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February: Heart Health + Prostate Cancer

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In February, Prostatepedia is talking about cardiovascular risk in prostate cancer patients. Dr. Charles Snuffy Myers frames the discussions for us.

“It turns out that the relationship is complex. Men with cardiovascular disease have a higher incidence of prostate cancer. This may, in part, be due to an impact of elevated cholesterol on prostate cancer progression. However, other factors may also be involved. For example, obesity is associated with an increased risk of cardiovascular disease and with progression of prostate cancer. Similarly, a diet rich in calories and meat is associated with an increase in insulin like growth factor 1 and this hormone has been linked to prostate cancer progression.

Removal of androgens, such as testosterone and dihydrotestosterone, plays a central role in the treatment of prostate cancer. In turn, low testosterone exacerbates insulin resistance, diabetes, visceral obesity and hypertension—known risk factors for cardiovascular disease.

In this issue, Dr. Pedro Barata from Tulane University gives us an overview of the issues at stake when we discuss prostate cancer and cardiovascular disease.

Dr. Michael Freeman from Cedars- Sinai discusses the evidence that cholesterol might drive progression in prostate cancer and the possibility that lowering cholesterol with statins might have a therapeutic impact. One of the more interesting observations he discusses is that certain gene expression patterns might lead to a increase or decrease in sensitivity to cholesterol levels.

Dr. Matthew Roe, a well known cardiologist from Duke University’s Clinical Research Institute (DCRI), speaks about the PRONOUNCE clinical trial he’s running. PRONOUNCE compares the cardiovascular safety of Firmagon (degarelix) versus Lupron (leuprolide) in men with advanced prostate cancer.

Dr. Darryl Leong from Canada’s McMaster University talks about his RADICAL-PC clinical trial, which evaluates the effectiveness of modifying cardiovascular and lifestyle risk factors in men who’ve just been diagnosed with prostate cancer.

Finally, Dr. Christina M. Dieli- Conwright talks about her clinical trial evaluating a 16-week program of cardiovascular and strength exercises in men with prostate cancer.”

Join us to read our February conversations about heart health + prostate cancer.


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Combining Keytruda (pembrolizumab) and Xtandi (enzalutamide) For Prostate Cancer

Dr. Julie Graff is a medical oncologist at Oregon Health & Sciences University.

Prostatepedia spoke with her recently about her continuing work on combining Keytruda (pembrolizumab) with Xtandi (enzalutamide).

What are Keytruda (pembrolizumab) and Xtandi (enzalutamide)? How and when are they used in prostate cancer patients?

Dr. Graff: Keytruda (pembrolizumab) is an intravenous antibody to PD-1 or programmed death 1 on immune cells, in particular T cells. When that protein is present, it can interact with tumor cells that have PD-L1 and through that interaction the tumor cells turn off the immune system. We consider it a checkpoint inhibitor.

We’ve known for a long time that in some cancers T cells, which are the part of the immune system that can kill cancer cells, are present in the tumor and yet they’re not actually killing the tumor. Over the decades we’ve learned that some of those cells, not necessarily T cells but immune cells in the environment, are actually helping the tumor grow. We’ve also learned that some of them are trying to fight the tumor, but they’re being turned off by the tumor.

Keytruda (pembrolizumab) can block that negative signaling, thereby activating the immune system. It was first approved in melanoma and has received multiple subsequent approvals. So far we don’t have great markers for knowing who will benefit from the drug and who won’t, but we are working on that.

Xtandi (enzalutamide) is a drug that binds to the androgen receptor, which is inside the prostate cancer cells, and prevents it from interacting with androgens or male hormones. In that fashion, it leads to some cell death and helps people live longer. It’s been FDA approved since 2012 in the post-chemo setting, and now it has been approved in the pre-chemotherapy setting. It used to be approved only in metastatic disease, and now it’s approved in non-metastatic castrate-resistant disease. It’s being applied in different stages of the disease.

What is the rationale behind combining these two agents?

