Chemotherapy, Xtandi, and Zytiga

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

Prostatepedia spoke with her recently about chemotherapy, Xtandi (enzalutamide), and Zytiga (abiraterone) for prostate cancer.

Why did you become a doctor?

Dr. Graff: Even as a child, I wanted to become a doctor, so my whole life I thought about it. Then I went to college, I fell in love with science, and I thought I would get a job somewhere working in a lab.

During college, I volunteered for a hospice, and I realized how much I love patients, how special people are, and how people with cancer are among the strongest people. I was drawn to work with them, and also, my scientific side could still be engaged in research.

Have you had any patients over the years who stand out in your mind as having either changed how you see your own role as a doctor or how you view the art of medicine in general?

Dr. Graff: I’ve had multiple patients who’ve meant a lot to me over the years. Someone I met in hospice stands out. The first time I met him, he said, “I know that I’m 80. You look at me, and what you don’t realize is that I want to live just as much as you do.” He had emphysema and was dying, but the drive to live can stay so strong, even at 80. Your body’s not even working that well anymore, and you’re suffering. Still, just this drive to stay alive is important. I’ve kept that in mind since then.

On the other hand, I’ve had some patients who say that years don’t matter—it’s quality of life. I can appreciate both sides. When I talk to patients, even those who say they want to live forever, I tell them that what we want to do is help them live as long as possible while maintaining a quality of life that they can enjoy.

I guess each person falls somewhere along that spectrum.

Dr. Graff: Exactly. As a doctor, you really just have to educate people, and tell them, “I know you want to live and that you think it’s a good idea to get surgery, even though there’s a 50% chance you could die during surgery or whatnot. But what are your real goals, and how can we help you reach them?” We want to move the focus of the conversation a little bit.

Can you give us a brief overview of how and when chemo is used for prostate cancer. I know it’s different from how and when chemo is used in other cancers.

Dr. Graff: In prostate cancer, there are a couple of settings where chemotherapy is used. We’ve been using the drug Taxotere (docetaxel) for 15 years now. It used to be something we gave at the very end of the disease course, when the hormone shots stopped working, but as of 2015, we use it early in the disease also.

Chemo has a bad rap in some ways. It’s thought to be something you should avoid at all costs, but what people don’t realize is that, when symptoms of the cancer (such as bone pain) get bad, chemo can help. The type of chemo we use in prostate cancer is not as toxic as we do for other cancers. We just use one drug. It doesn’t cause a lot of nausea and vomiting, which is a lot of patients’ worst nightmare. We use it in early and late settings, and I don’t think anything’s going to replace it. Even though we have other drugs now, we run out of hormonal options, and chemo’s a decent option.

When and how are Zytiga (abiraterone) and Xtandi (enzalutamide) used in prostate cancer?

Dr. Graff: Zytiga (abiraterone) and Xtandi (enzalutamide) are similar to chemo in that, initially, they were used at the very end of the disease. Now they can be used up front when people are diagnosed with metastatic prostate cancer, so it depends.

Most people get some mileage out of one or the other, but there is a large degree of cross-resistance between the two. It’s not likely that people would get good cancer response out of both of them. It’s going to be interesting to see what happens to Xtandi (enzalutamide) now that there are other drugs that target the same pathway.

What is androgen-receptor splice variant 7 messenger RNA (AR-V7), and what is its role in resistance to Zytiga (abiraterone) and/or Xtandi (enzalutamide)?

Dr. Graff: The androgen receptor has several domains, and one of them is the ligand-binding domain, which is very important. As this androgen receptor floats around in the cell, the androgens (male hormones) bind to that ligand-binding domain, and so does Xtandi (enzalutamide) for that matter. Cancer cells can lose that part of the androgen receptor, then lose their dependence on the androgens that are circulating and lose the target for Xtandi (enzalutamide). The AR-V7 splice variant can predict resistance to both Zytiga (abiraterone) and Xtandi (enzalutamide), and it might be a reason why there’s cross-resistance between them.

What role does chemotherapy play in this resistance to Zytiga (abiraterone) and/ or Xtandi (enzalutamide) that we see?

Dr. Graff: Fortunately, chemotherapy is still active in people whose cancers are resistant to Zytiga (abiraterone) and Xtandi (enzalutamide), so it still plays an important role. It can be very useful when people have prostate cancer-related symptoms.

We use chemo early on in metastatic disease, right after diagnosis. There are three studies presented in the past year in which they use chemo followed by Xtandi (enzalutamide) or a drug like it. It might be more effective in combination with those other drugs. We’re trying to learn still.

Can chemo reverse resistance to Zytiga (abiraterone) and/or Xtandi (enzalutamide), or does it play any role in that scenario?

Dr. Graff: I don’t know if it can reverse it. I have seen data showing that, if you’re on Xtandi (enzalutamide) and the cancer cells become resistant to that, then if you put a patient on chemo, some of those cells that aren’t resistant to Xtandi (enzalutamide) might come back, and it might be reasonable to re-treat it then. That’s not carved in stone.

Is it being explored in any clinical trials that you know?

Dr. Graff: I hope so. I don’t know which trials those would be.

What about the side effects of these various agents?

Dr. Graff: It’s complicated. Chemotherapy can cause some low blood counts and a risk of neutropenic fever, but then it has other side effects, like neuropathy in the hands and feet, that don’t just reverse automatically. There is also some tear-duct scarring and watery eyes. These might get a little better off the chemo, but they could be permanent side effects for the patients.

This type of chemo doesn’t hurt the kidneys, you need good liver function to get it, and it doesn’t seem to cause hypertension. In those ways, chemo is a good option for elderly men with prostate cancer.

Zytiga (abiraterone) can cause mineralocorticoid excess, which means the adrenal glands aren’t functioning normally. You could get too many of one type of hormone that causes high sodium and low potassium. Zytiga (abiraterone) can also irritate the liver, so we’re careful to watch for the liver function. It can also exacerbate the hormonal side effects of castration.

Xtandi (enzalutamide) is known to cause profound fatigue, which was its dose-limiting toxicity. Of course, it’s linked to seizures, but in people without a history of seizures, that’s pretty unusual. And just like Zytiga (abiraterone), it can cause hypertension. Management of blood pressure and cognitive decline is critical. People have reported that they feel a bit foggier on Xtandi (enzalutamide), and they have also reported increased falls, especially in the elderly. Once you’re off Xtandi (enzalutamide), some of those things will reverse, but it’s possible that being on Zytiga (abiraterone) and Xtandi (enzalutamide) could result in muscle mass loss or other things that won’t recover off those treatments.

What would you suggest to manage those side effects?

Dr. Graff: Exercise is critical for any prostate cancer patient. The drugs we use—even just the initial hormone therapy of turning off the testicles —lead to so many side effects like thin bones, muscle loss, weight gain, and all those things can be mitigated with some exercise. They won’t be taken away, but they could at least be improved. That exercise should continue on the other drugs.

It’s really hard to exercise when you’re on these drugs because you’ve got more fatigue. A lot of patients with prostate cancer have arthritis or some barrier to exercise that makes it difficult for them, but as much exercise as possible is important.

