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Dr. Bertrand Tombal On Making Prostate Cancer A Chronic Disease

Dr. Betrand Tombal, Chairman of the Division of Urology at the Cliniques universitaires Saint Luc and Professor of Urology at the Université catholique de Louvain (UCL) in Brussels, Belgium, is the current President of the European Organization for Research and Treatment of Cancer (EORTC), the leading European academic research organization in the field of cancer.

Dr. Tombal is keenly interested in treating advanced prostate cancer and in the development of hormonal treatment and new biological agents

Prostatepedia spoke with him about how newer agents like Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) have changed the prostate cancer arena.

Join us to read the rest of this month’s conversations about Zytiga, Xtandi, and Erleada.

How have the newer agents, like Zytiga (abiraterone) and Xtandi (enzalutamide) changed the treatment landscape for men with castrater esistant prostate cancer?

Dr. Tombal: These drugs changed treatment in three ways. First, urologists know that hormone therapy may have a profound effect on some patients. Having said that, in the late 90s, we had hormone therapies of limited efficacy. For better or worse, there was no regulatory platform development for historical hormone therapy, so we are missing good evidence that they increased overall survival or even significantly delayed progression. These two new hormones build upon things we already knew for years, but they are far more effective, and more importantly, they have been developed following a strong regulatory context so that we know exactly their benefit.

But before that, the Taxotere (docetaxel) story was interesting for me because that’s one of the first studies I participated in. Seeing all these guys dying from prostate cancer, I thought it was unbelievable that we could increase overall survival. I was thus extremely surprised that urologists in charge of managing advanced prostate cancer at that time would negatively react to chemotherapy and claim that the benefit was limited and toxic. Hence, patients would be referred by the physicians. I thought that was strange. From day one, I thought that we should ask what the patients think. But the landscape changed again when we saw the results of the post-chemotherapy trials with Zytiga (abiraterone) and Xtandi (enzalutamide), how much they increased overall survival, and their major effect on PSA. We realized that we had game-changers.

But to me, changing the game was not necessarily about having patients live a little bit longer. I always go back to the many discussions I have had with patients who ask not whether they will live longer but if they will live better.

That’s why I was so excited about being one of the Principal Investigators on the Prevail trial. The Prevail trial was really not about Xtandi (enzalutamide); we already knew the drug worked. Prevail was about having a discussion early on in the course of the disease, when the patient was becoming metastatic and castrate-resistant. We would ask: what do you want to do? Do you want to wait a bit and only start chemotherapy after you’ve got symptoms? Or do you want to start the drug immediately?

The patient would then ask about the side effects. I would say that there are side effects, but to give it a try, and if they didn’t want to live with them, we could simply stop the drug and the side effects would go away. These are oral drugs, so if you have side effects that are severe, you can just stop the drug.

That’s what was new, that not only could we help the patient live longer, but we could delay complications of the disease and buy him quality time It has really changed the way we treat patients.

If you look at newer trials, like Prosper and Spartan, they are having the same discussion but going one step further.

You have no metastases, but your PSA is progressing rapidly. What do you want to do for the rest of your life? Do you want to do nothing, enjoy a few additional months until you develop metastases and then start the treatment? Or do you worry enough that you would like to try one of these drugs to see if you tolerate it? To me, it’s no more complicated than that. These drugs, Zytiga (abiraterone), Xtandi (enzalutamide), and now Erleada (apalutamide), have brought the possibility of discussing early on in the course of the disease what is important for that particular patient. Do you want to delay progression? Because in the end, these drugs are not very toxic.

That’s why these drugs are so important.

And this is just the beginning. We’re not going to speak four years from now about giving Xtandi (enzalutamide) or

Zytiga (abiraterone) in the metastatic castrate-resistant prostate cancer space because we’re going to give these drugs earlier and earlier to patients with high-risk disease together with radiotherapy and surgery. We have a chance. What we want is to have prostate cancer patients die from something else.

A few years ago, Andrew C. von Eschenbach, a urologist that became the twelfth Director of NCI, said that his grail was to make cancer a chronic disease. That’s what we’re doing with these newer drugs: we’re making prostate cancer a chronic disease. We have never said we were going to make someone immortal, but hopefully we still delay the appearance of metastases and symptoms, so that they will die from something else. That’s the beauty of trials like Spartan, Prosper, and (hopefully) Aramis in which Xtandi (enzalutamide), Erleada (apalutamide), or darolutamide are given at early signs of rapid PSA progression to delay the metastases. We used to say that at that stage of the disease, everybody will die from prostate cancer, but now we’re delaying progression so much that patients are going to start dying from something else and not have to go through all of the suffering associated with prostate cancer. That’s a major change. That’s the change these drugs are bringing. They bring the possibility of intervening early and making prostate cancer a chronic disease. And yes, there is a slight increase in toxicity. And yes, at a huge increase in cost. But that’s how the world is.

Do you think it’s of any concern that we don’t really understand the longterm impact of these drugs?

Dr. Tombal: When people discuss this aspect, they assume that we have effective treatments to treat the progression. That’s not true. It’s the same with bone-targeted therapy. I remember when bone-targeted therapy came on the scene, a famous medical oncologist said that what we are delaying is simply giving a little bit of cheap radiotherapy to the spinal column (on the lumbar spine). I said that was true, but you assume that cheap radiotherapy to the spinal column is effective. And it is not.

When are bone-targeted therapies like bisphosphonates and Xgeva (denosumab) traditionally used, and how has their use changed now that these newer drugs have come onto the scene?

Dr. Tombal: Less frequently. And that’s a major drama. Once again, it comes from a wrong interpretation of the data, from that oncological view that overall survival drives all decisions. When the major study on zoledronic acid and Denosumab was published, people said it doesn’t make patients live longer or increase overall survival. I said that I didn’t care: increased survival is not what we expect from this drug.

What we expect from this drug is that it delays skeletal complications. It reduces the total number of bone complications in a patient’s lifetime. This means that, if you’re a gentleman of 70 years, and God has written in your book that you’re going to live another two years, you’ll get your first skeletal event in 12 months. Xgeva (denosumab) will not make you live longer, but it will delay your first skeletal complication to 16 months. Once again, you’re buying quality time. You define that quality time as time without bone complications.