Dr. Graff: In studies where checkpoint inhibitors like Keytruda (pembrolizumab) are used alone, there’s not a lot of tumor activity. There’s certainly not a good rationale to use Keytruda (pembrolizumab) by itself in prostate cancer. Maybe as time goes on we’ll find that perhaps 2 out of 100 patients have certain mutations that make the Keytruda (pembrolizumab) alone helpful, but we’re not yet there.

There wasn’t a great reason to use Keytruda (pembrolizumab) by itself, so we began to think about combinations. Xtandi (enzalutamide) was felt to upregulate PD-L1 on dendritic cells, in particular when people became resistant to the Xtandi (enzalutamide), so that was one initial reason.

Castration therapy may reinvigorate the immune system. When you’re maturing as a child, you have a thymus gland behind your sternum that helps create new T cells. As you go through puberty, that gland shrinks and becomes inactive, so you don’t make new T cells.

It looks like maybe the thymus increases again during castration therapy; there’s a hypothesis that you’re creating new T cells.

There is also a reason to think about Xtandi (enzalutamide) in particular. It’s helping in those two regards.

Also, if you used Keytruda (pembrolizumab) in combination with chemotherapy, you would be at risk of killing a lot of immune cells with the chemo itself. If you used Keytruda (pembrolizumab) in combination with Zytiga (abiraterone), which is like Xtandi (enzalutamide), you would have to use prednisone, which would perhaps dampen the immune response. When our study was designed in 2014, it made a lot of sense to combine Keytruda (pembrolizumab) with the Xtandi (enzalutamide).

What have studies revealed about the combination? Is it effective? What kind of side effects do patients experience?

Dr. Graff: We did a Phase II study looking at 28 patients with metastatic castrate-resistant prostate cancer whose cancers were progressing on Xtandi (enzalutamide). We added 4 doses of Keytruda (pembrolizumab). We saw 5 responded in that group of 28. That’s only 18%, but when they responded, they responded spectacularly.

The most extreme case was a gentleman who started out with a PSA of 2,500 that went down to 0. He had big, bulky liver tumors that just shrank away. He must be two and a half, almost three years out from treatment and he’s still in complete response. His case is extreme. But when we do see responses, they’re spectacular.

If those five patients had only had a dip in their PSA or something less impressive, the study wouldn’t be as important as it was. Then we had four other people who had very durable responses as well. That’s the benefit part of the study.

But there are known side effects with each of these drugs. With Keytruda (pembrolizumab), when you stimulate the immune system you run the risk of the immune cells killing or attacking healthy tissue. For example, a patient on Keytruda (pembrolizumab) could develop autoimmune hepatitis where the immune cells are attacking a healthy liver. There are some bad sides to stimulating the immune system.

In our study, we did see some of those side effects. In these 28 patients who were treated, we did have patients who had autoimmune toxicities in which their own immune cells attacked healthy tissue. We had four patients who had thyroid dysfunction, which is a fairly well recognized side effect of Keytruda (pembrolizumab) that is easy to manage with thyroid medicine. We had a couple people with colitis, which happens when the immune system attacks the colon; that has to be managed with high-dose steroids and sometimes biologic drugs that GI specialists use. We saw side effects that we would expect from Keytruda (pembrolizumab) and we saw some side effects that we would expect from Xtandi (enzalutamide) such as fatigue. Since these patients had already been on Xtandi (enzalutamide) for a long time, we did not observe worsening of the Xtandi (enzalutamide) side effects with the addition of Keytruda (pembrolizumab). We mostly just saw those Keytruda (pembrolizumab) side effects.

Any follow-up studies planned?

Dr. Graff: We got funding from Merck to add another 30 patients on to that study. Those 30 have already been enrolled and treated. For those patients, we insisted on a biopsy. For the first 28 patients, we asked them to get a biopsy if they had a tumor that could easily and safely be biopsied. In the next 30 patients, we required that they have a biopsy. We have now a nice array of tissue from these 58 patients and we’re working on getting the results. We have some multiplex stains and hope that the paper can come out next year.

Join us to read about another of Dr. Graff’s clinical trials that will be accepting patients shortly.