I guess any exercise is better than none, right?

Dr. Graff: Exactly.

Do you have any further thoughts about chemo, Zytiga (abiraterone), or Xtandi (enzalutamide) that you think patients should know about or might not be aware of?

Dr. Graff: They’ve been out for a while now. Any prostate cancer patient starts with a blank slate and has to learn all this stuff with the help of the provider. Think about your goals in life and if these drugs are going to interfere with those. If your goal is to continue working as an architect or something that requires a lot of thought and careful planning, maybe Xtandi (enzalutamide) is not the best choice, and maybe Zytiga (abiraterone) is a better choice.

Some of these drugs are contraindicated in certain patients. A patient with bad heart function, like congestive heart failure or something, should not be on Zytiga (abiraterone), and a patient with a history of seizures should not be on Xtandi (enzalutamide). A lot of thought should go into picking these. The first drug you use is likely to be the most effective, and then as you go down the line, they become less effective.

As a prostate cancer patient, you have several options now; it’s not just chemo or nothing once the prostate cancer becomes resistant to the androgen blockade. Consider lifestyle when making a choice.

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Dr. Tanya Dorff On Chemotherapy For Prostate Cancer

Dr. Tanya Dorff is a medical oncologist who serves as associate clinical professor in the Department of Medical Oncology & Therapeutics Research and the Head of the Genitourinary Cancers Program at City of Hope, a research and treatment center for cancer based in Duarte, California.

Dr. Dorff’s research interests in prostate cancer range from clinical trials in PSA-recurrent prostate cancer to the role of fasting in chemotherapy tolerability to CAR T cells that are primed to target prostate cancer tissue.

She leads one of the largest clinical trial portfolios in genitourinary cancers.

Dr. Dorff spoke with Prostatepedia about chemotherapy for prostate cancer.

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Why did you become a doctor?

Dr. Tanya Dorff: When I was around three years old, I decided that what I wanted to do with my life was help people. And being a concrete thinker as a three-year-old, I felt like being a doctor was the only way to do that.

Have you had any patients over the years who have changed how you view the art of medicine or how you view your own role?

Dr. Dorff: There are so many who have influenced me. My mom had a rare form of leukemia when I was in college. It was uniformly fatal. But they had recently developed a new treatment with the discovery of a specific translocation of the retinoic acid receptor for acute promyelocytic leukemia (APL). All-trans retinoic acid was developed, and she received it as experimental (at the time) through compassionate access. She was cured, and she’s still alive today. That influences how I feel about clinical trials and translational science. If we hadn’t understood that biology, we couldn’t have designed the overwhelmingly effective treatment.

How is chemotherapy used today for men with prostate cancer?

Dr. Dorff: When I started treating prostate cancer, chemo was pretty much our only tool besides standard hormone therapy. It worked, but it was sort of end-of-the-line. People didn’t tolerate it very well, in part, because we used it in really advanced cases. Then, the drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) came out, dramatically improved the situation for prostate cancer patients, and chemotherapy got pushed later and later.

The CHAARTED study was presented five years ago. That study showed that using chemotherapy early with the initiation of hormone therapy dramatically improved survival, above and beyond using it later. About 75% of the patients on the control arm got the chemo when they became resistant, so it was a pretty good experiment of now versus later, and not now versus never. To see that just using it early added an extra year or more of life for these men was really profound. That reinforced the strong role chemotherapy has in this disease.

With which other kinds of agents is chemotherapy frequently combined?

Dr. Dorff: Combinations with Taxotere (docetaxel) have never yet been successful in prostate cancer. There was Taxotere (docetaxel) with a high-dose Vitamin D, which was not only negative in that it failed to improve outcomes, but patients who received the combination actually fared worse. There was Taxotere (docetaxel) with Revlimid (lenalidomide), Taxotere (docetaxel) with atrasentan, Taxotere (docetaxel) with GVAX… All of these combinations have failed.

One of the ASCO presentations that prostate cancer physicians might remember most vividly is a slide presented by David Quinn in his presentation of the negative results of the SWOG S0421, the study of Taxotere (docetaxel) alone or with atrasentan. He showed a slide of a graveyard, implying that any drug tried in combination with Taxotere (docetaxel) is doomed to fail.

Why do you think that is? Is it just that the combination is too toxic?

Dr. Dorff: I don’t know. I don’t think it’s too toxic. All of these combinations go through safety before they go into Phase III, and you can combine them safely. I do not understand why combinations fail. Maybe it goes back to biology. Why would the combination succeed? You want something that makes the chemo work better, or you want the chemo to make the drug work better. That’s where we should probably start when planning combination studies. Even then, things that look good in early testing can fail in Phase III, so in some cases it may be that we need to sub-classify patients in order to design more successful trials.

Maybe a more interesting question when we’re talking about combinations is: how do we get the best use of the chemo and do the least damage to the patients?

At University of Southern California, we started a study looking at a fasting-mimic diet to make the Taxotere (docetaxel) better. We found preliminary evidence that fasting prior to chemotherapy reduced toxicity, and I envision that could have two specific benefits in men with prostate cancer who might get Taxotere (docetaxel).

One might be that if we could mitigate toxicity, more men would actually receive it. There was a lot of therapeutic nihilism out in the community about how chemotherapy doesn’t work so well for prostate cancer, or that these older patients can’t handle it. If we could ratchet down the toxicity, maybe more prostate cancer patients would actually get chemo.

The second benefit might be that if we could reduce toxicity to normal host cells, we would be more likely to get in full doses on time, which might make it work better against the cancer versus what happens now, which is that we frequently dose-reduce and dose-delay because of toxicities. The fasting-mimic diet study is still ongoing but these are the outcomes I was hoping for when designing it.

How long are they fasting before they start the chemo? What does that look like?

Dr. Dorff: They fast for 48 hours on a fasting mimic diet, which means they get vegetable broth and an energy drink. So, it’s a liquid, low calorie diet. It’s hard, so that’s part of why the study is still ongoing.

In our earlier trial, in which we did fasting with platinum chemo for up to 72 hours (48 before and 24 after the chemo dose), people really swore by it. They really felt like they had so much less toxicity compared to chemo cycles in which they didn’t fast.

With the fasting mimic diet (created by L-Nutra), because it’s not pure fasting, we extended it to three days before chemo. The first day is a fairly robust number of calories, just plant based and with specific amino acids left out, which is felt to be part of the effect. Then there’s the two days before chemo with lower calories, and one day after. After fasting or the fasting-mimic diet the body needs a bridging diet for the first meal, and the L-Nutra regimen also included supplements to replenish the body.

If someone reading this is interested in participating, can they contact you directly or should they contact someone else?

Dr. Dorff: Sure, they can contact me directly at tdorff@coh.org. But the trial is going on only at USC, so they may wish to contact the clinical trials office at USC or the medical oncology group at USC.

Are you combining diet with chemo instead of another agent?

Dr. Dorff: Yes.

What kinds of side effects can patients expect from chemotherapy? What are you hoping to reduce?

Dr. Dorff: One of the most concerning side effects is the peripheral neuropathy, which can become permanent, but I don’t want to scare any readers.

Can you explain what that is?

