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Funding Clinical Trials

Dr. Jonathan Simons is the driving force behind the Prostate Cancer Foundation, one of the leading funders of prostate cancer research worldwide.

Prostatepedia spoke with him about what clinical trial participation can do for your own prostate cancer journey.

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How did you become involved with prostate cancer advocacy and the Prostate Cancer Foundation (PCF)?

Dr. Jonathan Simons: When I joined the Johns Hopkins faculty in 1993 as a young assistant professor, perhaps six laboratories in the world had prostate oncologists trained in molecular biology. Johns Hopkins did not have even one clinical trial in advanced prostate cancer using a medicine actually designed to fight the disease.

Then I met Mike Milken. He’d been diagnosed with advanced prostate cancer and was seeking third and fourth opinions—not only about his own case, but the state of prostate cancer research in general. Mike wasn’t new to medical philanthropy; he’d been funding a broad range of research for decades before his diagnosis. But he was new to prostate cancer, so it was encouraging when he left our meeting saying there would be an infusion of research funds and a foundation to make progress against this disease. My mentor and research director at Johns Hopkins, Dr. Donald Coffey, told me, “If anyone’s going to change this field, he’s the guy. I didn’t realize that later I’d end up being PCF’s CEO and President.

You were quite young.

Dr. Simons: I was an Assistant Professor eight months on the Johns Hopkins faculty, and I had a six-year-old and a four-year-old son running around in my office with coloring books on weekends while we set up experiments in my small laboratory. Back then, I was funded by PCF from across the hallway. They were within shouting distance. I have now a 30-year-old and a 28-year-old who do not use crayons.

What year did you officially join PCF?

Dr. Simons: I was there at the beginning in 1993 and was invited to the inaugural celebration of the founding in Washington, DC. Early funding from PCF allowed me as a physician-scientist to train in my laboratory another generation of young investigators who have gone on to become chairpersons and full professors at leading cancer institutions. Today they work toward better precision treatments and cures for prostate cancer in fields ranging from molecular biology to drug development, early clinical trials and nanotechnology. In 2007, I was recruited from the Emory University Cancer Center as its Founding Director and appointed CEO and President of the Foundation. I feel an awesome responsibility and the privilege to continue to serve the field in this way.

PCF funds quite a bit of research, both in United States and abroad. Is there a theme behind the kind of research you fund? What is your overall strategy?

Dr. Simons: The overall strategy is to fund the world’s best, most innovative ideas early enough to reduce deaths from prostate cancer, reduce suffering from prostate cancer, and ultimately eliminate prostate cancer as a plague on humanity. What that means, though, is that we fund mostly laboratory-to-clinic, game-changing, early-stage research in university and cancer center laboratories. We find partners to leverage this funding with additional government or biopharma support. We also fund research to help guide those therapies into the clinic to test whether they are successful or not.

If the treatment shows promise, we try to leverage further the tens of millions of philanthropic dollars that we put in at the beginning with hundreds of millions more from Department of Defense, National Cancer Institute, Stand Up 2 Cancer, the V Foundation, and private foundations. About 80% of what we fund is precision treatment science, 10% basic biology, and perhaps 10% prostate cancer prevention including precision nutrition research.

Additionally, PCF was established with more in mind than accelerating cure for prostate cancer. From the beginning, we aspired to change the face of cancer research and to produce results that could help people suffering from a broad range of serious diseases. We never saw the process as a zero-sum game where increased funding for one disease diminished support for others. Rather, it has always been one of our key goals to increase the size of the research pie in ways that would benefit the greatest number of people.

Your organization funds the beginning idea—sparking research—and then other organizations like pharmaceutical companies or research institutes take the ball and run with it?

Dr. Simons: That’s exactly so. Spark, instigate, cultivate scientific proof-of-concept, and convene stakeholders to ensure there is a strong ecosystem to take those concepts forward for patients.

You partner with pharmaceutical companies. You partner with medical institutions and the United States government. What about other countries? Do you work with groups in other countries?