Then came Taxotere (docetaxel), Xtandi (enzalutamide), and Zytiga (abiraterone). They all extend overall survival and skeletal events. Physicians are starting to not prescribe these drugs because they say we don’t need them now that we have Zytiga (abiraterone) and Xtandi (enzalutamide).

Recently, Bayer conducted a clinical trial comparing Xofigo (radium-223) plus Zytiga (abiraterone) versus Zytiga (abiraterone) alone. The trial ended after a little more than one year because there was a significant excess of fractures and death. One of the striking observations is that only one-third of the patients in the trial received bone-protecting. The European Medicines Agency’s statement says that, most likely, this excess of fracture happens only in patients not receiving bone-targeted therapy. Clearly, avoiding bone-targeted therapy has been a big mistake. We believe that if we have drugs that increase overall survival, we don’t need bone-targeted agents. But now we realize that if patients live longer with bone metastases, we increase the likelihood that they’re going to have complications. These drugs are even more important than they were before.

Would you say that most men on drugs like Zytiga (abiraterone), Xtandi (enazlutamide), or Erleada (apalutamide) should consider bone protecting therapy?

Dr. Tombal: If they have bone metastases, I would say yes. The question then becomes what to do if you only have one bone met. In Europe, we use a lot of modern imaging technologies, such as PSMA and whole-body MRI. Sometimes, you see a man with a rising PSA and one or two bone mets that you don’t see in a bone scan. If that man has two, three, or four bone metastases that show signs of progression, such as increased alkaline phosphate, he should be on bone-protecting agents.

What sort of combinations do you think seem the most promising or have the most benefit?

Dr. Tombal: At this point in time, we have failed to show that any combination is better than a single agent for prostate cancer. When I’m speaking about combinations, I’m speaking about combining drugs to increase overall survival.

When Taxotere (docetaxel) came out, there was an epidemic of shotgun experiments where everybody tried to combine Taxotere (docetaxel) with all sort of agents, all usually having shown a strong rationale in the lab. Not one of those trials was positive. Most of them showed a benefit in favor of Taxotere (docetaxel) alone. When Bayer said we’re going to combine Zytiga (abiraterone) with Xofigo (radium-223), that seemed like low-hanging fruit. They were combining two drugs with different modes of action and different toxicities that both showed an increase in overall survival when used alone. Nobody could have imagined that it would end in catastrophe—that combining the two agents would shorten survival.

At this point in time, there is not a single indication that one combination is better than a single agent in prostate cancer.

What should patients take away from that?

Dr. Tombal: These agents: Zytiga (abiraterone), Xtandi (enzalutamide), Erleada (apalutamide), Taxotere (docetaxel), Jevtana (cabazitaxel), and in the United States, Provenge (sipuleucel-T), have been used sequentially, but not in combination. Combinations don’t have any benefit.

Do you think that is because there is some synergistic effect in terms of side effects?

Dr. Tombal: I have absolutely no idea. That’s where we stand today.

Do you have any thoughts for men who’ve been prescribed Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide)?

Dr. Tombal: I would say that one of the great messages of the Prosper and Spartan trials is that we probably do too much imaging, that it’s probably better to follow a patient just with PSA. Then when his PSA starts to increase rapidly, that is probably the time to talk about earlier treatment with one of these agents. That is when to have the overall discussion about what you want to do and where you want to go.

Why shouldn’t we use imaging as much?

Dr. Tombal: Because we are tempted to offer additional treatments, such as radiotherapy, which have limited value, when we have at least five or six large Phase III trials that establish the philosophy of starting Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) earlier.

In Europe, we do a lot of imaging and a lot of salvage treatment. But we have to be honest, it’s driven by belief more than data.

Europe is ahead of the United States in that regard.

Dr. Tombal: Being ahead has started to make us realize that we probably over-treat more patients than we help.

That’s a huge issue because men can live for a long time with often debilitating side effects.

Dr. Tombal: Exactly.

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Dr. Bertrand Tombal On Why He Became A Doctor

Dr. Bertrand Tombal, Chairman of the Division of Urology at the Cliniques universitaires Saint Luc and Professor of Urology at the Université catholique de Louvain (UCL) in Brussels, Belgium, is the current President of the European Organization for Research and Treatment of Cancer (EORTC), the leading European academic research organization in the field of cancer.

Dr. Tombal is keenly interested in treating advanced prostate cancer and in the development of hormonal treatment and new biological agents

Prostatepedia spoke with him about why he became a doctor.

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Why did you become a doctor?

Dr. Bertrand Tombal: My mother was a nurse who went to patients’ homes. When I was young, I went with her on weekends and became interested in healthcare. I was very scientific. I have always been driven by science, so it was natural for me to become a doctor.

When I was around 17, I got interested in archaeology. Maybe because of Harrison Ford’s movie, I wanted to be an archaeologist. But I wasn’t sure what major to declare for college, so I decided to become a doctor while still enjoying archeology.

For a long time, I wanted to be a pediatrician, and I was quite good at that, so I was preselected to do pediatrics. In Belgium, we had a certain number of obligatory rotations. You have to do four months in internal medicine and four months in surgery. Because I so wanted to be a pediatrician, I skipped one month of surgery, but they wouldn’t let me graduate without that month.

I ended up working in a peripheral hospital for a month with a private urologist. I became crazy about urology, went back to my professor in pediatrics, and told them I didn’t want to be a pediatrician anymore. I wanted to be a urologist. And that’s how I started as a urologist.

Funny. Life takes you on different paths.

Dr. Tombal: I like that urology is a broad specialty. You treat cancer patients and incontinence patients. You engage in a lot of private emotional things, so I liked it from day one. After two years, I did my PhD thesis on prostate cancer, which took about four years in the end, and that’s when I got interested in prostate cancer.

Have you had any particular patients whose cases have changed how you either see your own specific role as a doctor or how you view the art of medicine?