Dr. Dorff: It’s damage to the small nerves out in the fingers and toes that can manifest as numbness or pins and needles, burning kinds of discomfort. That can be permanent.

Is there anything patients can do before or during getting chemo to reduce the likelihood of that happening?

Dr. Dorff: Not that we know of.

There’s no way to predict who might suffer from that or not?

Dr. Dorff: It’s not a complete no. We know patients who already have some preexisting neuropathy, whose nerves are already damaged, are more susceptible, for instance patients with diabetic nerve damage. That’s one reason we might try to get them Jevtana (cabazitaxel) instead of Taxotere (docetaxel) because Jevtana (cabazitaxel) doesn’t impact the nerves in the same way. I’m not sure if that’s what patients worry about, but that’s one of my number one concerns because I’ve seen patients a few years after chemo who are still vexed by the neuropathy.

If Jevtana (cabazitaxel) doesn’t result in neuropathy, why wouldn’t you use that agent over Taxotere (docetaxel)?

Dr. Dorff: Because insurance typically won’t cover it. Head-to-head, they were compared in the FIRSTANA trial, and they were equally effective; one wasn’t much better than the other. So, insurance companies can say that Jevtana (cabazitaxel) is not more effective; it’s equally effective. Taxotere (docetaxel) is a fraction of the price because it’s off-patent, and Jevtana (cabazitaxel) is actually approved specifically in post-Taxotere (docetaxel) patients, so it’s off-label to use it first-line. You can make a case when you have a guy with neuropathy, but even if you have a guy without neuropathy, you sure would like to leave him without neuropathy at the end of his treatment.

We start to see the neuropathy around dose five. If you stop, it’s more reversible, but if you keep going, that’s where it can become permanent, and so again, when we’re getting to how we can enhance the efficacy, if we could get more doses in without being limited by neuropathy, maybe we would do better with the drug, or maybe we just avoid the neuropathy, have equal efficacy and patients suffer less. There’s two ways we can win.

Equal efficacy and side effects are a huge issue for men.

Dr. Dorff: Patients really worry about hair loss. I don’t think we’re impacting that with the diet, unfortunately. That is reversible. They also complain about the taste changes and mouth sensitivity because that really impacts eating.

Does that go away once chemotherapy is finished, or does that linger after?

Dr. Dorff: That goes away.

It’s just while they’re getting chemo that they lose sense of taste?

Dr. Dorff: Yes, but it’s a long time to not be able to taste.

And the hair loss only happens while they’re getting chemo, too? It comes back?

Dr. Dorff: Yes, it grows back.

What combinations with Taxotere (docetaxel) do you think will work best?

Dr. Dorff: The ongoing combinations that I think people are still interested in are platinum with taxane and carboplatin with Jevtana (cabazitaxel). That’s an important combination for the more aggressive variants.

Part of how we think Taxotere (docetaxel) chemotherapy works is that it interferes with antigen receptor (AR) translocation in the cell to the nucleus, because the microtubules are needed for that. It still may be more for patients whose cancer is using a lot of AR signaling whereas platinum is more for cancer that might not be as dependent on that mechanism. That combination is pretty important.

There are some other biologics being studied together with Taxotere (docetaxel), but I’m not sure that those will be successful. There’s Taxotere (docetaxel) with immunotherapy, but we have the negative GVAX trial that tried combining vaccines with Taxotere (docetaxel). We are also combining it with Xofigo (radium-223), which is a little interesting, but I don’t know why those agents would necessarily help each other. Again, when you’re looking at a combination, it’d be nice if there were a reason to expect synergy.

What about favorite sequences?

Dr. Dorff: We know that after you’ve had Zytiga (abiraterone) or Xtandi (enzalutamide), you can induce the androgen receptor splice variants such as AR-V7. These are associated with less responsiveness to Zytiga (abiraterone) or Xtandi (enzalutamide). Patients might want to go from Zytiga (abiraterone) straight to Xtandi (enzalutamide), but we know there’s a lower likelihood of success, and we know AR-V7 is a big part of that. If we sequence in chemo, since they’ve shown that AR-V7 positive patients still benefit from chemo, I view the optimal sequence as Zytiga (abiraterone) or Xtandi (enzalutamide), followed by wiping out the AR-V7 population with a chemo drug, and then going to Zytiga (abiraterone) or Xtandi (enzalutamide) next. We don’t know for sure if that’s what happens when we use that type of sandwich approach, but it has theoretical appeal, and that’s how I talk to patients about it. The other way to go is a clinical trial, especially for combination with Zytiga (abiraterone) or Xtandi (enzalutamide).

What about the side effects profile when you do those kinds of sequencing?

Dr. Dorff: Hormone drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) have much better side effect profiles, generally speaking, but the chemo side effects are largely reversible, and we tell patients that it’s not forever. There are good days and bad days, so it’s important to note that most people are not feeling bad every single day that they’re on the chemo. I don’t think the side effects vary based on sequence.

Some of my colleagues feel that when they use chemotherapy up front like in the CHAARTED study, they see more side effects if they start the chemo right away, but they see fewer side effects if they wait a month or two into the hormone therapy to add the chemo.

Is that because the patients become used to the side effects and learn how to manage them before you add something else?

Dr. Dorff: No, because the side effects are totally different between the two treatments. This is speculative, but I think you debulk. I think that part of the reason people get a lot of chemo side effects is that when we’re killing a lot of cancer there’s a big inflammatory reaction. You can feel sick from it, and we see that anecdotally in certain patients. If you can debulk the cancer a little bit with a couple months of hormone therapy, and then give the chemo, it might be better tolerated.

That’s interesting. So as the cancer’s dying, it throws off some kind of signal?

Dr. Dorff: It does. There’s a lot of dead stuff that has to be cleared by the body, and maybe that means it doesn’t have as much attention to do the healing that it needs to do with the chemo. I don’t know; that’s purely speculation.

Is there anything else you think men should know about chemotherapy for prostate cancer?

Dr. Dorff: First and foremost, chemo is effective. People downplay the role but CHAARTED really showed us that this is a good tool. We are working on tools that have fewer side effects. I’m working on whether diet can help mitigate side effects, and other people are looking at things like exercise, but the bottom line is that chemo is a good tool.

But still some patients draw a line in the sand and say they’ll never receive chemo because they’ve seen other patients getting chemo for other cancers. The chemo we use for other cancers is different than what we use for prostate, and every person’s reaction to chemo is different. Of course, you can’t erase that impression that’s made on you when you see someone who you care about struggling through chemo, but it doesn’t mean that’s what your experience is going to be.

Your doctor’s job, and your oncologist’s job, is to make it livable, to allow you to still do the things you want to do and to keep you safe and healthy through your chemo. There are tricks up our sleeves that we use to make that happen.

Sometimes patients are surprised to hear that they can actually feel better on chemo.

Why would that be?

Dr. Dorff: Because sometimes the cancer’s driving their side effects. It’s a catch-22. There are patients who might want to wait until they’re feeling better to get chemo, but if they’re feeling bad from the cancer, it’s really the chemo that’s going to make them feel better.