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Immunotherapy For Prostate Cancer

In January, we’re talking about immunotherapy for prostate cancer. Dr. Charles Myers introduced the issue for us.

Not a member? Join us to read this month’s conversations about immunotherapy.

The goal of this issue is to capture the current state of the art in immunotherapy of prostate cancer. We live in a time when immunotherapy is making major contributions to the treatment of many malignancies. The Nobel Prize was recently awarded for the discovery of checkpoint inhibitors that have revolutionized the treatment of melanoma. Chimeric antigen receptor T (CAR T) cell therapy represents a major advance in the treatment of B-cell lymphoma.

Unfortunately, immunotherapy has not yet had such a dramatic impact on prostate cancer treatment. The Provenge (sipuleucel-T) vaccine has been approved for prostate cancer treatment because it results in a modest improvement in the survival of patients with advanced disease. The checkpoint inhibitors have not shown useful activity in prostate cancer, although a small group of patients have had dramatic responses. The current situation may be best summarized by saying that immune response to prostate cancer can be demonstrated in patients, but various factors appear to limit cancer cell kill.

In this issue, we feature conversations with investigators who are doing interesting research on how to overcome factors limiting the effectiveness of immunotherapy in prostate cancer.

Dr. Charles G Drake talks about the state of immunotherapy in 2018 and looks ahead to what we can expect to happen in 2019.

Dr. James Gulley talks about why the initial trials with the prostate cancer vaccine ProstVac didn’t prove as promising as we’d all hoped. He also outlines a number of prostate cancer vaccine clinical trials looking for patients.

Dr. Julie Graff discusses clinical trials—both completed and those looking for patients—that combine Keytruda and Xtandi.

Dr. Fatima Karzai tells us about clinical trials at the National Institute of Health that combine PARP and PD-L1 Inhibitors.

Dr. Bruce Brown, Chief Medical Officer of Dendreon, discusses a clinical trial that looks at using sipuleucel-T in men on active surveillance.

Each conversation this month includes information on clinical trials that are recruiting prostate cancer patients. If you think you may be a fit, please don’t hesitate to contact the investigator.

Join us for more information.


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Dr. Mohit Khera: Treating ED

Dr. Khera, a urologist specializing in male infertility, male and female sexual dysfunction, and declining testosterone levels in aging men, is the Director of the Laboratory for Andrology Research and the Medical Director of the Executive Health Program at Baylor College of Medicine in Houston, Texas.

Prostatepedia spoke with him recently about current and emerging approaches to erectile dysfunction (ED) after prostate cancer.

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Khera

Why did you become a doctor?

Dr. Mohit Khera: Originally, I was a healthcare analyst. I did my MBA and then worked as an analyst in Boston for two years. I realized that it wasn’t very satisfying for me. I really wanted to be able to help other people and to help patients. I went to medical school and became a doctor. I have never looked back. It’s the best decision I ever made.

There’s something very gratifying about being able to help other people, particularly those who are in need and are in pain or hurting.

Have there been any particular patients who’ve changed how you see your role as a doctor or how you view the art of medicine?

Dr. Khera: There are numerous patients who stand out in my mind, particularly those who have suffered from prostate cancer and are trying to recover their lives, whether it be in terms of sexual function, incontinence, or even just keeping the cancer from coming back. It’s very challenging. These patients just

who is not very skilled or who does not do robotic prostatectomy quite frequently, their ED rates tend to be higher than someone who does the procedure on a regular basis. Surgeon skill is critical.

Typically, radiation does have a lower rate of ED initially, but several years down the road, the rate of ED can catch up and accelerates past the rate of ED from surgery.

We know that in androgen deprivation therapy (ADT) when you drop testosterone values, the risk for ED is significantly increased. Many studies show that you start losing nocturnal erections when the testosterone levels fall below 200. That’s exactly what happens when you give men ADT: ED rates should go up significantly.

Does erectile function come back after a man goes off ADT?

Mr. Khera: Yes, many times it does come back. The only problem is that not all men have their testosterone levels bounce back into the normal range after they stop ADT. Some men will actually have testosterone levels that remain in the low range. Of those men in whom levels do go up, whether they build up naturally or through testosterone supplementation, many will experience improvements in their erectile function once again.

