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Clinical Trial: Exercise For Metabolic Dysregulation After Prostate Cancer

Dr. Christina Dieli-Conwright is an Assistant Professor of Research in the University of Southern California’s Division of Biokinesiology and Physical Therapy.

She’s particularly interested in understanding physiologic mechanisms and designing exercise interventions for cancer patients.

Prostatepedia spoke with her about her clinical trial.

What is the thinking behind your clinical trial?

Dr. Dieli-Conwright: This study spawned from my interest in the side effects and changes that patients were experiencing as they underwent treatment. For some of the more prevalent cancers like breast, prostate, and colorectal cancer, there is literature to provide evidence that individuals are experiencing what I broadly call metabolic dysregulation, which encompasses things like gaining weight, insulin resistance, elevated inflammation, and elevated blood pressure.

Whether they have metabolic dysregulation before diagnosis or whether it develops during treatment, they are at higher risk for experiencing diseases like heart disease, diabetes, and obesity. In prostate cancer in particular, when men are prescribed androgen deprivation therapy, there are side effects to that therapy that lead to metabolic dysregulation.

If you look at individuals who exercise who have not had cancer, we know that exercise can successfully offset metabolic dysregulation. It can improve insulin resistance. It can reduce body composition changes, etc. We wanted to apply exercise to this particular population so that these patients may also experience the benefits of exercise.

If a man who’s reading this ends up participating, what can he expect to happen step by step?

Dr. Dieli-Conwright: This is a randomized controlled trial. Individuals will be randomized to either the exercise group, and receive a 16-week, 3 times a week exercise program immediately, or the delayed controlled group. Everybody eventually gets the exercise program, but the “exercise group” gets it first. The delayed controlled group gets the program 16 weeks later.

We ask them to come to our facility, which is here at University of Southern California, to exercise. We pair them one-on-one with a certified cancer exercise trainer. They perform both aerobic and resistance exercises for about one hour every time they come. They perform the exercises in an interval circuit training, high-intensity manner. We’ve done that so that we can really challenge the metabolic systems for energy balance that have been shown to be more effective at targeting metabolic dysregulation as to opposed, for instance, just walking on a treadmill for 60 minutes.

We do a number of tests at the beginning, middle, and end of the 16 weeks. Those tests involve a blood draw so that we can measure glucose and insulin, as well as triglycerides, cholesterol, and markers of inflammation. We measure blood pressure, waist circumference, and body composition so how much muscle and fat the patients have. We also measure bone density. We do a battery of what we call physical function tests: how fast can the man climb upstairs? How fast can he walk six meters? How many times he can sit to stand? We do what we call a cardiopulmonary exercise test to test their maximal fitness and we do a series of strength tests to see how strong their muscles are.

We give them a packet of questionnaires about quality of life, fatigue, depression, and other cancer-related symptoms.

We are measuring the whole gamut of health outcomes even though our main focus is on insulin resistance and metabolic dysregulation simply because that’s the precursor to diabetes and heart disease.

We retest those measures at Week 8 and Week 16. We do follow participants after the 16-week period is over. Regardless of what group they were in, we check on them four months later to see how they’re doing.

Are there any specific eligibility criteria that you want to call attention to?

Dr. Dieli-Conwright: The main thing is that they’re over the age of 18 and that they have been on androgen deprivation therapy for the previous 16 weeks. That’s just so that we can allow the medication to stabilize the hormones. We also look to see whether or not they have been exercising regularly. If they are highly trained from a fitness perspective, then they are not eligible, so we do actually look for people who are relatively sedentary who are not participating in a structured exercise program already. We do that because we are trying to reach out to people who may be at a higher need for these interventions.

Do you care if a man has had surgery or radiation for prostate cancer?

Dr. Dieli-Conwright: No, we do not, as long as the surgery or radiation is completed. If they’re actively on radiation or actively on chemotherapy we would wait until that treatment is done. Often we get calls from patients who are very enthusiastic and eligible, but then tell us they’re starting radiation next week. We have to wait until that treatment is over and they’re cleared by their oncologist for exercise.

