be able to get. Other trials help scientists learn about prostate cancer biology or genomics. All are important and all advance our understanding of prostate cancer with the aim of eventually eradicating the disease all together.
Understanding clinical trial terminology will be important as you evaluate whether or not you’re interested in joining a particular trial. A Phase I clinical trial generally looks at drug safety and includes a smaller number of patients. A Phase II trial collects preliminary data on whether a given drug works in men with prostate cancer. A Phase III trial collects further information about drug safety and effectiveness—usually in different populations, different dosages, and in combination with other drugs. Phase III trials can lead to a drug’s FDA-approval.
Reading–and then forwarding the issue of Prostatepedia to your doctor–is a great way to start a discussion about clinical trials. Be sure to take notes and do your own research afterwards until you’re sure you understand the pros and cons of each trial you’re considering.
Support groups—online and in-person—can be wonderful resources as you evaluate your options.
The bottom line is that it’s worth investigating if there is a clinical trial available for you at this time whether or not you decide to join one in the end. You’ll learn a lot about your options moving forward and may just find one that’s a fit.
Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer.
His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.
Prostatepedia spoke with him about genomics, predicting side effects and the future of prostate cancer clinical trials
Can genomics predict who will have certain side effects?
Dr. Feng: There have been a number of studies that have used single nucleotide changes within DNA sequences, called single nucleotide polymorphisms (SNPS), to predict who will be most likely to experience side effects from radiation therapy for cancer.
In general, the signal from these toxicity studies has been weaker than the signals from biomarkers that predict responses to particular therapies, like the ones that I mentioned earlier. This may be reflective of the fact that radiation acts through a variety of mechanisms, so any single biomarker may not work well. Even when you cluster biomarkers, it may not account for the heterogeneous manner in which radiation causes a biological effect.
What should patients know about how genomics is impacting treatment?
Dr. Feng: Many of the clinical trials being developed nowadays incorporate genomics. We have clinical grade assays to look at genomics. We have strong biological rationale for why certain genomic biomarkers may identify subsets of patients who can respond to specific therapies. Because genomics is routinely used to personalize treatment in the context of diseases like breast cancer, colon cancer, and melanoma, it’s only expected that genomics will have a major role in prostate cancer going forward.
Will incorporating genomics into clinical trial design accelerate the speed of innovation?
Dr. Feng: I think it will. If you look at metastatic castration-resistant prostate cancer, for example, a number of therapies have been approved by the FDA over the last decade for those patients, including agents like Zytiga (abiraterone) and Xtandi (enzalutamide), next generation taxanes, Provenge (sipuleucel-T), and Xofigo (radium-223). All of these agents extend survival by just a few months.
This is invariably what happens when you treat prostate cancer as one disease entity rather than a variety of different entities that are governed by different genomic events. As we become better at selecting therapies based on a patient’s genomic events, we should see longer response times to available therapies and those currently being developed.
How did you find out that you had prostate cancer?
Steve: I don’t remember exactly, but I think I went to the urologist on the recommendation of a doctor who said I should have some PSA tests. I went to the urologist. The urologist ran some PSA tests and said, “They’re a little elevated. Maybe we need to run a biopsy,” which they did. That was about ten years ago. The biopsy came back with three or four cores indicating cancer with a Gleason score of 6 (3+3), which has remained the same over the last ten years. I think that’s what happened.
What kinds of genomic tests did you have and when?
Steve: That happened about five years later. I went to a support group and I heard about genomic testing. My doctor at the time hadn’t mentioned anything about genomic testing to me. I said to him that I didn’t see any downside in having genomic testing. Why couldn’t I have it? He said that he didn’t think it would be covered by my insurance and it’s not something they had done. I felt like a little bit of a pioneer.
I actually got on the phone with the people at Genomic Health in California and asked how much the test would cost. They mentioned a figure of about $500. I asked, “So that’s what I’m going to be charged?” They said, “Probably.” They weren’t really clear about it. In the end I was never charged.