Dr. Tombal: After completing my PhD thesis in 1998 in Brussels, I got an appointment at Johns Hopkins, where I finished my PhD. My former boss recognized that I liked to treat prostate cancer, but he preferred surgery, so he had me take care of the advanced cancer. I took care of advanced prostate and bladder cancers, which was not really a multidisciplinary approach at that time because there was no Taxotere (docetaxel) yet. Medical oncologists were not involved at all. We had a handful of old, hormonal treatments like estramustine phosphate (estrogen) or dexamethasone. That’s how I got interested in this. The bottom line is that I would follow many of my patients until death.

In 2000, supportive and palliative care were not yet developed. As a urologist, you would take care of guys usually in their 70s, and that’s where I started to speak with them and learn about interesting things, such as the relative importance of overall survival as compared to quality of life. That was meaningful. I learned from a few patients that, at some point, the only advantage you have as a doctor is that your patient has started the last round or two. You know he will die from the disease. You don’t know when, but you know it’s not that good. I learned that it’s important to have discussions and ask lots of questions. Where do you want to go? What is important for you? Do you have a point you want to reach? What are you ready to accept?

It’s always been extremely important that we don’t impose the treatment sequence at the very end. There is always a point beyond which we should discuss with the patient the philosophy of the treatment and what we expect. In the end, we have to make the choice together. To me, it’s always been extremely important having that kind of conversation, so many of these patients gave me this philosophical approach.

I still believe that managing castrate resistant prostate cancer is more about philosophical choices than scientific evidence. That’s why my background, having seen many patients before these drugs existed, is so important to me.

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Dr. Mary-Ellen Taplin On Zytiga, Xtandi + Erleada

Dr. Mary-Ellen Taplin is the Director of Clinical Research at the Lank Center for Genitourinary Oncology at Dana-Farber Institute. Prostatepedia spoke with her about the impact Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) have had on how we treat prostate cancer patients.

Taplin_ Headshot Crop 12.16.15

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Why did you become a doctor?

Dr. Mary-Ellen Taplin: I was drawn to medicine because I really like the science behind cell biology and cell growth. I was attracted to oncology because I like being able to think about how to attack unbridled cell growth. Oncology is about understanding mechanisms of response and resistance. My goal is to give patients the highest level of care through application of basic discovery and not just go with the same status quo. For me, it was the intellectual pursuit of cell biology that then connected with oncology and oncology patients.

Have you had any particular patients over the years whose cases have changed either how you see your own role as a doctor or how you practice medicine?

Dr. Taplin: I treat all my patients as if they were family. I try to go to where they are, provide support, and be a healer. I give them the best go at the best quality of life and length of life that they can have.

Can you talk to us a bit about how Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) have changed the treatment landscape for men with prostate cancer?

Dr. Taplin: First, in castrate-resistant cancer, these agents have provided patients with fairly well-tolerated oral therapies that work well in most people, at least for a significant period of time. It’s never long enough, but for a year or two, they work well.

Prior to these agents, all we had was ketoconazole, which works similarly to Zytiga (abiraterone) but is less targeted and has a lot of side effects. Ketoconazole wasn’t approved specifically for prostate cancer and wasn’t an optimal drug. We also had chemotherapy. Patients’ lifestyles are always more hindered by having to come in for IV chemotherapy every three weeks compared to taking oral medications.

These newer drugs not only provide effective therapy, but also provide therapy that is more conducive to keeping patients in their regular lifestyles.

Secondly, with newer data that has since evolved, these agents have also been found to improve outcomes for patients when used earlier, like in patients with non-metastatic castrate-resistant prostate cancer, in the case of Erleada (apalutamide), and for hormone-sensitive metastatic disease, in the case of Zytiga (abiraterone).

So, firstly: men with castrate resistant metastatic prostate cancer have more tolerable options, an improved life expectancy, reduced cancer related symptoms on many levels, reduced intensive pain, reduced need for narcotics, and reduced need for early chemotherapy. All things that go along with improving people’s quality of life while treating them.

And then secondly, moving these agents up earlier in disease progression has provided benefits to earlier stage patients. There are a lot of ongoing investigations looking at using these drugs earlier in conjunction with radiation and even prostatectomy. The field is not done with trying to optimize the timing and improving outcomes for patients with these particular clinical tools.

Which combinations are being explored, and which might be the most promising in the long run?

Dr. Taplin: To date, there are no combinations that have been proven effective in any sequential therapy in castrate-resistant prostate cancer (CRPC), but combinations are important and should be evaluated. There is strong biologic rationale to combine Xtandi (enzalutamide) with a CPY-17 inhibitor (abiraterone), Xtandi (enzalutamide) and a PD-1 inhibitor, or Xtandi (enzalutamide) or Erleada (apalutamide) with a PI3 kinase pathway inhibitor.

These are important combinations to explore. But in prostate cancer, at least in the 28 years that I’ve been practicing, despite many trials, not one combination regimen has been approved in CRPC. It’s tough to build a combination therapy in prostate cancer for unclear reasons. That doesn’t mean we shouldn’t explore them, but it means it’s unclear how effective combination therapy will be, at least in the short term.

There is a Phase III Alliance trial looking at Xtandi (enzalutamide) and Zytiga (abiraterone) together in patients with castrate-resistant prostate cancer. Dr. Mike Morris is the Principal Investigator. The biologic rationale is strong to explore more intense androgen receptor pathway inhibition with the combination of a second-generation AR antagonist with a ligand antagonist like Zytiga (abiraterone).

The preclinical rationale is promising, but to date, combination therapy in prostate cancer has been an unfulfilled dream.

What are the side effects like for each of these agents?

Dr. Taplin: There are differences, but they all cause some degree of fatigue, muscle wasting, and hypertension. With Zytiga (abiraterone) we have to watch for low potassium and elevated liver enzymes. We don’t see those things with Xtandi (enzalutamide) or Erleada (apalutamide). In a subset of patients, there is some cognitive clouding, some reduced concentration even to the point of confusion with Xtandi (enzalutamide), though rarely with Zytiga (abiraterone). Erleada (apalutamide) can rarely cause hypothyroidism, which is specific to that drug, so it needs to be monitored.