Dr. Simons: We fund research in 21 countries. We have working partnerships with five foundations. We usually lead invest, but we are delighted to co-invest in research, particularly new kinds of treatment. We should really be called the Global Prostate Cancer Foundation.

It has been difficult for researchers to get patients to enroll in clinical trials. Why do you think that is? What has been the obstacle to getting men to participate?

Dr. Simons: It is complex. I wish I knew all the answers. I think one reason is that patients feel fear about receiving a placebo and about being a guinea pig. That almost never happens in the kind of treatment research that we fund.

But I also think there is a lack of access to information about trial availability. I still think patients aren’t empowered to ask which clinical trials could help them have a better outcome and also help others. I don’t think the system is proactive. (Crate and Barrel bothers me a lot more about their products than the National Cancer Institute bothers patients about whether or not they might be eligible for a precision medicine trial.)

We’re trying to increase awareness of these newer precision medicine clinical trials that have a much higher probability that the drug will work because the target gene is expressed or mutated. Basically: your tumor is vulnerable now and we’re getting access to it, so the investigational drugs have a real chance of getting you back into remission. I think those are the major challenges.

Another issue is distance and travel time and associated costs. Clinical trial participation goes way down if it takes the patient more significant time to get to the hospital. If you are enrolled in a clinical trial, you have to go back and forth more often to see the doctor and nurses monitoring you. With a longer commute, participation rates fall. We’re therefore very interested in telemedicine, or using the internet, so patients don’t have to drive as much. That’s still experimental. Dr. Matthew Galsky, from Mount Sinai, is working on that problem.

Using telemedicine in clinical trials?

Dr. Simons: Yes. Most everything in the clinical trials world is still analog, and yet we live in this extraordinarily digital age. I’m talking to you on my phone—a piece of glass with some metal off ultra high frequency radio waves. Right before this call I was looking at an MRI scan on my iPhone. I can do that, but we still make patients drive 90 minutes to see a doctor when we could probably use a smartphone.

There are a lot of ways we could very reliably take care of patients in an outpatient fashion. We just haven’t fully digitized clinical trials, particularly for patients at a distance. There are a lot of ways to innovate around digital healthcare that would help make clinical trials easier for prostate cancer patients.

I think some men assume that a clinical trial might not be an option until their cancer has advanced. They wait until things have gotten really bad and then they look for a trial. I don’t get the impression that many people think about trials when they’re first diagnosed.

Dr. Simons: No.

But there are trials for the newly diagnosed, aren’t there?

Dr. Simons: Absolutely. And a lot of them offer the possibility of much greater longevity and survival. Your instinct should be: where is the right clinical trial? But you’re still processing, thinking, “My God, I have cancer!” We could do a much better job of educating patients.

How do most people find out about clinical trials? Just waiting for your doctor to say that she has found a trial you might want to consider? Or is the burden on the patient to find the trial?

Dr. Simons: Most of the time, if your physician isn’t a real champion, it’s just not a part of the consultation. Most clinical trial enrollment happens because you have a urological oncologist who believes in putting patients on clinical trials and is probably participating in one. We’d like patients at every stage in their journey to look for a clinical trial with the idea that it might offer a better plan of care than they would otherwise have. We could also do a better job of encouraging nurses to talk with patients about clinical trials.

How would you suggest men look for trials?

Dr. Simons: The site http://www.clinicaltrials.gov is an excellent place to look. I think www.PCF.org is an excellent place to look as well. Making a habit of asking your doctor if there are any new clinical trials for where you are is also a great idea. Create the expectation that your doctor has to pay attention to potential trials.

The site http://www.clinicaltrials.gov tends to be a little bit technical. I would think it might be difficult for the average person to sort through.

Dr. Simons: You can always just ask your nurse or doctor about it. But I agree. We put more than 82 cents on the dollar into our research mission every year. But we wish we had the resources to create an incredibly patient-friendly, readable, real-time, digital website for clinical trials. Until somebody does that, clinicaltrials.gov and pcf.org are good places to find the really important trials.

I suppose you could always come up with a list of trials and then bring it to you doctor and ask if any are appropriate for you.