They sent three results to my physician after a few weeks. Because my physician had never given them instructions as to what risk category he felt that I was in, they sent back three results based on different risk profiles. To this moment, I still don’t know exactly which risk profile I fit into.
All three results looked somewhat encouraging to my layperson’s eyes. I discussed the results with the doctor at the time and he said, “I think this confirms what we’re doing at the moment is right. You can continue on active surveillance, but of course it’s your choice.” They will always say that….
The results definitely changed your treatment path?
Steve: I was already on active surveillance, although in the first two or three years, I was thinking about some form of radiation therapy.
We talked about seeds. We talked about beams. I even talked to a friend a few years older than me who had gone through proton beam therapy and he was very encouraged by his results. My insurance at the time did not cover that, so proton beam therapy came off the table. I was not thinking about surgery. I was turned off by the idea of surgery, even though they had a DaVinci robot.
Then I got the OncoTypeDX test. I looked at the results with my physician and decided to proceed. It confirmed what I was already inclined towards.
Do you feel like it gave you more confidence in your decision?
Steve: Yes. I think so. I think that’s fair to say.
Would you recommend that other men take these tests?
Steve: Everybody has a very different psychological makeup. For example, I’ve got a brother-in-law who doesn’t have prostate cancer, but is very educated on medical matters. He’s a smart guy, and so I talked to him about it. He said, “God, if it was me, I would take care of it right away. I’d have that prostate out of there and have peace of mind.” I responded with: “I’ve lost very little sleep over the years about it.” That’s just my makeup. It doesn’t bother me. I’ve got other things to think about, other things I care about. Health is very, very important.
I’m not a complete passenger in this process. That’s why it’s called active surveillance. I’m very careful about going to my doctor’s appointments, following up, trying to keep myself educated, and so forth. Would I recommend it to somebody else? Somebody else who has the same psychological makeup that I do? Absolutely. Somebody who is a nervous person, a Type A person, somebody who is likely to lose sleep? Perhaps not. I don’t see any possible downside to the testing, though. It’s another tool for you and your doctor to use to help you make your decisions.
Dr. David J. VanderWeele is an Assistant Clinical Investigator in the Laboratory of Genitourinary Cancer Pathogenesis at the National Cancer Institute. He is particularly interested in investigating the progression of clinically significant prostate cancer.
Prostatepedia spoke with him about how genomics impacts patient care.
What is genomics, and how does it differ from genetics?
Dr. VanderWeele: Typically if you’re talking about genetics, you’re talking about an individual gene or a small set of genes. When you refer to genomics, you’re referring to all the genes or a very large set of genes. Genomics usually refers to the genes–the DNA sequence. But sometimes genomics is also used to refer to when those genes get expressed (as RNA), or to other changes to the DNA that don’t change the DNA sequence (also called epigenetics).
What do and don’t we know about why some men develop curable or indolent prostate cancers while some develop widely lethal diseases?
Dr. VanderWeele: A lot of effort has been put into trying to learn more about the genes you inherit from your parents and how that influences the likelihood that you’re diagnosed with cancer. Most of that effort has been unable to identify which alterations in your genes make it more likely that you will get an aggressive versus an indolent cancer.
As many of your readers probably know, many people get indolent prostate cancers. In fact, many autopsy studies have looked at patients who have died of other reasons and have never been diagnosed with prostate cancer. Once men reach their 70s or 80s, it looks like more than half of men develop prostate cancer. Of course, those are relatively slow-growing cancers.
The most information that we have now is that men who come from families with breast and ovarian cancer syndrome appear to be more likely to get cancer and more likely to get aggressive cancer. These involve BRCA1, BRCA2, and other DNA repair genes in a similar pathway. Though there aren’t FDA-approved therapies yet, there are trials suggesting that these patients are also more likely to respond to certain therapies approved for breast and ovarian cancer.