In general, patients need to have laboratory and blood pressure monitoring on a regular basis, every 2-8 weeks depending on the patient and the individual risks.

At present most patients are castrate resistant when they start on these drugs, so they’ve already had years of adjusting to medical castration. These patients have usually adjusted to the typical side effects that you see with medical castration when you start them on Lupron (leuprolide) or similar LHRH agonists/antagonists and have been more or less familiar with side effects such as hot flashes and weight gain for years.

A lot of patients talk about the high price of these medications. Do you have any thoughts about that?

Dr. Taplin: It’s a big problem. The copays are anywhere from $0 to $4,000 if you have coverage. Then there are the people who don’t have any coverage. This is the nature of Big Pharma in the United States and because the United States bears the burden of research and development of these products for the rest of the world. They’re expensive, and as a society, we have not prioritized dealing with the costs. Sometimes what we would consider even a small copay for a particular patient is too much for them. They’re faced with paying their phone bill or getting their medication.

It’s been well documented that, especially in the elderly, these expensive medications lead to people not taking their medication correctly, trying to stretch them out, skipping days or reducing doses, or not taking them all together. It’s a little different for cancer medication than, say, for blood pressure medicine. Cancer patients are more motivated to take the medication, but probably, they do not often take it correctly to try to make it last longer.

Family members sometimes share the burden. The patient can’t afford the drug, so family members try to patch together the funding. It can be a family problem as well as an individual problem.

I don’t know what the answer is, but it’s definitely true that, as we develop more oral therapies in prostate cancer, patients could be on very expensive sequential oral therapies for many years. For instance, a patient may go from bicalutamide to Zytiga (abiraterone) to Xtandi (enzalutamide) to Lynparza (olaparib). Three out of those four are expensive oral therapies. You’re not just talking about big copays for a year—because Zytiga is only going to work for a year—but sequential copays. These patients are probably going to be on these oral drugs for many years.

Does that ever factor into your choice of which agents to use in which patient?

Dr. Taplin: If we had more choice, it would. Most insurance companies require, at least in castrate-resistant prostate cancer, that you use Zytiga (abiraterone) first because, though still expensive, it is less expensive than enzalutamide. You don’t have a choice as a physician because the insurance companies decide what will be covered. Zytiga (abiraterone) is less expensive than Xtandi (enzalutamide) by almost 50 percent. I’ve stopped doing appeals to insurance companies for these drugs because insurance denials are rarely over turned.

Do you have any thoughts for men who’ve been prescribed any of these agents?

Dr. Taplin: Get guidance from the physician who is prescribing them so that you understand the common potential side effects. Take them as prescribed. If there is toxicity, discuss with your doctors the potential for a dose reduction. Even though there’s the FDA-recommended dose, often these medicines work well at lower doses. You might have less toxicity or feel better, say, on 750 mg instead of 1,000 mg of Zytiga (abiraterone) or 120 mg instead of 160 mg of Xtandi (enzalutamide). Don’t do that on your own, but it’s something that could be discussed with your doctor.

Another important message to get out to patients on these medications is the importance of keeping strong and of regular exercise. Find exercise and activities that you like. Get a trainer. Join a YMCA. Do the LIVESTRONG program. Commit to some sort of strengthening activity to keep your muscles. That will reduce side effects over time and be helpful. Of course, diet is important. A good heart-healthy diet is a good prostate cancer patient diet as well. Exercise and diet are often neglected by patients and physicians but are really important tools for patients on second generation hormone inhibiting drugs.

Diet and exercise can put patients in a better place so that they don’t have a fall or other toxicity problems. If you get a prescription for Xtandi (enzalutamide), you should also get a prescription to go to the gym four times a week. You need more than just a walk to the mailbox and back or to go grocery shopping. You don’t have to be an Olympic athlete, but doing some type of strength training will help build muscle, or at least reduce the reduction in muscle tone that a lot of these men suffer from.

Join is to read the rest of our October conversations about Zytiga (abiraterone), Xtandi (enzalutamide) and Erleada (apalutamide).


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Can You Self-Manage Your Symptoms?

Dr. Sarah Hawley is keenly interested in decision-making among cancer patients and physician-patient communication. She recently completed a study that looked at using automated voice-response technology to help veterans self-manage erectile dysfunction, urinary incontinence, bowel incontinence, and general loss of vitality after prostate cancer treatment.

Prostatepedia spoke with her about her study and its implications for men with prostate cancer.

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How did you come to focus on decision-making in cancer patients? Why patient-physician education?

Dr. Sarah Hawley: I have had a long-standing interest in cancer outcomes and delivery, growing out of my doctorate program. My postdoctorate program was in the area of cancer care delivery and quality and studying access. As part of that, I became interested in how decisions that patients make, both on their own and in collaboration with their providers, influence the care they get. I noticed that even in similar health systems there were groups of patients who got different types of care. Some people get too much care; some people are not getting enough care.

I became really interested in the role that the decision-making process plays in that. Could that be a potential mechanism for improving access and outcomes for patients? Part of that is the patient-physician communication process and the patient-physician-caregiver communication process. Many patients have loved ones who join them in making these very difficult and challenging decisions.

How did you come to be working with patients from the Veterans Administration?

Dr. Hawley: I’ve been on the faculty of the University of Michigan and an investigator in the Ann Arbor Veterans Administration (VA) center for clinical management research since 2004. When I came to this position, it was a joint position. I had not worked with veterans before. I had not worked in the VA system before, but I was really excited about the chance to study communication and decision making in the Veteran population.

As part of my career over the last 10 or so years, I’ve been able to do similar projects, both within and outside of the VA, and I have looked at veterans and non-veterans. It’s been very rewarding to be able to do that in both settings.

How common is prostate cancer among veterans?

Dr. Hawley: Obviously, the veteran health system is predominantly male. Although that has been slightly changing, especially in more recent years, it still predominantly services male patients. Prostate cancer is the most common cancer in veterans. Lung cancer remains the most commonly diagnosed cancer outside the VA.