I have patients who’ve been unable to eat, in too much pain to really get out and do anything, and when they start chemo, they feel better, they eat better, they have more energy, and they can do more. If you take someone with no cancer symptoms, sure, the chemo’s going to make them feel worse. But if you take somebody with cancer symptoms, they may actually feel better.

That’s interesting because there’s this whole cultural perception of chemo as being catastrophic. The idea that chemo would make you feel better seems bizarre, but it makes sense the way you explain it.

Dr. Dorff: Yes, I think a lot of patients are shocked to hear it, and I think that’s a good thing to put out there.

Do you have any suggestions for men as to how to handle side effects before going into it?

Dr. Dorff: Communication with your doctor is the way to be successful in your chemo. A lot of people don’t want to bother the doctor, or they want to tough it out, but the earlier they tell the doctor that there’s a side effect, the easier it is for the doctor to intervene and reverse it. There’s no medal at the end of chemo for not having had to take a treatment for a side effect or not having called the doctor. Just pick up the phone and call. That’s how your doctor can do their best by you, and how you can be most successful with your treatment.

Aside from that, staying active is really important. Getting out and walking, even if you’re not exercising per se, but just moving around and not being sedentary is important for circulating the blood. We don’t want you to get a blood clot during chemotherapy because you’re not moving. It helps you expand your lungs, so maybe it can help keep your respiratory tract and heart healthier. Go into chemo as fit as possible, and try to maintain activity and mobility during treatment.

Read the rest of this month’s conversations about chemotherapy for prostate cancer.

Frontiers In Prostate Cancer Genomics

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer. His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about the state of genomics for prostate cancer today.

Not a member? Read the rest of this month’s conversations about prostate cancer genomics + prostate cancer genomics clinical trials.

What would you like prostate cancer patients to know about the state of genomics for prostate cancer today?

Dr. Feng: Genomics is becoming an important reality for patients with prostate cancer. We’ve talked about genomics for years in the context of research and possible advances for patients, but we are now reaching the era when these advances are being used in clinical practice or being assessed in clinical trials.

For patients with metastatic prostate cancer, patients with alterations and mismatch repair genes should be treated with immunotherapy (checkpoint blockade) at some point in the course of their treatment. At some point in their treatment, patients who have alterations in the BRCA1 and BRCA2 genes or other DNA repair genes should also enroll on a trial involving a PARP inhibitor.

There are many other trials testing specific biomarkers for selection for patients. For example, a few years ago, Prof. Johann de Bono presented the results of a study looking at an AKT inhibitor for patients with PTEN deleted prostate cancers. That’s currently being explored in a Phase III trial, and we’re eagerly awaiting the results of that.

In addition, the presence of androgen receptor (AR) splice variants is being used to select patients for studies. These need to be tested out. Some are molecular biomarkers rather than genomic biomarkers. But for patients with metastatic prostate cancer, we can point to definite examples where science is becoming clinical reality.

In the context of patients with localized prostate cancer or non-metastatic prostate cancer, we’re also seeing a number of advances. There are several tissue-based biomarkers that are now covered in various contexts by insurance companies, and they can be ordered as standard-of-care clinically.

In one of my roles, I chair the Genitourinary Cancer Committee for the Clinical Trials group NRG Oncology. A number of our national trials are Phase II and now also Phase III. The trials that we’re developing incorporate these genomic biomarkers for patient stratification or patient selection. When you start to see genomic markers like Decipher incorporated into NRG or PAM50 trials, it means that, sooner or later, these will become standard-of-care, assuming that the trials are positive.

Are there any open and enrolling clinical trials that either focus on prostate cancer genomics or incorporate genomics into their design that you think men reading this may either want to look into or ask their doctors about?

Dr. Feng: Two of the most promising studies are in patients who have had surgery for prostate cancer and now have a PSA recurrence. They are both actively enrolling.

The first trial that I would highlight is NRG-GU006. This study is open at hundreds of hospitals in the United States and Canada; it takes men who have a PSA recurrence after prostatectomy. We go back, we profile the prostate cancer sample from those patients, and we assess a biomarker called the PAM50 classifier, which we helped validate in prostate cancer as predicting response to hormonal therapy. Patients get stratified by this biomarker and are then randomized to standard-of-care, which is radiation alone, or to radiation plus the next-generation antiandrogen Erleada (apalutamide). They get both genomic testing with the PAM50 classifier and randomization, as well as the opportunity to be on Erleada (apalutamide).

Another trial that is actively enrolling is the NRG-GU002 trial, which takes patients who have very aggressive recurrences of their prostate cancer after surgery, and tests them using the genomic classifier Decipher. In the control arm, those with aggressive disease get randomized to radiation and hormone therapy or radiation and hormone therapy plus chemotherapy with Taxotere (docetaxel).

We and other groups have many other trials in development trying to incorporate these biomarkers, but those are the two trials that are open and accruing.

Who are the lead investigators on these two trials?

Dr. Feng: On NRG-GU006, the co-leads are Dr. Daniel Spratt from the University of Michigan and me. On the NRG-GU002 trial, the lead is Dr. Mark Hurwitz from Thomas Jefferson University.

Is there anything else that patients might want to consider?

Dr. Feng: For patients with metastatic disease, there are a number of PARP inhibitor studies in development right now. We’re looking to move PARP inhibitors into earlier and earlier disease spaces in select patients, largely based on the presence of DNA repair alterations.

This study using the Genentech AKT inhibitor is exciting to me. It’s a Phase III study for patients with PTEN alterations. Not all prostate cancers are the same, but we have traditionally put prostate cancer into one disease. But the many different cancers that comprise prostate disease could be genomically selected or stratified.

That is the future, right? Smaller and more precise categories?

Dr. Feng: Yes.

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How You Can Participate in Genomic Research

Dr. Eliezer Van Allen, Assistant Professor of Medicine at Harvard Medical School, a clinician at Dana-Farber/Partners Cancer Care, and an Associate Member at the Broad Institute of MIT and Harvard, focuses on computational cancer genomics, using new technology in precision medicine, and resistance to targeted prostate cancer therapies.

Prostatepedia spoke with him about how even those of you in remote areas can participate in nationwide genomic research study for men with advanced or metastatic prostate cancer.

What is it about medicine and caring for patients that keeps you interested and engaged?

Dr. Eliezer Van Allen: There are two answers to that question. One, the scientific answer, is that it’s been so remarkable to see how quickly advances that we’ve learned from studying patients with cancer have immediately translated into the clinic and have impacted my patients’ lives. It’s impacted people I don’t know, and that cycle of innovation is becoming quicker. It’s so exciting. It’s a privilege to be part of that from a professional level.

The other answer is more of a humanistic thing. I went into medicine because of my experiences at Camp Kesem, which is a camp for kids whose parents had cancer. It was a life-changing experience to be involved with that and to help drive it from the beginning. Whether or not any individual therapy works for any of my advanced cancer patients, there’s a human element to this job that’s very profound. That is also a privilege, to be involved with that day-to-day, no matter what.

Camp Kesem is still around, right?

Dr. Van Allen: Yes, it’s growing amazingly. There are over 100 camps now around the country, and thousands of families are involved. It’s wonderful.