This is a pretty small subset of all the men with prostate cancer, but the percentages increase with any kind of measurement of aggressiveness. If you look at people with localized cancer, that percentage increases if you have high-grade cancer versus low-grade cancer. The percentage increases if you compare people with advanced castrate-resistant prostate cancer to those with localized cancer.
If you look at the length of time between a man’s diagnosis and when he dies, that rate increases significantly the shorter that time is. That is just looking at three of these genes, BRCA1, BRCA2, and ATM. If you look at a broader number of these DNA repair related genes, it looks like ten to twelve percent of all patients with castrate-resistant prostate cancer harbor a mutation that they inherited from their parents. It seems likely that for most of those patients, that inherited gene contributed to their prostate cancer.
That has led to some debate about how often we should test for mutations in these genes. Is that a high enough number that we should test everyone with castrate-resistant prostate cancer? Should we still rely on family history to provide guidance for which people should be tested?
Is it really expensive to test those men? Why wouldn’t you just go ahead and test?
Dr. VanderWeele: Depending on how you do it, testing costs have come down quite a bit.
But when you’re testing for genes that could potentially be passed on to your offspring, or that siblings or other family members may have inherited, there are implications for your other family members, not just for you.
Some members of your family may definitely want to know that information and think that more information is better. Others may feel that if they find out that they harbor that gene mutation, they will just feel like they’re waiting for the other shoe to drop. It’s not information that they’d want to know.
Generally, we advise people to get counseling to help them think through some of these issues before getting tested for genes they’ve inherited from their parents.
Do we know why some men respond to certain drugs and therapies and others don’t?
Dr. VanderWeele: There’s a lot of interest in that. There has been some progress made in terms of identifying the biomarkers that might suggest which patients are more likely to respond to which types of therapies. At this point, however, most patients still get treated with most therapies.
There are some genetic biomarker-driven therapies that look like they’re on the horizon. Patients with mutations in BRCA2, ATM, and related genes are more likely to respond to a type of therapy called PARP inhibitors, which are currently approved for patients with ovarian or breast cancer, but not yet for prostate cancer.
There was a single Phase II study that showed that patients who had loss of a specific tumor-suppressor gene called
PTEN are more likely to respond to a certain type of targeted therapy. There are larger ongoing trials to demonstrate that these are indeed predictive biomarkers for response to these therapies.
There are companies like FoundationOne and GenomeDX that look at the molecular features of a man’s cancer. Are those tests useful? What do they tell a patient?
Dr. VanderWeele: The FoundationOne test looks for mutations, deletions, or amplifications of specific genes that are relevant for a wide array of cancers. There are a lot of companies offering this type of sequencing.
Many hospitals offer their own version of it. A FoundationOne type of test can tell you if you have a mutation in BRCA2 or ATM. They should also be able to tell you if you have a deletion in PTEN. When they detect a mutation is present, however, generally they are not looking to determine if you inherited those changes from your parents versus the mutation being present only in the tumor cells.
These genetic tests are more popular in other types of cancers, because for prostate cancer there aren’t yet any FDA-approved therapies that would be given based on the results of these tests. These tests will become more popular as we make progress in demonstrating the benefit of these specific therapies and in our ability to predict which patients are most likely to respond.
If a patient reading this gets one of those tests, is it likely that his doctor is going to know what to do with the results? Will the results actually impact his treatment?
Dr. VanderWeele: There are probably a small number of patients who will have a result that will directly impact their therapy. At this point, the way that it would impact therapy is that it might suggest that they should find a clinical trial testing a specific type of drug.
I see.
Dr. VanderWeele: There are also other commercially available prostate specific genetic tests, like the one performed by GenomeDX, that are mostly aimed at men with localized prostate cancer who are trying to decide how aggressive their therapy should be. Typically, this means whether they should pursue active surveillance or get surgery or radiation.
Sometimes these tests are also used to determine if a patient should get radiation after undergoing a prostatectomy or if he should just continue to follow PSA numbers. The prostate specific gene expression tests are RNA-based tests, which are a little different.