Approximately 12,000 veterans are diagnosed with prostate cancer every year. Most of those men have early-stage prostate cancer, partly because of the use of PSA screening to identify potential prostate cancer as opposed to identifying later-stage cancer, which has metastasized. This means that the patient has to make a treatment decision about how to manage his cancer: surgery, radiation therapy, or, increasingly, active surveillance, which is an active management strategy without any medical intervention. That is a complicated and difficult decision and one that veterans face daily.

Talk to us about the study you did on self-managing symptoms after prostate cancer treatment.

Dr. Hawley: To do this study, we took a jump from the decision-making side of things to the survivorship side of things. A patient who has received a cancer diagnosis—of any cancer— makes a treatment decision early on: surgery or radiation. As I mentioned, in prostate cancer there is now the option of active surveillance. Early-stage prostate cancer is very survivable. Most of the patients live and thrive into survivorship.

However, many of them have received surgery or radiation. Both of those treatments have side effects, which are very present in the first few months following treatment. A lot of these side effects remain issues for men for months, and even years, following their diagnosis. Patients then transition from that initial treatment phase into survivorship. But there’s no clear time point when that happens. They are released back into their regular follow-up care and do quite well except for these symptoms.

Programs do not really exist, either within or outside of the VA, to help men who are dealing with these long-term symptoms.

The symptoms can include urinary and sexual symptoms. They can have problems with incontinence and pain with urination. Men can have impotence. There are also some bowel problems that men experience and general health or vitality issues.

Those are the grouping of symptoms that we were interested in trying to help improve in this long-term survivorship population. Again, this is a group that hasn’t really been the target of many interventions. All of these symptoms, to some extent, can be self-managed. There is a trajectory of less serious to more serious symptoms.

One of the things that we try to do is help the patient understand when the symptom is so serious it may need a consultation with a specialist.

How was your study structured? How many patients did you have?

Dr. Hawley: We developed an intervention, which was based on some prior work that our team had done, using automated voice-response technology: you get a phone call and can interact with the phone system, not a person on the other end. We used that approach to measure symptoms using an established measure of prostate cancer symptoms. The EPIC, or the expanded prostate cancer index, is an established measure that assesses urinary, sexual, bowel, and general health.

We programmed that into an automated system and allowed men to interact with it. After that interaction, they could choose through the automated system one of the symptoms that they felt they wanted help with. We then mailed them a tailored newsletter with information about the symptom they had chosen to focus on and what they could do at home. We also included information about when it’s more important to seek specialist care.

We also had a component of the newsletter that focused on coping. Some patients deal with these symptoms for a long time. Whether we can actually improve the symptom or not, we felt it was important to offer coping strategies based on cognitive behavioral therapy.

The intervention consisted of four automated phone call assessments followed by a newsletter over a four-month period.

What did the control group get?

Dr. Hawley: They got one newsletter, which focused on general symptom self-management. Symptoms can be self-managed. Be aware of that. These are things that you can do at home. You can talk to your physician if things get worse. The newsletter wasn’t tailored to a symptom of their choice. It didn’t include the coping strategies based on behavioral therapy approaches.

What did you find?

Dr. Hawley: The overall study was a randomized control trial. We enrolled men from four VAs and randomized them online to one of those two groups. At five months, we evaluated their symptoms using the EPIC, their confidence and their ability to manage symptoms, and then some secondary outcomes related to how they viewed cancer and their outlook. What we found in the overall comparison between intervention and control arm was a slight signal in some of the intervention measures of being better than in the control measures but nothing was statistically significant.

When we did a more detailed analysis we saw a positive effect in the intervention arm in each area that men chose to focus on. That was really exciting to see.

It suggests that this intervention can be useful in helping men improve their symptoms over time. We also found that the patients themselves thought the intervention was extremely positive. We had extremely good participation and experience rates, even in the intervention arm, which did require a fair bit of work with four phone calls over four months. We had really positive reports among the participants at the end of the intervention; they found it useful and helpful.

We even found positive reports in the control arm as well. We think some of this is probably a reflection of the fact that there just is not a lot available for this population. To be offered help, and to identify that there’s a problem and that the VA is interested in trying to help support prostate cancer survivors was genuinely appreciated by all participants, even if they only received the nontailored newsletter.

What are the implications of this study?

Dr. Hawley: An intervention like this shows promise for helping improve symptoms over time if tailored to an area of focus that the patient desires to focus on. We would like to look at this in a bigger sample and match interventions, control and a choice of symptom, which we weren’t able to do in this study.

Interventions like this are very well received in prostate cancer survivors in the VA. Enrollment rates were good. Persistence with the intervention was good. Fidelity to the intervention was good. There’s a need for some kind of program for prostate cancer survivors to help them get through these debilitating symptoms.

There’s always further work to be done. We would love to continue to refine the intervention and then perhaps roll it out to some type of dissemination or implementation study to see if we could continue to see an improvement for these patients.

What do you think are the obstacles to implementing something like this across the entire Veterans Administration?

Dr. Hawley: The obstacles are the same for any system the size of the VA. It’s more of a technology system challenge, I think, which is always there for any health system. I think if it were solved, veterans would use it.

Do you have any final thoughts for patients about self-managing symptoms?

Dr. Hawley: Management of symptoms is possible. Self-management is one way to manage symptoms, and for some better than others. I encourage patients to keep having conversations with their providers if they’re not satisfied with the management that they experience.

Finally, I’d like to acknowledge the critical input of Dr. Ted Skolarus, Section Chief of Urology at the Ann Arbor VA. I would also like to acknowledge the study team in Ann Arbor, as well as the 4 study sites—the VA Ann Arbor Healthcare System, the St. Louis VA Medical Center John Cochran Division, the Louis Stokes VA Medical Center, and the VA Pittsburgh Healthcare System University Drive Division.

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Dr. Arthur Burnett On Erectile Dysfunction + Cancer Treatment

Dr. Arthur Burnett is the Director of both the Basic Science Laboratory in Neurourology and the Sexual Medicine Fellowship Program at Johns Hopkins University in Baltimore, Maryland.