Is there anything a man can do before treatment to prevent problems or reduce problems after treatment?

Dr. Khera: The concept of penile rehabilitation has been up for debate in my field. There are those who are proponents and those who don’t believe that it will help. I personally believe that penile rehabilitation is effective and will help patients recover their erectile function faster and more effectively.

In my program at Baylor College of Medicine, I start patients two weeks prior to the surgery on daily Cialis (tadalafil). I teach them how to use the vacuum erection device as well because I want them to use it after surgery. I check their testosterone levels before surgery, as some studies have shown that the testosterone levels do go up after a prostatectomy.

I also teach them the concept of penile injections just in case they need to use them after surgery if they’re not able to recover their erectile function.

There is a lot of counseling that goes on before the surgery. I put them on certain medications. I’m trying to prepare them for the surgery and to keep their tissue healthy and in the best condition possible.

There are a lot of doctors, though, who don’t do that kind of thing and who don’t talk about penile rehabilitation. Some aren’t even comfortable talking about ED with their patients except in the most cursory way. What would you say to a patient who’s encountered that? Should he go see someone who is a specialist in ED?

Dr. Khera: I think that patients should voice their opinions. If you look at this field 20 years ago, you realize there are three things that occur. A man wants to make sure that he gets his cancer out; he wants to make sure he can still get good erections; he wants to make sure that he’s not leaking urine after the procedure. Those are the three big categories of patient concerns.

In the past, many surgeons just focused on getting the cancer out and felt patients should be grateful for that. Yes, you may have some ED or incontinence, but we saved your life.

But now patients are very savvy and are demanding more. They’re demanding that they should have their cancer out and also have great erections and no incontinence after the procedure.

I think it’s very important when a patient has a diagnosis of prostate cancer that he discuss all three of these categories with his surgeon. They should discuss outcomes and the surgeon’s skill. They should discuss how many cases that surgeon has performed in this field.

Some patients in smaller communities don’t have access to doctors with your experience. Are there online resources for men in that position?

Dr. Khera: I think one of the best online resources is at http://www.sexhealthmatters.org. They have a phenomenal website with lots of literature and education on sexual medicine and rehabilitation. It’s an excellent resource that I share with my patients.

What about men who have already been through treatment and are suffering from ED? Which approaches seem to be most effective after which prostate cancer treatments?

Dr. Khera: There are many treatment options available to men with ED following a radical prostatectomy. The most common treatment options are PDE5 inhibitors. Those are called phosphodiesterase inhibitors—Viagra (sildenafil), Levitra (vardenafil), Cialis (tadalafil), and Stendra (avanafil).

These medications are very useful. Many of us give these medications on a daily basis to help men recover the nerves and penile tissue. I think it’s important.

Men can also use a vacuum erection device, which is exactly what it sounds like. It’s a vacuum that induces an erection. A band is placed at the base of the penis to maintain the erection.

Men can also use an injection therapy. We spend an hour in the office teaching them how to inject themselves with a very small diabetic needle. They inject into the base of the penis a solution that causes a very rigid erection. Then very early on they can start engaging in sexual activity.

I believe psychologically it’s very important that men start engaging in sexual activity early after surgery; it has a large psychological impact not only on the patient but also on the partner.

Other therapies include urethral suppositories called MUSE (alprostadil). These are placed into the urethra and dilate the penile tissue to give an erection.

Finally, I would say one of the best treatment options for many men is a penile prosthesis. We do perform this procedure. We place a penile implant into the penile tissue and a pump into the scrotum. Men can then pump saline into their penile tissue to induce an erection.

Isn’t it dangerous for a man to begin sexual activity soon after surgery? Is there any risk to him?

Dr. Khera: Typically in our practice, we like men to wait at least one month so that all the sutures heal and there is no risk of injury with the urethral anastomosis. We encourage men to start engaging in sexual activity one month after surgery.

Do you have any advice for men who are either worried about ED before going into treatment or who are struggling now?

