POSTED: February 10, 2020

Dr. Julie Graff on 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.

“He had emphysema and was dying, but the drive to live can stay  so strong, even at 80.”

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 crossresistance 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.

“The type of chemo  we use in prostate  cancer is not as toxic  as we do for other  cancers. We just use  one drug.”

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.

“Exercise is critical  for any prostate  cancer patient.”

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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