Prostatepedia spoke with him about erectile dysfunction (ED) and prostate cancer treatments.

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Why did you become a doctor?

Dr. Arthur Burnett: I was inspired by seeing other individuals through either the media or just personal contacts who were physicians at the time. I was a young man, perhaps in my teenage years, when I was inspired by the impact the profession allowed a physician to have on people’s lives. I sensed that I had a talent for that sort of thing and certainly had an aptitude for science and medicine as the years went on. That was the groundwork for my continuing on to do the appropriate academic training to become a physician.

Have you ever had any particular patients whose cases changed how you see yourself as a doctor or how you approach the art of medicine?

Dr. Burnett: I think patients, in general, have been reinforcing in many respects. There are certainly patients whose case stories inspire you by their humanness and just by the fact that they connect with you as a person and show compassion and caring themselves. That is what has been inspirational about being a physician.

How common is ED after prostate cancer?

Dr. Burnett: Prostate cancer in and of itself is not necessarily connected with ED; it’s more the treatments unless the cancer really is at a more advanced stage. Advanced prostate cancer can have either local effects because of cancer progression on structures of the pelvis or systemic effects—that is, it progresses and then weakens the person’s body.

Treatments that reflect either local treatments or more systemic, or body-wide, treatments can have a negative impact on one’s sexual function, including erectile physiology or erectile functions. Local treatments include surgery and radiation as conventional interventions. More systemic therapies include various kinds of hormone suppressive agents, or even chemotherapies, that can adversely affect the physiology of the erection and impact how nerves, blood vessels, and hormones interact to bring about an erection response.

Are there any steps a man can take before he starts treatment that might help prevent problems after?

Dr. Burnett: I certainly believe that’s so. I think patients need to be informed about the factors that can adversely affect erectile function. I think patients assume all too often that the physician is responsible for their best health. But patients also need to recognize that their best health status is also key to retaining function in the face of any treatments we can bring.

Being healthier and physically fit— not out of shape, not overweight, not a cigarette smoker—can increase your likelihood of preserving better health in the face of our treatments. Those patients who do not observe these kinds of health habits are setting themselves up to have less reserve function in the face of our treatments.

Not just in terms of ED, but in terms of general recovery?

Dr. Burnett: Absolutely. Even more specifically, because we’re talking about erectile function, those patients who are out of shape, who are smokers, who have adverse health conditions that they may not have control over, are not helping themselves with regard to their erection function as well as to their overall body health.

What could you say to a man who brings up the subject of ED with his doctor and finds that the conversation isn’t as in-depth as he would like? What do you suggest he do? See another doctor? See a specialist in ED?

Dr. Burnett: I think that’s an all-too-often scenario, that sometimes the care provider is neglectful about some of the basic aspects of a person’s health status. As the care provider himself is certainly attentive to his own sexual function, he should be aware of that for the patient. All too often, that’s not done. My advice would be to tell the patient that he should go ahead and be assertive or proactive about asking about these sorts of things and really inquire.

An informed patient, perhaps with this kind of communication I’m sharing, will be empowered to communicate that this is important to him. While he is seeking the best intervention for his cancer management, all aspects need to be put on the table for discussion. Ask that care provider to help address these things. If that care provider is not able to address it, ask him who else can be of service, as part of the care team perhaps, to address these problems or potential problems as they may arise expectedly with interventions.

What treatments are available for men suffering from ED after prostate cancer treatment? Are there some treatments that are more effective after surgery or radiation or hormonal therapy?

Dr. Burnett: We have a host of treatments that are available and can be offered for managing ED in this scenario, as much as for any presentation of ED in our modern times. We’re certainly much better in terms of what we can offer medically than where we were a generation ago, but we still have interventions that largely are addressing the symptom presentation of erection dysfunction; they don’t necessarily correct the erection disorders. They treat the symptomatic presentation of a man saying, “I cannot get an erection, and what do you have to offer?” These interventions, more or less, are used on demand to help him achieve an erection response when needed.

These therapies range from the oral medications that are very effective and are FDA approved, to semi-intrusive interventions brought to the genital area in the form of penile injection therapy or vacuum erection device therapy. We also have penile prosthesis surgery, which obviously is much more invasive. Some patients either prefer this approach or they find that the other options are just ineffective or contraindicated.

We have to understand the patient’s case, his preferences, and the severity of his ED. Certain men who’ve had prostate cancer treatments may have more severe erection dysfunction and may not respond well to oral therapies such as Viagra (sildenafil) and Cialis (tadalafil). That patient may be inclined to move forward with some of these somewhat more intrusive, or even invasive, surgical options if needed.

Do you have any advice for men who either are worried about ED before treatment or who are already suffering from ED after treatment?

Dr. Burnett: The sobering truth is that some of the interventions for managing prostate cancer can have adverse effects on your sexual function. At the same time, understand that we have interventions to address ED. Fear of losing one’s erections hopefully should not lead one to avoid proper treatment.

As one patient quipped to me once in the past: “The ultimate form of ED is death.” Not addressing your cancer and not being around for your loved ones is certainly not the best option to pursue. You have to be attentive to addressing your disease but also recognize that we can address your ED or other sexual dysfunctions. Know that these interventions can be sought amidst the treatment for the prostate cancer.

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Switching from One Chemo Drug to Another

Dr. Emmanuel Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

Prostatepedia spoke with him recently about his work on the benefit of switching men from Taxotere (docetaxel) to Jevtana (cabazitaxel)— or vice versa—if his PSA doesn’t go down by 30% in the first twelve weeks of treatment.

You’ve published a paper on switching patients from Taxotere (docetaxel) to Jevtana (cabazitaxel) and vice versa. What is the thinking behind switching chemotherapeutic agents? Why would you want to switch agents earlier as opposed to when the first chemotherapy drug stops working?