Have you had any patients who changed either how you view the art of medicine or your own role?

Dr. Van Allen: Absolutely. At some level, every single patient both challenges and reinforces aspects of what it means to be a doctor and deliver care. Each in their own way has changed the way I think about things. There are obviously some stories that stand out and some experiences.

Some of the patients who’ve had the most catastrophic outcomes and succumbed to the disease in rapid form have taught me the most about what it means to live your life to the fullest, whatever that means to you. I have a lot of respect for them.

It’s a special thing to care for people at the particular moment, when they face big life questions.

Dr. Van Allen: About eight or nine years ago, I wrote a piece for the Journal of Clinical Oncology’s Art of Oncology series. It was about this one patient I had as a first-year fellow who had this positive thinking attitude in the wake of the most potentially catastrophic scenarios up until he passed away. It was such a surreal thing. In that case, it was rare, but I think it teaches you a lot about what it means to be human and how hard this disease is.

What is the goal of the Metastatic Prostate Cancer Project?

Dr. Van Allen: The Metastatic Prostate Cancer Project is a patient-driven research project whereby, rather than expecting the patients to come to us to join and participate in advanced research, we bring the project to their doorstep, and we engage with patients in new ways. We give patients an opportunity to share information about themselves and share their tumor specimens for us to do genetic testing. The goal is building the largest genomic registry of prostate cancer that we can learn from, and in so doing, accelerate that discovery to translation cycle even more.

Can you give us some updates on how the project has been going since you launched?

Dr. Van Allen: We launched this project in January 2018 in a patient population that is known not to talk about their disease in any venue, under any circumstances, to anyone. There’s no social media presence for this disease space, or at least on the surface, and frankly, we would’ve been thrilled had ten people signed up. Our sister project, the Metastatic Breast Cancer Project, has a loud and overt presence of women taking selfies with their saliva kits, so we weren’t sure how this was going to work.

We’re a little past a year from launch and over 700 men have engaged in research, given us consent to access their samples, filled out the patient-reported survey, and joined this Count Me In movement. It’s remarkable, but not only have these 700 men signed up, we’re already at the other end of the cycle of this project now, and we’ve generated complete data sets for the initial wave of these men. By complete data set, I mean genetic, clinical, and patient-reported data, and we’ve put that data out to the entire community in the research setting to learn from.

This proves the principle that we mean what we say when we’re generating data for the community. We’re not trying to build a silo here. This is patient-demanded, and therefore patient-driven, from day one. From every aspect across the board, it’s been remarkable and exciting to see how we’ve done so far.

We are 150% absolutely still looking for patients. We’ll always be looking for patients. Anyone who’s interested should feel comfortable to go to MPCProject.org and click Count Me In.

What kinds of patients should join? Anyone with prostate cancer?

Dr. Van Allen: This project is for advanced or metastatic prostate cancer, which means prostate cancer that’s left the gland. That could be folks with local, regional prostate cancer involved in the lymph nodes, folks with biochemical recurrence only (only PSA detected in the blood), and all the way to patients with heavily pretreated, advanced disease that’s spread to bone, liver, or wherever. Anyone in that spectrum is considered advanced or metastatic from our perspective.

The project is basically unending, right?

Dr. Van Allen: That’s the goal, releasing it as fast as we can.

Do you just release the data, or are you also forming collaborations with other institutions or projects?

Dr. Van Allen: We’ll release the data. We’re obviously going to try to learn from it ourselves and use it to come up with perhaps new drug targets, biomarkers, and whatnot, but also we would like to connect with other efforts that are spiritually aligned in any way that’s feasible.

One of the best outcomes would be that some researcher who is in no way affiliated with our project finds our data useful and uses it for their research to inform what they do. We’re already starting to see that happen with our sister projects where there are scientists and labs that we are not affiliated with who are using the data to inform how they think about their research and their projects. All of those outcomes are on the table, and we’re excited to pursue all of them.

Is there anything else you want patients to know about how the project is doing, about further studies you’re doing, or other studies you think people may find interesting?

Dr. Van Allen: This is a patient-driven project. Some of the patients who’ve given us feedback on their experiences so far have also prompted questions that we can ask that we, in our little academic bubble, probably would’ve never thought of. That’s how we’re starting to dive into things that are driven by patient experiences or that we’re observing in the patients who have signed up, down to questions that might seem curious but are illuminating, ones that we hadn’t intended initially.

For example, in the first patient data release, when asked if they had surgery for their prostate, almost half the patients marked: “unknown.” We can compare that to their medical record and sort that out, but it provides a window into something that wasn’t the initial intent of the project. That feedback opened up a lot of interesting questions and opportunities for research that we hadn’t necessarily anticipated up to that point.

Men didn’t know if they’d had prostate cancer surgery or not?

Dr. Van Allen: It may have been the way we asked the question. It may have been that patients were interpreting what they were supposed to answer. We don’t know. The point is that this is not something we initially set out to do, but it is an early example of how patients can guide where the research needs to go.

I just presented this project at the American Urologic Association meeting, and a gentleman came up to me afterwards. He’s had metastatic prostate cancer for four years and a complete response to cancer immunotherapy, and he wanted to know if he was eligible for this project. Not only is he eligible, but he’s an extraordinary case. We want to understand why. This patient is not within 500 miles of an academic medical center, and he would otherwise never be approachable or available to engage in research. We exchanged information, and he’s going to sign up.

Patients may not realize: they have the power to drive this field forward in this unique way. It’s not something that medicine is used to doing. We want to get the message out that this is all starting with patients and their ability to contribute. That will determine how far this goes.

It’s easy for them to participate: go to the website, fill out the forms, and give a blood sample?

Dr. Van Allen: Yes. You don’t even have to do the blood sample if you don’t want to. It’s exactly what you described. Go to the website, click a few buttons. There’s a very simple online consent form. We’ll send you a saliva kit and a blood biopsy kit and take it from there.

Can you still participate even if you’re in a remote area?

Dr. Van Allen: Yes, anywhere in the United States and Canada. For the blood biopsy, we send you a kit, and you bring it to your next lab draw, PSA test, or whatever, and there are instructions in the kit for the phlebotomist. In some cases, phlebotomists have not been willing or able to participate, so we can provide vouchers to patients to do it at a Quest Diagnostics lab or somewhere convenient to them. The intent here is that the patient bears no financial burden in participating.

Not a member? Join us.

Focal Therapy

In April, we’re talking about focal therapies.

Dr. Snuffy Myers comments:

“Interest in focal therapy is fueled by the promise of cancer control with fewer side effects than are seen after radiation or radical prostatectomy. From the patient perspective, this is certainly an attractive option. As a result, we have seen the development of an increasing list of approaches to focal therapy.

There are a number of issues that make critical evaluation of the various focal therapies problematic. First, with the exception of a recent trial that involved laser, randomized clinical trials are absent. There is even a controversy about what is the best control group. The laser trial just mentioned used an active surveillance control group. The second approach would be to randomize against surgery or radiation therapy. The major problem is that such trials have proved nearly impossible to run because of poor accrual. For this reason, I suspect that focal therapies are most likely to find a clinical niche as an alternative or add-on to active surveillance.