They measure the levels of expression of a few specific genes. Tests like FoundationOne look for mutations, amplifications, or deletions of genes—which means they are DNA-based tests.
Tests like Decipher are more widely used now, right?
Dr. VanderWeele: Yes. They’re probably used mostly by urologists. My sense is that how often urologists order those tests and how heavily they rely on them versus other ways to predict the risk level of the prostate cancer varies quite a bit from urology practice to urology practice.
Dr. David J. VanderWeele is an Assistant Clinical Investigator in the Laboratory of Genitourinary Cancer Pathogenesis at the National Cancer Institute. He is particularly interested in investigating the progression of clinically significant prostate cancer.
Prostatepedia spoke with him about why he became a doctor.
Dr. VanderWeele: Physicians come to the job through a number of ways. For me, it was both an interest in biology in general and in cancer biology specifically. I really enjoyed learning in undergraduate school, and later on in training, how cancer represents a normal biological process gone awry.
Of course, many people also have a family member who helped inspire their choice, either directly or subconsciously. My mother had breast cancer; I’m sure that was part of my internal motivation and interest in oncology.
How did you end up specializing in prostate cancer?
Dr. VanderWeele: I was interested in genitourinary oncology—prostate cancer, bladder cancer, kidney cancer, and testicular cancer—because there is a wide range in the natural history of those diseases and how we treat them. I became especially interested in prostate cancer in part because some prostate cancers are very aggressive and others are more indolent. The first step of managing prostate cancer is assessing the risk of the disease and not just treating all cancers the same way.
Dr. John Gore is a clinician, surgeon, researcher, and educator specializing in urologic oncology and general urology at the University of Washington.
Prostatepedia spoke with him about how Decipher changes the way doctors treat men with prostate cancer.
What is Decipher?
Dr. Gore: Decipher is from a family of genomic tests. In general, it tries to look at some of the alterations in people’s genes associated with cancer or its progression. Decipher attempts to create a panel of genes associated with the likelihood of a cancer coming back. It takes that panel of genes and integrates it with clinical information to calculate the risk of developing spread of cancer to sites that could be detected clinically, like the bones or the lymph nodes, within five years after prostate cancer surgery.
When is a man likely to encounter this test? After that initial biopsy when he is first diagnosed? After his prostatectomy?
Dr. Gore: The most common scenario would be after surgery. If a man has his prostate removed and the pathology shows that he has a cancer that by all accounts seems to have been successfully treated with the surgery, Decipher may not be the right test for him.
If he has some high-risk features— his cancer is potentially encroaching on the shell of his prostate, he has a positive surgical margin, or there is involvement of the seminal vesicles that sit behind the prostate—then he might benefit from Decipher.
That way we can ask if—in addition to knowing that he had some high-risk pathology features—he appears genomically to have a high-risk cancer?
What do the results look like? Do they change how a man is going to be treated post-surgery? How?
Dr. Gore: The actual report that a patient or doctor gets tells them the probability, or percent risk, that he will have clinical metastases within five years of having his prostate removed for prostate cancer. In general, those numbers tend to be in the single digits to low teens. It’s not a common event.
For most people, prostate cancer surgery successfully treats their cancer. That is why this is best used on higher-risk individuals.
In our study, we looked at a cadre of patients who were either found to have high-risk features at the time of their prostate cancer surgery, or now their PSA is subtly rising after going to zero after surgery. Those patients should potentially have more aggressive treatment.
We showed that if a patient had the Decipher test, physicians’ recommendations changed. If your Decipher results showed a lower risk score, your doctor was more likely to recommend observation.
Patients with a higher risk Decipher score were more aggressively treated. They were recommended to go ahead and get additional radiation to the area where their prostate was removed, rather than just active surveillance.
The bottom line is that Decipher changes how men are treated?
Dr. Gore: Yes. We have some follow-up data we just presented at the American Society of Clinical Oncology, Genitourinary meeting in February that showed that those treatment recommendations were actually followed 80% of the time.