Dr. Emmanuel Antonarakis: The motivation behind this paper was that the FDA-approved recommended dosing schedule for both Taxotere (docetaxel) and Jevtana (cabazitaxel) is a course of ten doses, given three weeks apart. When patients begin FDA-approved Taxotere (docetaxel) or FDA approved Jevtana (cabazitaxel), they’re often told by their oncologists that they should expect to receive this chemotherapy once every three weeks for up to ten doses. A patient may not receive ten doses or might stop the therapy before he reaches ten doses because he cannot tolerate the therapy and has unmanageable side effects, or his cancer begins to progress before he ever get to dose number ten. If his PSA begins to increase again at dose six or seven or the tumors begin to grow again, his oncologist might ask him to stop chemotherapy.

We then wondered whether the ten doses was a reasonable time to wait or whether there could be an early indicator, or an early sign, of therapy resistance or therapy futility without having to go through six, seven, eight, nine or ten doses.

The idea that we had was to test an early intermediate marker of sensitivity or resistance to the chemotherapy. The best marker of early sensitivity or resistance that we could think of was whether or not a patient had a 30% PSA drop within the first four cycles of therapy. As you recall, if the therapy is given once every three weeks, four cycles basically means 12 weeks, which roughly equates to about three months.

The decision to use this intermediate endpoint was not arbitrary; it was based on some large retrospective meta-analyses that have shown that the strongest predictor of overall survival in patients receiving both Taxotere (docetaxel) and also separately Jevtana (cabazitaxel) was whether or not patients had a 30% PSA reduction after 12 weeks.

Patients who do achieve at least a 30% or greater reduction in the first 12 weeks have a survival that’s longer than patients who don’t achieve that endpoint. We thought, well if this endpoint is strongly correlated to survival, perhaps we can use it as a decision point. If after four doses of therapy or 12 weeks of therapy a patient don’t achieve a 30% reduction in PSA perhaps we should switch him to the other chemotherapy, rather than sticking with it and just waiting for either the toxicity to develop or the PSA or the radiographic disease to progress. That was the hypothesis.

We designed a relatively small study of about 63 patients. We used a 2:1 randomization so they were twice as likely to get Taxotere (docetaxel) compared to Jevtana (cabazitaxel). Approximately 41 patients got Taxotere (docetaxel) first. The other 22 patients, got Jevtana (cabazitaxel) first. Irrespective of which arm they were randomized to, they received the first four doses of chemotherapy in 12 weeks. We checked their PSA every three weeks.

At the end of the fourth dose, if the PSA level had dropped by 30% or more, the patients would continue on the same therapy on which they started. However, if patients did not achieve a 30% reduction or more, they would be switched to the other chemotherapeutic agent.

If a patient had a 25% reduction, we would switch him to the other agent because we thought that was not good enough. If someone received Taxotere (docetaxel), and their PSA dropped by 25%, even though it dropped by 25%, it did not meet that 30% threshold so they would then switch for the fifth dose to receive Jevtana (cabazitaxel) for the remainder of their chemotherapy. The inverse was also true. If the patient received Jevtana (cabazitaxel) first and also did not get a 30% reduction by week 12, in other words four doses, they would also switch to receive Taxotere (docetaxel). The interesting thing that we found in both treatment arms was that the chance that a patient had a favorable PSA response, which was defined as a 50% or more decrease, was higher than we had seen in historical trials using each drug by itself without switching. To put some numbers on that, we found that there was about a 54% chance that patients would have a 50% reduction in PSA if they had to the opportunity to switch from one chemotherapy to the other, compared to about a 45% chance of PSA reduction in the historical data where patients did not switch.

Did it matter if they got Jevtana (cabazitaxel) first or Taxotere (docetaxel) first?

Dr. Antonarakis: What we found out is a bit of a paradox: people could benefit from the switch in both down over time and the availability of non-chemotherapy agents is going up. A lot of these patients who may not have a 30% PSA reduction with one chemotherapy, might choose to do another hormone therapy, a radiopharmaceutical drug like Xofigo (radium-223), immunotherapy like Provenge (sipuleucel-T), or even a PD-1 inhibitor, or potentially a PARP inhibitor.

It might be difficult to convince a patient who has just failed one chemotherapy after four doses to go immediately to a second chemotherapy. I’m not 100% sure what the future will hold. I also don’t think this is a trial that we could have conducted today.

What would you say to a man reading it? That this is worth talking to his oncologist about or is this just something interesting for him to know about?

Dr. Antonarakis: Patients who are beginning their first chemotherapy should discuss this trial with their oncologist, and together with the oncologist decide in a joint fashion whether switching from one chemotherapy agent to another after four doses might be right for him, especially if he’s tolerating the chemotherapy well. If he tolerates the drug and his PSA has not dropped by 30% or is continuing to increase, then in my opinion rather than continue with the potentially futile therapy, a patient and his oncologist may wish to consider using this trial to guide or justify their choice of switching drugs earlier rather than later. directions. That was fascinating to us because, as we all know

Jevtana (cabazitaxel) was specifically approved by the FDA as a second-line curative therapy only indicated in men who have failed Taxotere (docetaxel) first. Based on that reasoning, one might expect Jevtana (cabazitaxel) to work better after Taxotere (docetaxel) but not Taxotere (docetaxel) after Jevtana (cabazitaxel).

This is not what we found.

We found that in both directions, both from the Taxotere (docetaxel) to Jevtana (cabazitaxel) switch, but also in the Jevtana (cabazitaxel) to Taxotere (docetaxel) switch, there was a significant amount of patients, approximately half, who were salvaged by the crossover therapy. By salvaged, I mean those who did not achieve a 30% PSA reduction with the first drug but did achieve a PSA reduction of 50% or more after crossing over to the second drug.

As I mentioned before, this occurred in both directions, both in patients receiving Jevtana (cabazitaxel) after Taxotere (docetaxel) and Taxotere (docetaxel) after Jevtana (cabazitaxel).

Are the side effects of Jevtana (cabazitaxel) a little bit easier to take than the side effects of Taxotere (docetaxel)?