Another issue is that we lack trials that randomize between two different focal therapies, so it is difficult to know what approach to recommend for a given patient.

For example, cryosurgery and high intensity focused ultrasound (HIFU) have both been around for many years and have never been directly compared in a clinical trial. In developing focal therapies, it is currently common practice to treat a group of patients with a new technology and then follow those patients over time. Results are reported after 1, 5, and 10 year follow-ups and comparisons made to historical results with radiation or radical prostatectomy.

However, we have long known that such comparisons with historical data are often unreliable. As mentioned above, a better, more time efficient approach would be to test focal therapies as an alternate or add on to active surveillance rather than as an alternate to radical prostatectomy or radiation.”

Join us to read this month’s conversations about focal therapy.

Dr. Daniel George on PSA Recurrence

Dr. Daniel James George is Professor of Medicine and Professor in Surgery at Duke University.

Prostatepedia spoke with him recently about biochemically recurrent prostate cancer.

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

Dr. Daniel George: As we evolve new therapies and indications for treatment, it’s really interesting how that affects our relationships with patients. As an oncologist, my relationships with patients have become more longitudinal. What I mean by that is: people are living longer than ever. I’m beginning to recognize my treatments in the context of not just the short-term endpoint of how to control my patient’s disease in the next few months but in terms of the ramifications for his life and long-term survival. What does it mean in terms of his functional well-being, not simply now, but in a year from now or five to ten years from now?

In many ways, it comforts patients to hear the perspective, that I see them as a long-term survivor, and that I’m thinking about the implications of our treatments in a long-term perspective. That helps the patient invest in his own life and well-being for the long-term, whether that be diet, exercise, sleep, or all these other behavioral interventions that can really impact their quality of life.

You’re basically saying that prostate cancer is becoming more of a chronic disease.

Dr. George: It has been for some patients, and we’re beginning to recognize it more and more for all patients.

We used to think of short-term goals for some of our most advanced cases of prostate cancer—just in terms of disease control or palliation and not worry about the long-term implications of treatment. While on the other end of the spectrum we would have cases where we don’t have to treat the disease at all or maybe treat it minimally in others. Now I’m recognizing prostate cancer as a chronic disease for everybody, and so everybody needs to think of the long-term implications of treatments.

Likewise, we need to think of the implications of our sequential therapies and their cumulative side effects.

Can you define M0 prostate cancer, or biochemically recurrent prostate cancer, for patients?

Dr. George: This is probably confusing because of its name. We refer to prostate cancer in terms of stage. Stage refers to the extent of the disease. The Gleason Score or grade refers to how it looks under the microscope, its aggressiveness. But stage refers to the progression of this disease. Do they have bone metastases? Do they have distant lymph node metastases or other sites of disease? Or is it localized?

We usually use three categories: the T stage, which is the localized tumor, the N stage, which is the lymph node status, and then the M stage, which is the presence of metastases that are distant from the prostate. M0 refers to patients who have no distant metastasis. Think of M0 in terms of patients who are newly diagnosed with prostate cancer.

Recurrent prostate cancer patients are those who’ve had local therapy, surgery, or radiation, and who now have evidence of disease recurrence by PSA. After these treatments, we know that your PSA should be 0 or very low, and it should stay low. If your PSA rises and continues to rise, that’s an indication of disease recurrence. Yet, in many cases, they’re what we call M0 because, when we stage the patient with a bone scan or a CT scan, we can’t see any evidence of cancer. Many of those patients have what we might otherwise refer to as microscopic metastatic disease, disease that’s just below the level of detection. Some of them could have local recurrence or recurrence just within the pelvis and regional nodes that’s not distant. We now know from recent studies that the majority of those patients are going to relapse with distant metastatic disease. In other words, they have distant metastatic disease, but it’s just below the level of detection.

So, this is a bit of a misnomer because we’re treating them with systemic whole-body treatment therapy now because we recognize the risk of distant metastatic disease for the majority of these patients. We’re beginning to use newer imagining techniques, such as PET scans, that could be more sensitive at picking up this microscopic metastatic disease. That shouldn’t deter us from applying the current data to that patient population.

I think of M0 prostate cancer as being low-volume castrate resistant prostate cancer. When we think of it that way, it makes sense that the drugs we’re using work and work even better in that low-volume population. We should use them because M0 is just an early continuation of that metastatic process.

What are these systemic approaches that patients are likely to receive? What are the implications down the line in terms of side effects, and in terms of the longer longitudinal quality of life issues you mentioned earlier?

Dr. George: This is an important aspect of the care for these patients because we have two studies—and a third will soon be reported—that demonstrate a clinical benefit from using what we have broadly termed secondary hormonal therapies, therapies that we add to primary androgen deprivation (ADT) or testosterone suppression.

Patients for whom testosterone suppression has failed can respond to another hormonal intervention later. These are drugs that target the androgen receptor, the protein that testosterone binds to, and inhibits it from signaling. It shuts off what seems to be the most common mechanism for resistance to testicular testosterone suppression. That is an overexpression or overabundance of this receptor, which makes prostate cancer cells sensitive to low levels of residual testosterone in the body.

Xtandi (enzalutamide) and Erleada (apalutamide), in two separate Phase III studies, have demonstrated a clinically significant benefit: a delay in the time to metastasis. The FDA has accepted this as a meaningful endpoint because of the degree of delay. It was associated with about a two-year delay in the time to metastasis in this population.

Patients who were at high risk for developing metastatic disease were in the control arm and developing metastatic disease within about a year of coming on the study for the placebo arm. For the treatment arms, with Xtandi (enzalutamide) or Erleada (apalutamide), we’re seeing a delay of about two additional years. That means three years until the time of metastasis.

The results suggest that we’ve changed the progression of this disease dramatically. In addition, both studies showed a strong trend in favor of the treatment arm for improved overall survival associated with this delay in metastasis. Even though the data may not be as complete because it takes a longer time to report, we’re seeing this correlation in metastasis-free survival, if you will.

Again, I caution the semantics here because these patients do have metastases; they just can’t be seen yet. But the delay in that radiographic appearance of metastasis is associated with an improved survival.

What’s the approach to finding smaller metastases earlier on with the newer imaging techniques? And if they are very small, do you treat them aggressively with radiation, do you continue using the systemic therapies, or do you use a combination?

Dr. George: There is a mix of presentations of patients. When we image with a novel PET-imaging tracer, we’re going to see more than one site of disease in most patients. We’re going to see multiple lymph nodes, multiple bone metastases, or maybe lymph and bone metastases.

For a subset of about 20 percent of patients, we see this disease limited to only lymph node disease or only one or two bone metastases. We refer to this as oligometastatic disease, which we have yet to biologically define. Clinically, we know that it’s associated with a longer survival.

Oligometastatic prostate cancer raises the question of whether or not these patients could be managed with therapy localized to those sites, therapy that does not necessarily expose them to further systemic therapy. We don’t have a lot of data in the castrate-resistant setting, but in the hormone-naïve setting, there are some data that suggest that there can be a delay in the time to initiating subsequent hormonal therapy by doing that.