You said only men who are high-risk should really be tested. Not everyone getting prostate cancer surgery needs a Decipher Test?
Dr. Gore: That’s right.
Is Decipher widely accepted in the medical community? If a man in rural Minnesota goes to his local urologist or local community oncologist, will he likely be offered the Decipher Test? If not, should he ask his doctor to order it?
Dr. Gore: I think it’s definitely worth requesting it. One thing that has come up is insurance payer coverage, not just for the Decipher Test, but also for other tests like it. The bar that some of these companies have to cross to get their test approved is fairly high.
Some insurance companies are asking if the test not only changes treatment for patients. The trial they’re looking for will compare patients who got the Decipher Test with patients who didn’t to see if the decisions that were made impacted cancer outcomes. If, for example, your Decipher results say you’re high-risk, and you get radiation based on that information, was that the correct decision? The challenge is that prostate cancer is immensely slow-growing. Even when it’s high-risk, even when it’s aggressive, we’re talking about clinical outcomes that take years and years to manifest. It imposes an irrationally onerous burden to prove that these tests are the right thing.
You could wait 10 years to find out if the treatment decisions were correct. Meanwhile, time is passing and these men need to make choices…
Dr. John Gore is a clinician, surgeon, researcher, and educator specializing in urologic oncology and general urology at the University of Washington.
Prostatepedia spoke with him about how Decipher changes the way doctors treat men with prostate cancer.
Why did you become a doctor?
Dr. John Gore: My initial vision for my life was that I was going to be a lawyer. Then I found that I really enjoyed my experiences while interning at the hospital. That brought about an application to medical school. I think being a doctor offers a chance to have a daily meaningful impact, which is a unique part of the job.
How did you end up working in urology?
Dr. Gore: Urology is a specialty that very few people enter medical school thinking that they want to do. In part, most people are like I was and don’t even know about the specialty. I don’t have any doctors in my family. The only doctor I knew was my own pediatrician. I just assumed I was going to be a pediatrician.
But I really enjoyed surgery. I enjoyed being in the operating room. I just really enjoy the generic construct that someone has a problem and I have the tools to fix it.
Urology is an interesting hybrid. Most surgeries have a homolog in internal medicine. For example, there’s cardiothoracic surgery and cardiology. There’s colorectal surgery and gastroenterology. We don’t really have that in urology. We do a lot of chronic disease management. We do a lot of long-term follow-up of our own patients. It is, in many ways, a hybrid of internal medicine and surgery, which is really cool.
Eric A. Klein, MD, is an international leader in the biology and management of prostate cancer. Dr. Klein serves as Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.
Prostatepedia spoke with him about the differences between the various genomic tests available to prostate cancer patients.
Dr. Eric Klein: These tests measure the expression of genes in prostate cancer. That’s what they’re designed to do. They predict the likelihood of your having higher-grade cancer or cancer that penetrates the rind around the prostate (called extraprostatic extension), or cancer in the lymph nodes or seminal vesicles. These tests predict that better than biopsy or plain old Gleason grading. This gives us a leg up in deciding who is a good candidate for surveillance.
If your biopsy only shows Gleason 6, but you actually have higher-grade cancer in the prostate, or you have some cancer that’s through the rind or in the seminal vesicles, you’re not a good candidate for surveillance. We know that from decades of doing radical prostatectomies. These patients are at highest risk for progression and that’s what these tests measure.
They also tell us whether a pure Gleason 6 cancer is one of the 5-10% that has molecular features of high-grade cancer.
These are biopsy-based tests. For example, if a patient has a biopsy that shows Gleason 6 cancer and otherwise favorable features, such as a PSA below 10, and a PSA density below 0.15, we wonder whether he’s a candidate for surveillance. We always do a confirmatory test after a first biopsy. Decipher can also be used after the prostate has been removed to help decide on the need for additional treatment.
