Nicholas J. Vogelzang, MD, FASCO, FACP, Comprehensive Cancer Centers of Nevada

Nicholas J. Vogelzang, M.D., FASCO, FACP:

 As part of my work with the Southwest Oncology Group, we are working on the use of PARP [poly ADP ribose polymerase] inhibitors combined with chemotherapy, earlier in patients. We have a tough one that we’re working on, that is patients who have BRCA mutations when the prostate cancer is either localized or may be outside of the prostate. And we’re working on doing a project of giving them a PARP inhibitor or chemotherapy right away and then removing the prostate and seeing how much cancer remains. Hopefully, that will come to fruition.

We’ve been working on this for two years, it’s a challenging study. Heather Cheng, M.D., Ph.D. is working on this. She’s up at the University of Washington. There is a variety of other research programs underway, either looking at chemotherapy, with hormone therapy. There is one study looking at it with immune treatment. The patients with BRCA mutations tend to have more response to the immune treatments. The immune treatments don’t work very well for the majority of prostate cancer patients, on the order of 10% or less. But if they have a BRCA-type mutation, the immune system combined with a PARP inhibitor may be more effective. That’s a very active area of investigation. No data yet, but it’s being worked on.

What I would remind the patients about is that each one of you has a special journey ahead. And that journey is not predictable, and it can be influenced by the drugs that we have. When we get a highly effective drug you don’t go downstream, you go upstream. If you’re in Tennessee and you get a good drug, it’ll reset your clock so that you’re up in St. Louis.

And your journey lengthens. Don’t be afraid of taking treatments. For heaven’s sake, this is your life, and you want to extend your life, and you want to extend your quality of life. And your quality of life is not necessarily going to be negatively affected by these drugs. We, as doctors, know these are hard on you, and we want to make your life better. But most importantly, we want to make your life longer.

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The Future of PARP Inhibitors in Prostate Cancer

: There are many support groups for patients. I strongly recommend them. I helped start the prostate cancer group called Us TOO, back in the ’80s. We started it at the University of Chicago with five of our patients. I fondly remember Mr. Vincent Young and others who started it. That is a national group now, they’re all across the country in various towns.

There was one over the hump of the mountains here in Pahrump, Nevada, and I’ve gone over the hump to Pahrump a few times to give talks to the prostate group. We have one here in town, run by one of my patients, Tony. I get over there when I can, and we talk about the reality of prostate cancer. Everyone has a slightly different reality. Some will be cured by having had either radiation or surgery. Some will be in remission with hormone treatment. Some will be in the midst of treatment. I always describe prostate cancer like the Mississippi River. It’s a long journey, and if you start way up in Minnesota it’s going to take a long time to get to New Orleans.

But if you start in Memphis where the cancer is advanced, it’s not going to take that long to get to New Orleans. It all depends on where your journey started, and how many twists and turns there are as you float down that river of prostate cancer. The bottom line is most patients’ journey has to be interpreted for them. They don’t know where in the river they are. They may be at St. Louis, they may be in Minneapolis, or they may be in Vicksburg, Mississippi. You don’t always know exactly where they are. And educating them about where they are in the journey is important. Some patients live 20, 30 years with prostate cancer.

And you have other patients who only live two or three years. You must adjust that journey appropriately and educate them. I’ve learned that sometimes I can be a little bit too blunt, and I don’t mean to be blunt. But it is important for the patient to know where they are to make appropriate arrangements. If somebody is right about to enter the Gulf of Mexico, they need to know that, and they need to have their affairs in order and they need to have a plan of action. On the other hand, if they’re in Minnesota, and you’ve got 20 years of floating down the river, you don’t need to worry too much. And you can tell them don’t worry, this is going to be OK. They need to know that, and doctors need to educate the patient on that journey.

Patient’s Role in Decision-Making for Prostate Cancer

 When a patient is diagnosed with prostate cancer, as there was today, I saw a patient of Japanese ancestry. He was young, only 65 years old, it had spread out, and it was prostate cancer. The first thing I wanted to do is get his genetic testing. There’s a 25% chance that he’ll have an abnormality. He didn’t have any family history. His mother had a brain tumor. I don’t know what that means as far as his genetics are concerned. He’s already been on the hormone treatment, and that has caused him to be miserable.

The hormone treatments caused hot flashing, muscle loss, and poor quality of life. He is eager to get off the hormone treatment, but if he cannot get off the hormone treatment and the cancer gets worse, then my choices, if he has the BRCA mutation, would either be chemotherapy or PARP [poly ADP ribose polymerase] inhibitors. Genetic testing will determine which one I will choose depending on the mutation he has. If he has a BRCA1 or a BRCA2, he could get either one. If he has a CHEK2 or a PALB or a RAD51 genetic abnormality, then he’ll have to get olaparib. But that aside, the quality of life on these PARP inhibitors is good.

The quality of life is somewhat better than it is on chemotherapy. There is no hair loss, at least not generally. There can be some mild nausea, fatigue, arthritis, etc. You’ll follow the patients carefully. The worst thing that happens is the anemia, and if they get anemic, then many times you must hold off, back down, reduce the dose a little bit, or delay. On rare occasions you have to give them a blood transfusion. But that is rare. Usually, just by holding the medicine for a short period, the blood counts come up and they’re back feeling well again. It can be a very dramatic effect when pain is present, and the patient has already had chemotherapy.

Sometime these drugs work within days and the pain melts away. It can be encouraging to the patient. And as a result they’re optimistic, and their quality of life improves. These are broad estimates. Each patient will differ. Each side effect will affect their quality of life to some extent. Generally, the drugs have a high level of retention of a good quality of life. That would be the best thing I can say.

Quality of Life With Prostate Cancer

 These drugs, rucaparib and olaparib, are what we call PARP [poly ADP ribose polymerase] inhibitors. And they bind to cells that already have the missing gene, they’re missing the BRCA or they have a bad BRCA gene. When they do that, they create what’s called synthetic lethality. The DNA fragments and breaks up, and when cell damage occurs with DNA damage, it dies. Which is exactly what we want the cancer cell to do, die. And if we can get that to die, then the patient lives longer. These drugs have been approved for the treatment of ovarian cancer with a mutation of BRCA.

There’s been widespread use of these drugs in ovarian cancer. The drug may also be approved in breast cancer with the mutation, and recently both the TRITON study and the PROfound study allowed the FDA to approve these drugs in prostate cancer. Many physicians are now familiar with these drugs and their adverse effects. Both of these drugs can cause low blood counts. They can make you anemic, lower your white cell count, and they can lower your platelet count. They cause some liver abnormalities. They can also cause some minor kidney problems.

They could cause joint pain, diarrhea; there is a variety of adverse effects that each one of them give. You don’t want to give these drugs unless you’re absolutely certain that these will be beneficial. The benefit rate is high. It’s on the order of 40% to 50%. We don’t know why they don’t work in some people, but they don’t. And we also don’t know why they don’t last a long time. They last longer in ovarian cancer than they do in prostate cancer. But they are clearly beneficial in prostate cancer compared to the alternative treatments. When we have an appropriate patient with prostate cancer where the cancer has already spread, and it is outside of the prostate and they’ve already had a hormone treatment, these drugs are highly appropriate and are recommended by the guidelines to give.

Nicholas J. Vogelzang, MD, FASCO, FACP, Comprehensive Cancer Centers of Nevada

The Future of PARP Inhibitors in Prostate Cancer

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