There’s a study out of Europe, but the median effect was relatively small, just a few months. It’s not clear that this is going to be a meaningful difference for most patients, but it is something that can be discussed.

A lot of those treatment approaches can be done with minimal intervention, external radiation, ablations, or limited surgery. Those will be options. But in the majority of these patients that we do this molecular imaging for, we’re going to find evidence of more than one site of disease or multiple lesions. This suggests that they need a systemic therapy approach.

It’s reasonable to extrapolate this data because we know from the placebo arm of these studies that these patients went on to develop metastases in their bone scan or CT scan within months, 50 percent of them within a year, and many of them in just a few months of their subsequent scan. The likelihood is, if we’d done the molecular imaging at baseline on these patients,we would have seen it. Yet still, in this population, we’re seeing a treatment effect.

We see the treatment effect regardless of what level of PSA doubling time you have. In patients who have a PSA doubling time of just two or three months, we see a dramatic treatment effect. In patients who have a doubling effect of eight or ten months, we still see a dramatic treatment effect in terms of prolongation in the time to metastasis—fewer events in those cases, but still, we see that treatment effect.

The PSA doubling time is an important parameter that we’re using now, in addition to these imaging stats, to determine who we should treat with these drugs and their prognosis.

Isn’t doubling time an indication of the aggressiveness of the disease?

Dr. George: It is. We knew this earlier in disease prior to hormones. PSA doubling time was very prognostic for time to metastasis and overall survival. It’s been less studied in the castrate-resistant setting, when patients have progressed on primary hormonal therapy, but we’re still seeing it there. In fact, the results are really dramatic.

There were some abstracts at the Genitourinary Cancer Symposium (GU ASCO) around this data. There have been reports from these two Phase III studies with Xtandi (enzalutamide) and Erleada (apalutamide) that demonstrate this. We believe there is a strong correlation between a shorter PSA doubling time—a shorter time to bone metastasis—and shorter overall survival.

Just to put these studies into context, the requirements were that PSA doubling times were less than ten months. If doubling time is a year or longer, these are slow-growing cancers. Even though they’re castrate-resistant, these are patients who will live for many years with no metastasis, so it’s reasonable just to observe their disease. For the studies, the median or 50th percentile PSA doubling time was around four months. That’s really short and aggressive.

That’s why we saw that the average time to metastasis was just about a year in the control arms. It’s important to recognize where your patient is in this continuum because it guides whether we should treat him like we did on the study, or if their disease is too slow growing to justify the treatment.

What other considerations are important for patients who fall into this category?

Dr. George: The important thing for patients to know: not to worry. I know that as a physician, it’s easy to say ‘don’t worry about your rising PSA level,’ but as a patient, it is hard to ignore.

Join us to read the rest of Dr. George’s comments about biochemically recurrent prostate cancer.

Dr. Maha Hussain On Biochemical Recurrence

Dr. Maha Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology, Department of Medicine, and the Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

Prostatepedia spoke with her recently about biochemically recurrent prostate cancer.

What is biochemical recurrence?

Dr. Hussain: A biochemical recurrence implies that an individual with prostate cancer who has received therapy now has evidence of disease activity as reflected by their PSA blood test. In the context of negative imaging, the PSA is a flag. It generally indicates a relapse. Generally speaking, when the patient has a rising PSA, they get imaged. If the scans are negative, then this becomes purely biochemical recurrence.

Why is this a disease state that we’re particularly focused on? What are some of the key issues in how we approach treating these men?

Dr. Hussain: There are two settings of biochemical recurrence. One is the non-metastatic hormone sensitive setting. This means a patient has had local therapy with surgery and their prostate was taken out, or they’ve had radiation therapy with or without hormonal treatment, and now they have a PSA that’s going up. This implies there is cancer activity. Generally, imaging is done, and most of the time, conventional imaging such as bone and CAT scan are negative.

While not imminently harmful, non-metastatic hormone sensitive biochemical recurrence has significant psychological implications for the patient because it reminds them that there is cancer activity in their body that’s growing.

With regard to management, salvage radiation plus hormone therapy is the standard of care for patients who developed PSA-only relapse post radical prostatectomy as it reduces risk of mets and improves longevity. While there are options for patients who had radiation therapy plus hormonal therapy, they are not optimal.

For example, while hormone therapy is an option for patients whose PSA started to increase after salvage radiation and hormonal therapy, the totality of the data to date does not suggest significant benefit for early hormone therapy versus waiting until there’s a reason to treat.

This population; non-metastatic hormone sensitive PSA relapse, tends to live quite long, and some may not develop visible mets. The speed by which the PSA starts to go up and how fast it increases—what we call doubling time—can imply earlier versus later development of metastatic disease. Detailed discussion is needed to address options, pros and cons of treatment, and potential options for clinical trials.

The other setting of biochemical recurrence is the non-metastatic but castrate-resistant setting, which differs from the previous setting in that patients were treated with hormone therapy and now their PSA is rising while on therapy; that is the rising PSA is occurring despite the fact that hormone therapy has lowered their testosterone levels to the castration range. This is a different clinical phase of disease where the cancer has shown that it is no longer responsive biologically to the hormonal therapy that they are receiving. We know that, given enough time, cancer will show up. We know also that the speed by which the cancer is growing, as reflected by the PSA rate of increase, has an implication as to how soon the cancer will show up on the scans.

This is an area of an unmet need for decades, until last year when two drugs were FDA-approved for this particular patient population, specifically Erleada (apalutamide) and Xtandi (enzalutamide) based on significantly delaying time to development of metastasis. At this year’s American Society of Clinical Oncology GU (ASCO GU) conference, there was also positive data from another trial with Darolutamide in this disease setting. I believe the drug is in front of the FDA at this moment for review.

These three trials were done in a population of patients who had a worse prognosis as reflected by their fast PSA doubling time—a doubling time of 10 months or less. This is because these patients are likely to show metastases within an average of about two to two and a half years.

The issue is whether there is benefit for people who don’t have that kind of PSA doubling time. What if the doubling time is one or two years? It certainly is an area where we need to think about value to that patient.

For both Erleada (apalutamide) and Xtandi (enzalutamide), the FDA approval did not specify the doubling time requirement. The FDA approved it in all patients who have non-metastatic castrate-resistant disease. Clearly one size does not fit all. It’s critical to make shared decisions between the patient and the treating physician with regard to the value of the treatment, the risks from the cancer, the risks from the treatment, the treatment objectives, and when to initiate therapy.

Some good news about this disease phase is, because it’s invisible cancer, and while this means there’s micrometastatic disease, the patient has some time to think about things and also monitor carefully.

In my experience, probably about 8 to 9 out of 10 patients elect to be on treatment because of the concern over worsening disease and the value based on the clinical trials. There are some patients who feel great, and if they’re not going to have an issue tomorrow, then they want to wait a few months before deciding on treatment. That’s perfectly reasonable.

Isn’t that true for a variety of situations in prostate cancer, that you have time to gather a variety of opinions?

Dr. Hussain: Correct in general, but specially for this disease space because no one is going to die overnight from a PSA that’s not controlled. That’s to put it bluntly. There is that room. Patients should talk with their physician about that and discuss risk-benefit ratios as all therapies have side effects.