Dr. Khera: There are two important things men should realize. First, prior to going into any type of treatment for prostate cancer, you should discuss ED outcomes with your doctor. Ask them what success have they had with ED. What is their plan for managing the ED if it does develop after the procedure?

Second, men who are already suffering from ED should know that there are excellent treatment options available. Men do not have to live with ED following a radical prostatectomy.

There are new treatment options emerging. We have started two studies, one with stem cell therapy. We take stem cells from men and inject them back into the penile tissue, with some benefit. We have another therapy called low-intensity shock wave therapy, in which we deliver shocks to the penile tissue. It does help recover erectile function.

There are many new treatment options on the horizon.

We’ve spoken about stem cell therapy before. I think you were just starting a trial.

Dr. Khera: I finished that trial and am now starting a Phase II trial. This first trial went extremely well. We’ll begin recruiting patients at the end of this year.

What we did not discuss last time was shock wave therapy. That has been out for multiple years and has gained a lot of success and media in the United States. Some of your readers may have seen commercials for it. We believe at this point that shock wave therapy should be used only in a research protocol until more data is available.

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Dr. Charles Drake On A Memorable Patient

DRAKE charlesDr. Charles G. Drake is the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/Columbia University Medical Center.

Dr. Drake discusses a patient whose case intrigued him.

Have you had a particular patient who changed how you approach your work?

Dr. Charles Drake: Absolutely. I had a gentleman who had metastatic, castrate-resistant prostate cancer. He had been treated with hormonal therapy. He was about to go on chemotherapy. He had progression in his bone lesions, but he developed hematuria.

On CT scan, there was a fairly clear lesion in his bladder. We couldn’t tell what it was just by the scans, and his PSA was doubling quickly, it had reached 30 or so in less than a couple of months. We sent him to Dr. Ronald Rodriguez, who was at Johns Hopkins at the time, and he thought it looked like this was probably metastatic prostate cancer invading the gentleman’s bladder. Dr. Rodriguez did a transurethral fulguration, meaning he burned all of the tumor he could find in the bladder. After the procedure, he told me that there was a fair amount of prostate cancer left behind. While the procedure went well, and he got most of the tumor, he didn’t get all of it.

What happened next was fascinating. The patient’s PSA dropped. His PSA went from 30 to 20 to 10. It eventually nadired, or reached its lowest point, at less than 1 ng/ ml and he remained in remission for nearly two years. Although clearly anecdotal, in my mind, there is almost no question that this was one of those anecdotal abscopal responses, which makes you believe that it can happen. Almost certainly that was what happened for this patient. I’ll never forget it, frankly.

Interesting. An unexpected systemic response from local treatment, right?

Dr. Drake: Yes. It was brilliant. Just by treating the local disease in the bladder, this gentleman did well for over two years before it apparently progressed again, and he wound up getting chemotherapy. He also did very well with the chemo, so in my hopeful view, that suggests that maybe this fulguration procedure sparked a systemic immune response.

Join us to read the rest of Dr. Drake’s comments on the elusive abscopal effect.


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Dr. Robert Bristow On Precision Radiation Therapy

Robert Bristow portraitDr. Robert G. Bristow is the Director of the Manchester Cancer Research Centre (MCRC) at the University of Manchester in the United Kingdom.

Prostatepedia spoke with him about precision radiation therapy.

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What is meant by precision radiotherapy?

Dr. Robert Bristow: There are at least two aspects to precision radiotherapy. The first is the “physical precision” of radiotherapy; the actual targeting of the radiation beams or radioactive compounds to the specific tumor tissues that you want to treat, with maximum protection to the normal tissues that surround that particular tumor. For example, external precision radiotherapy uses intensity modulated radiotherapy or proton therapy where you then deliver the radiation in very precise defined volumes.

The other type of physical precision in radiotherapy uses brachytherapy, actually placing seeds or catheters with radioactivity directly in the prostate and being able to conform the dose tightly to the prostate gland, with that dose falling off rapidly around the surrounding normal tissues that could acquire side effects (e.g. the bladder or rectum). The concept of physical precision has allowed us to increase the total dose to the prostate cancer and yet maximally spare the normal tissues from side effects.