Is there anything else you’d like patients to know either about this trial in particular or about exercise for cancer patients in general?

Dr. Dieli-Conwright: We’ve had a number of patients participate already. It’s been very successful. It’s safe. It’s feasible. Everybody’s enjoyed the program. We’ve had very high compliance to date—almost 100%.

But it’s a strong time requirement—3 times a week for 16 weeks—so I would just say that if anybody is interested, even if it’s just a small amount, to contact us. We have very flexible scheduling times and can accommodate exercise almost 24/7. We have a large staff and a number of trainers who are eager to help. We try not to turn anybody away because of scheduling and try to work around work schedules if that’s a concern.

We would love to take more patients.

Subscribe or download our February issue to read more about this trial.

 


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Clinical Trial: Cardiovascular + Lifestyle Interventions For Prostate Cancer

Dr. Darryl Leong is a cardiologist and Assistant Professor in Medicine at Canada’s McMaster University. He’s particularly interested in the prevention, identification, and management of cardiovascular disease in those with complex diseases. He is also leading the development of a clinical research program for the evaluation and treatment of cardiovascular disease in patients with cancer at Juravinski Hospital.

Prostatepedia spoke with him about the RADICAL-PC clinical trial, which is a randomized intervention of cardiovascular and lifestyle risk factors in prostate cancer patients.

Why did you become a doctor?

Dr. Leong: Within a generation, our society has added 20 years of lifespan. This is consistent whether it’s in wealthy countries like the United States and Canada or in developing countries. We have been really successful in a short time at prolonging people’s lives, and so the science that went behind that was really interesting to me.

When you look at the history of the world, in hundreds of millions of years, I don’t think any species has seen such a lengthening in their life expectancy in such a short period of time. I hope to build on that with our research and help to improve not just life expectancy but also people’s quality of life.

Would you tell us about the thinking behind your clinical trial?

We read some papers that came from the United States and Europe that suggest two things. First, men with prostate cancer seem to have quite a high risk of developing cardiovascular disease, heart attacks, and strokes during the course of their follow-up.

Second, there might be a link between (hormonal) androgen deprivation therapy (ADT) and the occurrence of these sorts of cardiovascular events. So, our thoughts turned to cardiovascular disease and prostate cancer. We proposed a study to the charitable organization Prostate Cancer Canada that supports research to understand why this link exists. We were fortunate enough that Prostate Cancer Canada agreed to fund our proposal, and so that’s how we came to study over 2,000 men with prostate cancer in Canada.

We’d like to expand this research internationally because we know that what happens in one country may not necessarily reflect what’s happening in another country. We have ongoing efforts to try to expand.

What will you be doing in the study? Should a man reading elect to participate what can he expect to happen?

Dr. Leong: One level of involvement, which we would ask of anyone who is interested in being involved in the study, is that we collect information about you, and we follow up with you over time. We hope that period of time will be at least another three years. If we are successful in getting more funding, we’d like to make it long term.

At the beginning, we collect information about health, cardiovascular disease, and risk factors that people have today, as well as information about physical characteristics, muscle strength, fitness, and a range of factors like that. Then we follow up with folks over the years to see if people develop cardiovascular disease or heart attacks and strokes and what predisposes people to these complications.

In addition to monitoring for cardiovascular disease, and because this is an opportunity to see whether we can make a difference to the cardiovascular disease rates in men with prostate cancer, we decided that people within the RADICAL-PC who give consent would be randomly allocated into one of two groups.

One group would receive usual care. Their medical care would not be changed at all. They would continue to see their general practitioner and their cancer specialist. The other group would be allocated to see a cardiologist on top of their usual care. The cardiologist would be instructed to provide very focused interventions to reduce cardiovascular risk. So, this is a trial built into the RADICAL-PC trial to see whether or not we can reduce cardiovascular events in these men.

Are there any specific eligibility criteria?

Dr. Leong: The criteria are simple. All we ask is that they’re over 45 years of age, and that either their prostate cancer has been diagnosed within the past year, or they’ve started hormonal therapy within the past six months or have a plan to start it in the next month.

To learn more about this trial, read our February issue.


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Who Is Dr. James Gulley?

Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.

Join us to read Dr. Gulley’s comments about prostate cancer vaccine clinical trials.

Why did you become a doctor?

Dr. James Gulley: I think this has to go back to my high school biology teacher. His name was Vernon McNeilus. He was a retired orthopedic surgeon who just found a way to instill inspiration and that sense of curiosity about life. He drove us to really be excited and interested in science and in biology in particular. I had decided that I wanted to do something in science or medicine, but there was no way that I was going to go spend all that time to become a doctor. I’d been in school long enough. One of my friends decided he was going to go into medicine. I said if he can do it, I can certainly do it.

Then it actually evolved even further than that because during my stint in college I got the opportunity to do a summer research program. I decided I liked research, so I applied to MD/PhD programs and got accepted into two. I decided to go to Loma Linda.

What is it about medicine that keeps you interested?

Dr. Gulley: I think the thing that really drives me is how fascinating it is to understand how things work. I’ve always been fascinated in what makes things work. As a little boy I would take things apart trying to figure out what made them work and then put them back together again. If something was broken in the house, my mom would just give it to me and I’d tinker with it and get it to work again.

To me, the ultimate machine is the human body and one serious puzzle is to figure out ways to bring back health from sickness. Not just a puzzle for curiosity’s sake, but because of the effect that cancer can have on families, to uncover ways to effectively treat cancer. I think it’s truly something that I have seen patients who were close to death who have had remarkable and prolonged clinical responses. That, to me, begs the question that if we can do it for some people, then why can’t we do it for all people? That is what I am passionate about.

Are there any patients you’ve had over the years whose cases changed how you see your own role or the art of medicine?

Dr. Gulley: I’ve had several patients that have been exceptional responders; that really has changed how I view things. One of my more recent exceptional responses from this past year is a retired army surgeon who has advanced metastatic castrate resistant prostate cancer. I have been treating him since 2005. He was initially treated with radical prostatectomy. It turned out that he had a high Gleason disease. He had radiation therapy, but he had recurrence of his disease, unfortunately. He was treated with hormonal therapy, with chemotherapy, with Provenge (sipuleucel-T), and Xtandi (enzalutamide).

He came to me last year having had multiple therapies including other experimental immunotherapies. He was clearly not doing well. His PSA was going up very quickly with a doubling time of less than a month. His symptoms were getting substantially worse. He articulated to me that even going to church every week was becoming difficult: one week he was able to sing the songs and the next week he was too tired to sing. Then the next week he was almost too tired to stand up.

We were able to enroll him in a study combining a vaccine with checkpoint inhibition. When we gave him that combination, his PSA dropped dramatically. It has now gone to undetectable. His lesion in his bladder, which was causing local symptoms so that he had to have a chronic indwelling Foley catheter, shrunk away. When we biopsied it there was no evidence of tumor there. He has some lesions that are seen on bone scan, but I’m not sure if that represents viable tumor or not.

He is now over a year out from when he started treatment. His energy level hasn’t been better since before he was diagnosed. He is out doing everything he wants to do. To me that is amazing. It is amazing we can see responses like that.

From a scientific standpoint, of course, I was stunned to see this and wondered could he have micro-satellite instability that leads to lots of mutations. It turned out that he had micro-satellite instability in his cancer, suggesting that the immune system was able to see his cancer much more readily, so all we need to do is allow those immune system cells to be functional with the Opdivo (nivolumab).

We also had one other patient that didn’t have micro-satellite instability with this combination who also had a really nice 90% or so drop in his PSA. It’s not undetectable, but he hasn’t had the immune checkpoint inhibition for well over a year now. He’s just on vaccine alone because he had some bleeding in his urine from the checkpoint inhibitor. To me, having responses like that changes my outlook. It says the immune system, even in patients with prostate cancer, can be harnessed to attack the tumor. We just have to figure out ways that we can make this more applicable to all patients.