A genomic test like this is appropriate in some patients. An MRI of the prostate is appropriate in others. Sometimes it’s appropriate to get both. We don’t have enough experience to know which is the best test for which scenario, although I have some ideas about that. Then, once we confirm that the patient has a low-grade cancer that lacks molecular features of high-grade cancer, we feel confident in putting him on surveillance.
The results can do two things. They can confirm that the patient is a candidate for surveillance. Sometimes they can convince a reluctant patient that surveillance is the right thing. We don’t want to over-treat people who have low-grade cancers that aren’t going to kill them because the side effects of treatment are worse than the likelihood of his dying of cancer. Sometimes, the results can convince a physician that surveillance is the right thing. If you look at the criteria for putting people on surveillance, it’s mostly patients who have just a minimal amount of cancer–low-grade cancer, a Gleason 6 on a biopsy.
We published a study in the Journal of Urology recently that showed that even among patients with high-volume
Gleason 6 cancer in multiple cores— four or five remove cores—many have no molecular features of high-grade cancer. In the past, they haven’t traditionally been considered good candidates for surveillance, but based on the biology of their tumor, they are good candidates for surveillance.
You may have someone who has a couple of cores of low-grade cancer, maybe a PI-RADS 4 lesion on MRI.
You’re not sure if they’re a good candidate for surveillance or not. If a genomic test confirms the absence of molecular features of high-grade cancer, you can put the patient on surveillance. That is the kind of information that genomic tests provide. They have their nuances.
Oncotype and Decipher are good for patients with very low, low, and favorable intermediate-risk disease. Prolaris is best validated for patients who have intermediate risk disease. It doesn’t have good discriminatory value for low-grade cancers. Generally, they all measure gene expression and they’re all are used in the same way.
These tests help determine whether or not someone is a candidate for surveillance. At the moment, we don’t use these tests based on biopsy to determine which treatment to give a patient, but that’s coming. Post-prostatectomy, Decipher can help tell us that.
There are challenges to active surveillance. Say we put someone on surveillance and he starts out with 1 core of Gleason 6 cancer. A year later, he is re-biopsed and has 3 cores of Gleason 6 cancer. We don’t know whether that’s true biologic progression that requires treatment, if all that Gleason 6 cancer was there in the beginning and was just not sampled by biopsy, or if the patient grew some new Gleason 6 cancer that doesn’t have any biologic potential.
This isn’t established yet, but I believe we can use these tests for what I call serial biologic monitoring, meaning you biopsy patients a year or three apart. These tests, for the very first time, allow us to measure true changes in biology as opposed to just changes in what we see on biopsy, which may underestimate what’s going on in the prostate. This is a new paradigm.
Another common scenario is a man who has a low-grade cancer on initial biopsy (1 core, Gleason 6) and a year later has a little bit of Gleason 3+4 with 5% pattern 4 and 95% pattern 3. In the past, that would always trigger treatment. But it’s my belief, based on what we’ve learned from these tests, that this is probably not correct. Many of those men can still stay on surveillance.
Eric A. Klein, MD, is an international leader in the biology and management of prostate cancer. Dr. Klein serves as Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.
Prostatepedia spoke with him about why he became a doctor.
Why did you become a doctor?
Dr. Klein: I don’t really know. I never remember wanting to do anything else.
Even when you were a little kid?
Dr. Klein: When I was in first grade, I missed a month of school because I had what they thought was rheumatic fever. My pediatrician came to see me a couple times a week. That doesn’t happen so much now.
No. It doesn’t.
Dr. Klein: I suspect that’s had some influence because my parents really respected him. But I can’t articulate it for you. I never wanted to do anything else. It was not an intellectual decision. It’s just what I wanted to do. I was born wanting to be a doctor.
Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer.
His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.
Prostatepedia spoke with him about how genomics is personalizing medicine for patients.
How is genomics changing how doctors decide who needs treatment for prostate cancer and who doesn’t?
Dr. Felix Feng: Our field is in an exciting time in terms of advances in genomics and prostate cancer. For the vast majority of the past few decades, prostate cancer treatment has been selected and optimized outside of genomics. We’ve had a number of breakthroughs in the last few years that have suggested that a large part of prostate cancer treatment in the future may rely on genomics.