Another aspect of precision radiotherapy is “biological precision” whereby we think about the entire treatment using radiotherapy based on the innate characteristics of a particular patient’s tumor.

This includes information about the genetics and microenvironment of the tumor cells within the cancer that make it uniquely suited to be cured by radiotherapy alone, or in combination with drugs that modify biology or the immune system.

This can have the effect of increasing the chance that the cancer is cured locally and also attack cancer throughout the entire body to kill what we call occult, or hidden, metastases.

Precision radiation therapy therefore now means both an understanding of the biology of the tumor in a specific patient as well as physics to optimally deliver that radiotherapy.

What role does functional imaging play?

Dr. Bristow: Imaging is a cornerstone for staging cancer and understanding its biology. It is absolutely required for staging patients to understand the anatomy of their cancer—not only where the local tumor is, but also the spread to the pelvic lymph nodes and beyond that to the bone, for example.

Anatomic imaging therefore gives us the geography of where those tumors are in the body. Functional imaging adds further components to start to understand the biology of those tumors. For example, by using functional imaging with MRI, we can look at differences in tumor blood flow, oxygen levels, or metabolically active versus metabolically inactive tumors.

For PET scanning, we can use specific radioactive tracers that will tell us about the glucose in the tumor, the amount of the tumor that has low oxygen status (called hypoxia), and the relative growth rate of tumors.

So imaging can now give us both anatomy and biology.

Totally different world, right?

Dr. Bristow: It is. If you understand the biology from the imaging and where things are, you can certainly target specifically those areas with precision radiotherapy using novel biological agents, which we call molecular targeted agents.

Join us to read the rest of Dr. Robert Bristow’s comments on radiation therapy for prostate cancer.


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Prostatepedia’s July Issue On RT

When you’re diagnosed with prostate cancer, you’re usually offered three options: monitor the cancer to see if it progresses, elect to have your prostate surgically removed, or elect to have the cancer treated with radiation therapy. Radiation is also used after surgery or in the event that the cancer comes back after that initial treatment.

Most of you are familiar with radiation therapy for prostate cancer—how it works, potential side effects, and special considerations. Even if you have not had radiation, chances are you’ve got a friend of relative who has.

This month, however, we’re delving into less often discussed aspects of radiation therapy: the role genomics will play in radiation therapy, why we might consider combining radiation with immunotherapy, the impact imaging has on radiation therapy, and the role radiopharmaceuticals play.

Dr. Robert Bristow of the University of Manchester gives us a sweeping overview of precision radiation therapy—from functional imaging to genomics—as well as a run-down of molecularly-targeted agents.

Dr. Charles Drake of the New York- Presbyterian/Columbia University Medical Center discusses radiation therapy and the elusive but intriguing abscopal effect.

Dr. William Hall of the Medical College of Wisconsin talks to us about the precision radiotherapy movement and how it will revolutionize patient care.

Dr. Daniel Spratt of the University of Michigan Health System talks about a clinical trial he’s working on with

Dr. Felix Feng from the University of California, San Francisco (UCSF) that uses genomics to determine which patients will receive a combination of radiation therapy and Erleada (apalutamide) and which will get a placebo.

From Dr. Ralph Weischelbaum of the University of Chicago we hear about the thinking behind combining radiation therapy with immunotherapeutic agents—with a cautionary note.

Dr. Johannes Czernin from the University of California, Los Angeles (UCLA) talks about a clinical trial he’s running on a radiopharmaceutical agent—a PSMA targeted lutetium-177. He is looking for patients to join, so if you think you might be a fit, please reach out to him at the email address included at the end of his conversation.

Ms. Merel Nissenberg offers the National Alliance of State Prostate Cancer Coalition’s stance on hypofractionated radiation therapy.

Finally, Ron B. tells us about his experiences with stereotactic body radiation therapy. He has some advice for those of you in a similar situation to the one in which he found himself.

We suggest you read through this month’s conversations and then send the issue to your health care team so that you can discuss the contents with them.

Download the issue.