Dr. Antonarakis: Interestingly, the side effects of Jevtana (cabazitaxel) in the published literature indeed appear to be slightly better. In this particular trial, which was very small obviously, they seemed comparable. In other words, we did not see any appreciable difference between the Taxotere (docetaxel) and the Jevtana (cabazitaxel) overall in terms of side effects. Taxotere (docetaxel) had a little bit more neuropathy nerve damage, which Jevtana (cabazitaxel) did not do. On the other hand, Jevtana (cabazitaxel) had a little bit more neutropenia, while the Taxotere (docetaxel) did not.

I would say that when patients receive these agents in a first-line setting, in other words, when they had not received another chemotherapy previously, their side effects were fairly comparable. I don’t think there was a clear signal in terms of one drug being clearly safer than the other.

Does it matter which you get first?

Dr. Antonarakis: From a side effect perspective, they’re both fairly equivalent in terms of tolerability, with slight differences in neutropenia, which is worse with Jevtana (cabazitaxel) and neuropathy, which is worse with Taxotere (docetaxel).

What is the next step? Are you going to run a similar trial with more patients?

Dr. Antonarakis: One question that arises is if this small randomized trial is enough to change practice. Should a community oncologist or urologist give Taxotere (docetaxel) for four doses and wait to see if the patient’s PSA drops by 30% or more? If it doesn’t drop to 30% or more, should he to switch to Jevtana (cabazitaxel)?

I have to admit that this is something that I have done in my practice a few times, but I really don’t believe that this is ready for clinical practice yet. Yes, in this trial, we showed that the PSA response rates could potentially be improved by this switch strategy. What we did not demonstrate was whether this improves overall survival.

The ultimate question is does switching chemotherapy agents after four doses improve survival, compared to just waiting until we see radiographic or clinical progression to switch agents. That would, as you mentioned, require a larger Phase III randomized study. The idea of study design would be to randomize patients to the switch strategy versus no-switch. We would randomize one group of patients to receive chemotherapy and switch if their PSA did not drop by 30%. The second group of patients would start chemotherapy but would not be given the opportunity to switch, even if their PSA did not drop by 30% or more. The randomization would not necessarily be the randomization to the chemotherapy, but would be randomization to a switch strategy versus a stick-with the first-chemotherapy strategy.

Sanofi, which makes both Jevtana (cabazitaxel) and Taxotere (docetaxel), have not been eager eager to respond to such a study because of financial considerations and also because the patent life of Taxotere (docetaxel) is over and the patent life of Jevtana (cabazitaxel) will be expiring soon.

Unfortunately, we might be left with a Phase II study that may, potentially, not translate into a Phase III study. I think individual patients and individual oncologists may look at these data and might be convinced that some patients might potentially benefit from a switch strategy, especially those who did not have any degree of PSA reduction after four cycles.

An added complexity is that the popularity of chemotherapy is going down over time and the availability of non-chemotherapy agents is going up. A lot of these patients who may not have a 30% PSA reduction with one chemotherapy, might choose to do another hormone therapy, a radiopharmaceutical drug like Xofigo (radium-223), immunotherapy like Provenge (sipuleucel-T), or even a PD-1 inhibitor, or potentially a PARP inhibitor.

It might be difficult to convince a patient who has just failed one chemotherapy after four doses to go immediately to a second chemotherapy. I’m not 100% sure what the future will hold. I also don’t think this is a trial that we could have conducted today.

What would you say to a man reading it? That this is worth talking to his oncologist about or is this just something interesting for him to know about?

Dr. Antonarakis: Patients who are beginning their first chemotherapy should discuss this trial with their oncologist, and together with the oncologist decide in a joint fashion whether switching from one chemotherapy agent to another after four doses might be right for him, especially if he’s tolerating the chemotherapy well. If he tolerates the drug and his PSA has not dropped by 30% or is continuing to increase, then in my opinion rather than continue with the potentially futile therapy, a patient and his oncologist may wish to consider using this trial to guide or justify their choice of switching drugs earlier rather than later.

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Clinical Trial: Intravenous Vitamin C + Taxotere (Docetaxel)

Dr. Channing Paller, an Assistant Professor of Oncology at Johns Hopkins University School of Medicine, focuses on translational research and clinical trials of developmental therapeutics in prostate and other solid tumors.

She is keenly interested in the rigorous evaluation of natural products in cancer treatment.

Prostatepedia spoke to her about her Prostate Cancer Foundation instigated and Marcus Foundation funded clinical trial on combining intravenous Vitamin C with Taxotere (docetaxel).

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Dr. Channing Paller: One of my interests is studying natural products that people take as dietary supplements. We don’t know whether they work or whether they cause harm, so I test them. Several of my clinical trials study these compounds rigorously in a placebo-controlled fashion, as we would with any cancer treatment.

I knew about a recent randomized study of high dose intravenous ascorbic acid (vitamin C) in ovarian cancer patients, which showed that ascorbic acid treatment combined with standard chemotherapy reduced toxicities from the chemotherapy and also trended towards improved overall survival. Vitamin C enabled the patients to receive more cycles of chemotherapy, and that was associated with longer overall survival.

In response to the findings in ovarian cancer, the Prostate Cancer Foundation sent out a request for proposals for early stage research on vitamin C’s role in treating prostate cancer. We decided to initiate a large (60 patient) placebo-controlled trial with co-primary endpoints of quality of life and cancer response to the combination of intravenous (IV) vitamin C and chemotherapy. We are extremely grateful to the Marcus Foundation for supporting the trial.

We chose Taxotere (docetaxel) because it was first line and an easy place to start to answer the question. Jevtana (cabazitaxel) would have worked just as well.

What can patients expect to happen during the trial?

Dr. Paller: We are conducting a randomized placebo-controlled Phase II trial of standard-of-care Taxotere (docetaxel) for metastatic castrate resistant prostate cancer with either ascorbic acid or placebo, which is electrolytes and hydration, given twice a week in between the cycles of chemotherapy every three weeks. Some people say that this is too big a commitment, so they get to take breaks if needed. They can miss a session or two here or there. They can even take two weeks’ break, if needed. We’re trying to help people live better, not chain them to the clinic.

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