The most important example of this is the use of PARP inhibitors in men with prostate cancer that have DNA repair alterations, and most commonly, alterations in the genes BRCA1, BRCA2, and ATM. Including this example, we have three examples in the context of metastatic prostate cancer where genomics is actively being used to personalize therapy.
A study from Dr. Johann de Bono’s group at the Royal Marsden in the United Kingdom first demonstrated that patients who have DNA repair alterations have responded particularly well to the PARP inhibitor Lynparza (olaparib). In a follow-up study, which was run out of the University of Michigan, Drs. Maha Hussain, Arul Chinnaiyan, and I confirmed these findings in the context of a randomized trial. It’s clear that using PARP inhibitors for patients with DNA repair alterations is one example of using genomics for personalized medicine. There are a number of different companies now exploring a variety of trials trying to get PARP inhibitors FDA approved as a therapy for patients with metastatic castration-resistant prostate cancers.
A study reported by Dr. Johann de Bono at the European Society for Medical Oncology Conference about two years ago demonstrated that patients with prostate cancers in which a gene called PTEN is inactivated responded well in a randomized trial to an AKT inhibitor. That is now being evaluated in a Phase III trial.
Another use of genomics to advance medicine is in cancers with alternations in a class of genes called mismatch repair genes, which have been shown to confer sensitivity to various immunotherapies. That represents an approved syndication across all cancers, not just prostate cancer.
In the localized prostate cancer setting, there are two genomic classifiers based on RNA expression that help identify patients with low-risk prostate cancer who are more likely to progress to more aggressive disease. This may be used to determine which patients should be followed with active surveillance. The two classifiers that are most commonly utilized in this setting are Oncotype DX by Genomic Health and Prolaris by Myriad.
In the context of higher risk patients treated with surgery, there’s a classifier called Decipher made by GenomeDX Biosciences. That has been shown across very large numbers of patients to be a prognostic of metastatic progression after radical prostatectomy. Already, that classifier has been incorporated into ongoing clinical trials to select which patients with aggressive disease should be candidates for treatment intensification.
Can genomic classifiers be used to select specific patients for specific therapies?
Dr. Feng: My team has helped develop two of the first clinical grade classifiers predictive of their responses to specific therapies. One is a biomarker panel called PORTOS, which stands for Post- Operative Radiation Therapy Outcomes Score, and may be useful in predicting response to post-operative radiation therapy—those treated with radiation therapy after radical prostatectomy. PORTOS predicts specifically which men will benefit from radiation therapy. We validated its performance in a manuscript published in Lancet Oncology two years ago.
More recently, we’ve applied a genomic classifier utilized in breast cancer to prostate cancer. It’s called PAM50 and is used to determine which women with breast cancer should get hormone therapy after surgery. It turns out that these molecular subtypes of breast cancer also exist in prostate cancer. Specifically, we found that there are luminal A, luminal B, and basal subtypes of prostate cancer.
When we look at which patients are most likely to hormone therapy, our initial data suggests that it’s the luminal B patients who have the most aggressive disease and who also benefit from hormone therapy. We did all of these studies in large retrospective cohorts, but because we wanted to validate this prospectively, we are about to initiate a trial in the context of a national clinical trial called NRGGU006, run by the NRG Oncology Clinical Trials Group.
With NRG-GU006, we stratify patients by their PAM50 molecular subtype. These are patients who have been treated with radical prostatectomy and have had biochemical PSA recurrence.
These patients are stratified by PAM50 status, and then they are randomized to standard therapy—which is salvage radiation alone—or salvage radiation plus short-course Erleada (apalutamide), which is a next generation anti-androgen.
From all of these examples, you can see that, across different contexts— from active surveillance to the more aggressive, locally advanced prostate cancer to metastatic prostate cancer, there are now a number of strategies that use genomics to personalize medicine.
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