Dr. Simons: Yes. For right now, that is the best thing to do. The first thousand men cured of advanced metastatic prostate cancer will all be on a clinical trial. That’s a true thing. This is how we talk to lymphoma patients. It’s just more and more possible to talk about it for prostate cancer.

Prostate cancer is undergoing a revolution that other cancers have already gone through?

Dr. Simons: We’ve cut the death rate down by 52%. That’s incredible. For the last 48%, we’re going to need clinical trials. We need patients on clinical trials to take the death rate to zero. Sometimes prostate cancer, unfortunately, escapes surgery or radiation and comes back. While we’ve significantly increased the overall survival rate, we’re not yet able to cure the majority of men. We think we can. We know we can, but we have more work to do.

What does the financial end of clinical trial participation look like? Do men have to pay a fee for the therapies?

Dr. Simons: In clinical trials, research drugs are always free. Medical care is always free. The inconvenience is what is costly. Some employers are very difficult about you missing work for a clinical trial. There is a lot of going back and forth. They call it wage and financial toxicity. One of the effects of the experimental drug is toxic to job security. (It’s hard enough when you’re a cancer patient and worried about your employer.) But the drugs, the pharmacy, the medical care, and the scans are all free.

Is there anything else you think patients might want to know about clinical trials?

Dr. Simons: The misperception is that patients will be treated like guinea pigs. But the first thousand patients cured of prostate cancer will all be on a clinical trial. Every major clinical trial is changing prostate cancer patient survival.

For example, in the SPARTAN trial for Erleada (apalutamide), the drug was so effective that within two weeks of presenting the results, it was FDA-approved. That’s a record. Data was presented showing that 800 patients were benefitting from the drug, and then it was approved.

The only drug that gained approval that quickly in all of oncology was Soltamox (tamoxifen) for breast cancer. We think this is going to happen all the time now.

The SPARTAN Trial focused on patients for whom previously there were no treatments. They saw their PSAs going up, but they were not metastatic. There was really nothing for them to do except wait until we started seeing metastases.

Now, with Erleada (apalutamide) there is a chance that they’re not going to see metastases for years. They’ve got hope. For that first group of men, all of this is possible because they found that clinical trial. Hundreds of men who participated in the SPARTAN trial are going to have a prolonged time without metastases.

Would you encourage newly diagnosed men to seek out clinical trials, even if their cancer is under control?

Dr. Simons: Yes. I encourage every patient to think about joining a clinical trial. It’s not an easy message, but there are many studies showing that you get better nursing just by being on a clinical trial. You just get more attention. You can be there for the cure.

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Dr. Fred Saad On Why He Became A Doctor

Dr. Fred Saad, MD, FRCS, is Professor and Chairman of Urology, and Director of Genitourinary Oncology at the University of Montreal Hospital Center.

Dr. Saad’s main research interests include novel therapies for advanced prostate cancer and molecular prognostic markers in prostate cancer.

Prostatepedia spoke with him about why he became a doctor.

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Why did you become a doctor?

Dr. Fred Saad: I really never had a second choice. I was really quite young, and for some reason, I was attracted to medicine and caring for patients. It sounds ridiculous, but it started when I was eight years old. It’s a little weird for an eight year old to say that’s what he wants to do, but for some reason it was an obsession of mine. Fortunately, it worked out the way I had hoped because I never even thought about what else I could do in my life.

Like a calling?

Dr. Saad: I don’t know if it’s a calling or an attraction to the challenge of the human body and how it works, seeing if you can do something to improve people’s lives. At eight years old you really don’t know what you’re getting into. The older I got the more convinced I was that this was what I wanted to do. Fortunately, somebody accepted me into medical school. The rest is, as they say, history. Two out of my four kids have decided to become doctors, so my example wasn’t all bad I guess. One is already a doctor. One is starting medical school.

A family business.

Dr. Saad: I’m married to a doctor. So yes, I guess medicine is part of the family, part of us.

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Genomics + Prostate Cancer Care

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.

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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.

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Dr. David VanderWeele: Why Prostate Cancer?

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.

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Why did you become 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.

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