For certain patients, those side effects might be more important, especially for those who have significant cardiovascular disease. It becomes important to incorporate risk-benefit and close monitoring, but it doesn’t mean that no treatment should ever be done.

Do you have any other advice for men in this situation?

Dr. Hussain: One thing to remember for men with hormone-sensitive biochemical recurrence who have had salvage therapy or post radiation and hormonal therapy is that if therapy is to be done, it ought to have a good reason. Lowering the PSA alone is not the objective; clinical benefit should be the objective.

There is potential harm from treatment in the absence of proof that giving hormone therapy for a PSA of let’s say 0.5 or 0.6 will have a benefit. One has to balance the risks from the treatment and both physical and monetary risks to the patient and ultimately implement a shared decision.

These conversations with patients can be long and potentially stressful to the patient. Yes, hormone therapy can be given. The issue is not whether it can be given but whether it should be given, and if so, when.

There’s a fair amount of population-based data that suggests there’s no clear advantage, but there’s limited prospective clinical trial data. I would encourage patients to discuss these issues with their physicians, understand the upsides and downsides, and also discuss opportunities for clinical trials. Clinical trials are one space in which we need informative data and partnerships with patients to come up with better answers.

For patients who had radical prostatectomy (surgical removal of the prostate), and then their PSA is going up, their best treatment option is salvage therapy, which involves radiation with hormonal treatment.

Based on the more recent data from Radiation Therapy Oncology Group (RTOG), the radiation involves the prostate bed and the pelvis to include the pelvic lymph nodes with four to six months of hormone treatment. This is something that should be discussed with the care team. Radiation alone is not enough, and certainly the data indicate the combination is better with regard to outcomes. If the patient doesn’t want to do the hormones, that’s fine, but the hormones can reduce risk of progression and potentially add to overall survival.

The other side would be situations where patients have had radiation therapy and have received hormonal treatment as part of their primary treatment. Then they stopped the therapy, and now months or years later, the PSA is rising. That’s a different scenario. The issue is whether to resume hormone therapy or not. That’s when a careful conversation is necessary between patients and their physician because there is no compelling data that say it’s necessary to do the hormone therapy.

So, there are a variety of situations.

Dr. Hussain: Yes and/or access to clinical trials. We know the phases of prostate cancer now. The same disease state now has multiple phases, and it’s becoming complicated. That’s important because this speaks to the importance of personalizing care for the patient at all levels.

We’re becoming more and more personalized about how we categorize the different disease states.

Dr. Hussain: Yes, absolutely, and we do individualize the care. A 50-year-old who comes in with non-metastatic castrate-resistant prostate cancer and no comorbidities has a very different disease than someone who is 85, had a stroke, and is in a wheelchair.

Patients should ask their physicians specifically about the type of biochemical recurrence they have, their expected prognosis based on their PSA doubling time, their risk-benefits ratio, and which scientific information from prospective clinical trials can help guide their decisions. Patients should ask for educational material, and doctors should help patients make a decision that’s not based on being afraid but being informed about the choices, pros, and cons.

Would you give similar recommendations to anyone along any stage of the disease progression?

Dr. Hussain: Absolutely. Informed decisions are critical in every disease setting. But biochemical recurrence is a complicated phase of disease. In the setting of metastatic disease, it’s relatively easy in that there is no question regarding the disease risks. Earlier therapy, before symptoms or before the disease worsens, is better generally. This a disease setting that is likely to cause harm if therapy is delayed significantly.

But with non-metastatic hormone sensitive biochemical relapse, a patient can go for years without having any visible metastasis. It’s more complicated when there’s no imminent danger. At the end of the day, I tell patients with non-metastatic hormone sensitive disease in whom there is no clear data to support benefit from systemic therapy, that this is a gray area where we don’t have compelling data to say that giving hormone treatment is going to give a meaningful benefit. Therefore, one option is we monitor closely with interval PSA checks and periodic imaging. Based on doubling times and trends, what new evidence that comes up, and patient comfort we can watch. Once the patient is informed about the specifics, it is fascinating that the majority tends to be comfortable with watching and about a third are not comfortable with not getting therapy. There is not a one-size-fits-all approach. Personalized shared decision is critical.

Not a member? Join us to read more conversations about PSA recurrence.

Biochemical Recurrence

In March, we’re talking about biochemical recurrence.

Dr. Snuffy Myers frames the issue for us below.

Not a member? Join us to read conversations with Drs. Daniel George, Pedro Barata, Julio Aguirre-Ghiso, and Rahul Aggarwal.

This issue focuses on treatment issues for men with an increasing PSA after prostatectomy or prostate radiation. In this introduction, I will review some basic concepts that should help you follow the discussion more easily.

If surgery has successfully removed the prostate gland, the only source of PSA will be surviving cancer cells. After radiation, there can be normal prostate cells in addition to cancer cells. However, prostate cancer cells differ from normal prostate cells because the cancer cells are able to grow in a particular manner. Cancer cells grow by doubling: 1 cell becomes 2; 2 become 4; 4 become 8. Cancer cells do this at a constant rate.

For example, if the cancer cells double every year, then on subsequent years, the number of cancer cells would be 1, 2, 4, 8, 16, 32, 64, 128, 256, and so on. As a general rule, it takes 15 doublings to go from 1 cancer cell to a mass 1 centimeter across. At 1 centimeter, cancer masses generally become detectable by CT scan. As a rough rule of thumb, it takes another 15 doublings to reach a lethal cancer burden.

The implication is that half of the cancer growth occurs below the level of detectability.

Unlike most cancers, our ability to follow prostate cancer is not limited to imaging tools like the

CT or bone scans. We have PSA as a biochemical marker that can be used to follow the cancer. The PSA is a much more sensitive indicator of cancer presence than both CT or bone scan and can indicate the presence of recurrent cancer months to years earlier.

In most patients, the PSA level is roughly proportional to the size of the cancer mass: if the cancer doubles in size, the PSA will double. Thus, the PSA doubling time is thought to provide an estimate of the cancer doubling time. PSA doubling times faster than 3 months usually indicate rapidly growing disease associated with short survival unless treated aggressively. PSA doubling times slower than 9 months usually indicate much less aggressive cancers. PSA doubling times greater than two years are associated with prostate cancers that can take a decade or more to cause metastases detected by the scans.

As a result, it is common to see men after surgery or radiation who have an increasing PSA, but no other evidence of disease. In those patients, PSA doubling time represents the only well established tool to determine the aggressiveness of the cancer and how soon metastatic cancer might manifest itself.

PSA, however, provides no information about the location of the cancer. Is it present in bone, lymph node, liver, or lung? The recent advances in PET scans mean that the cancer can now be detected while it is much smaller than would be the case with CT or bone scan. However, clinical trials have yet to prove this early detection improves the outcome of treatment.

Finally, there is the problem of late relapses. After surgery, patients can have an undetectable PSA for years—even more than a decade— and then recur. What was going on during that silent interval and what changed to trigger recurrent cancer? This phenomenon is called cancer dormancy and is also reviewed in this issue.

Charles E. Myers, Jr., MD

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. 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).