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Merel Nissenberg On Non-Metastatic Castrate-Resistant Prostate Cancer

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Non-metastatic castrate-resistant prostate cancer (nmCRPC) is a clinical state in which a patient on androgen-deprivation therapy (ADT) has a rising PSA but there are no radiological findings of metastases on CT or bone scan. Management of nmCRPC is evolving quickly, but it is a field in which there have been recent drug approvals amid a strong and growing interest in keeping patients metastasis-free for as long as possible. About 10-20% of prostate cancer cases are castrate-resistant, but nearly 16% of those castrate-resistant patients have no evidence of metastatic disease at the time their castrate-resistance is diagnosed.

Not all nmCRPC disease is the same. For some patients, observation is a viable option; for other patients—especially those with a PSA doubling time of less than or equal to 10 months—randomized Phase III clinical trials have shown a benefit and an increase in metastasis-free survival with the use of Xtandi (enzalutamide) or Erleada (apalutamide). New imaging techniques on the horizon may also be very helpful in assessing nmCRPC patients.

In February 2018, the FDA approved Erleada (apalutamide) for nmCRPC patients and was the first such FDA-approved treatment for this subset of patients—i.e. those who are no longer responding to ADT but who have no radiological evidence of metastasis. The Erleada (apalutamide) approval followed the release of the results of SPARTAN, a randomized clinical trial of 1,207 patients in which patients received either Erleada (apalutamide) or placebo, discussed at the American Society of Clinical Oncology Genitourinary (ASCO GU) Meeting in February of this year. All of the patients who were enrolled also received hormone therapy. The exciting results showed that the median metastasis-free survival for patients in the Erleada (apalutamide) arm was 40.5 months versus 16.2 months for the placebo group. Both applications received priority review from the FDA due to the exciting results with clear benefit for nmCRPC patients.

The results of another trial known as the PROSPER Trial were also first presented at the 2018 ASCO GU Meeting. In PROSPER, with 1,401 participants, men with nonmetastatic castrate-resistant prostate cancer (nmCRPC) were given either Xtandi (enzalutamide) or placebo; these were men in whom the PSA doubling time was 10 months or less, but, again, there was no evidence of disease seen by CT or bone scan or by MRI. Those nmCRPC patients receiving Xtandi (enzalutamide) had delayed time to metastatic disease or death (whichever occurred first) by a median of 21.9 months, versus placebo (36.6 months compared to 14.7 months), signifying a 71% reduction of the risk for metastasis or death. Another result: Xtandi (enzalutamide) delayed the time until men needed additional cancer treatment, compared to placebo (a median of 39.6 months compared to 17.7 months). On July 13, 2018 the FDA approved Xtandi (enzalutamide) for the treatment of nmCRPC patients.

This means that men with nonmetastatic castrate-resistant prostate cancer now have two choices that they did not have before, when they would simply be continued on ADT. We still do not know, however, if the added Xtandi (enzalutamide) or Erleada (apalutamide) will increase overall survival for these patients.

[This article deals only with nonmetastatic CRPC. There have also been various trials conducted in the metastatic space, and there are other trials currently underway or planned involving anti-androgens such as Zytiga (abiraterone), including some in combinations with other types of therapy, dealing with metastatic disease (mCRPC patients). One of the trials looking at the metastatic disease space is the PEACE1 Trial, which is looking at the benefit of Taxotere (docetaxel) plus ADT, with or without Zytiga (abiraterone) and prednisone, and with or without radiotherapy. This trial is expected to conclude in October 2018 and may help answer the question of whether it is of benefit to patients to add Zytiga (abiraterone acetate) to Taxotere (docetaxel) in metastatic disease that is still castrate-sensitive. The Phase III STAMPEDE Trial showed that adding Zytiga (abiraterone/ prednisone) to standard ADT lowered the relative risk of death by 37% and improved progression-free survival by 71%, versus ADT alone. The CHAARTED Trial looked at Taxotere (docetaxel) plus ADT or ADT alone in patients with metastatic, castrate-sensitive disease, resulting in a greater median survival in the ADT + Taxotere (docetaxel) arm (57.6 months versus 44.0 months with ADT alone).]

Learn more details about these drugs by viewing the Evidence Report from Institute for Clinical and Economic Review (ICER). ICER also held a public hearing on the topic on September 13, 2018 in Chicago.

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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.

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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).