Alan H. Bryce, MD, Mayo Clinic

 How do you feel when you hear about these advances, knowing that you participated and can see where the field is going?

 It excites me because, just last week when I was in your office after my regular series of blood tests and scans, that was my question to you. When and if in fact this does stop working for me, is there anything else out there new for me? You said, “Yeah, the next generation of treatments is just exploding. We have all kinds of things to talk about.”

It’s encouragement. The thing you always have to hang on to as a patient is hope. You’ve got to have hope, and you’ve got to listen for the encouragement because there are so many new options out there. And you need to find the ability to trust your oncologist and know that he is trying to lead you down the direction of, as Dr. Bryce says, putting him out of work—hopefully finding a cure for this prostate cancer. Honestly, I encourage every one of you to get into depth of what it is that’s going on with your particular type of cancer. Talk to your oncologist. Get as much information as you can. It will put your mind at ease. It will allow you to get a lot more sleep at night.

 That’s wonderful. Thank you for that, John. It’s always a pleasure to talk to you. The audience probably understands by now—you and I have been doing this so long that we’ve become buddies. Right?

: Any last words of advice for the people listening, the caregivers as well as the patients? You’ve already given some great advice, but any last thoughts?

 For the caregivers, just keep up the support. Do all the encouraging that you can. To the patients, trust your oncologist. Don’t be afraid of trying something new, finding what it is that’s out there that will work for your cancer. Because the worst thing you can do is be fearful of the disease. You must keep a positive attitude. You have to move forward every day, and your attitude has an awful lot to do with it.

 Very good. Thank you, John, for your friendship over the years and for your advocacy for patients. I also want to thank the people watching and the team at 

® for putting this together. For the patients and caregivers, thank you for your encouragement, for your courage, and your ongoing commitment to helping us find a cure for prostate cancer. Please help put me out of business. That’s the goal. No more oncologists. That’s the world we want to live in.

Videos

Advances in Prostate Cancer

 Let’s talk about the future of prostate cancer and where rucaparib fits into the current practice and where we see the next steps in the development of rucaparib—Rucabra is its trade name—in prostate cancer. Rucaparib is approved for the late-stage treatment of prostate cancer after one of the oral androgen pathway inhibitors, such as abiraterone or enzalutamide and after chemotherapy with a taxane, most commonly docetaxel. That ends up putting it as a fourth-line therapy, if you will, for men with prostate cancer who have this 

 mutation. That is part of the normal drug development process. There are practical and ethical reasons why we usually develop new cancer drugs in late-stage treatment rather than early stage.

The next steps are to start moving those drugs forward. We do the initial study late to get a clear, positive signal and know that we’re on the right track, but then what we start doing is start testing the drug in earlier stage, in combinations, start tweaking the dose, the regimen, finding ways to optimize the drug and make it more effective. Make sure we’re getting the most out of it for every patient.

In prostate cancer, those studies are ongoing. For rucaparib specifically, there is the TRITON3 study, which is testing rucaparib earlier, before chemotherapy, but after one of the oral androgen pathway inhibitors. In the future, you can fully expect that there will be lots of combinations with PARP inhibitors in prostate cancer. Many of those studies are already ongoing. I fully expect there’s going to be a steady drumbeat of data and results over the coming years as the cancer community starts to figure out ways to optimize these treatment options.

In my own practice, rucaparib is one of our standard drugs for the 20% to 25% of men with prostate cancer who have a qualifying mutation. It’s a big part of the population. Almost a fifth or a quarter of men are going to have the kind of mutation that makes rucaparib a good treatment option.

In our practice at Mayo Clinic here in Arizona, every man with advanced disease should have genetic testing, and in our practice every man gets it. We test his inherited genes, his germline genes right from the beginning. Usually from the first appointment we’re having that conversation. Then we get biopsies to test the tumor whenever there is a growing spot where we can easily get a piece of the tissue.

A key point here is that cancer evolves. By definition, cancer is a cell that’s mutating. The prostate cancer might look relatively quiet in the beginning, but after years of therapy, hormones, and chemotherapy, it can start to acquire more mutations and look different. An important point is repeat testing. As we saw in John’s case, his inherited genes were normal, but the tumor had the mutation. It’s not enough to just look at the inherited genes. We also must look at the tumor mutations. Then look at it again as the cancer evolves over time.

Future Use of PARP Inhibition in Prostate Cancer

 What support services or support structures do you have around you? You talked about your daughter, you talked about our relationship. Is there advice you would give to other prostate cancer patients or perhaps other types of support you would like to have or would have liked to have had in the past as one prepares for this journey?

I would like to have been closer to my twin sons too. My children are in their late 30s. Because of the frequency of my treatments, for the first year I tried flying back and forth from Alaska to Phoenix for my treatments, and then finally the expense of the flights just got to be too great. I was forced into making the decision that I should just relocate down here. I’ve been living here relatively close to your services for going on 10 years. Yes, it would’ve been nice to have the personal hugs and touches of your family, as opposed to being able to do it over the telephone. I’m very blessed. My family has always been very close. I can feel the love through the phone.

They’ve never once given me anything other than encouragement. You’re doing the right thing, Dad. I’m glad you’re where you are. We miss you, but the proof is in the pudding. The proof is in what has transpired with me—eight years ago saying I had at least three to five years to live. Well, here I am eight years later, and I feel as healthy as a horse. I wish I could control my weight a little more, but I have a great appetite. There are upsides and downsides, but nothing that I can point a finger to that would tell me that I should have done something differently. I really think that these new genetic treatments are the answer for some prolonged treatments for most of you who are out there under the same conditions that I am with the metastatic prostate cancer. I really believe in that.

Advice to Patients Facing mCRPC

 I’d like our viewers to be aware that there are now two PARP inhibitors approved. Six months ago there were none. Rucaparib was the first. There’s also olaparib. These two drugs are very similar. They’re both PARP inhibitors. They’re both pills. You take them both twice a day. The side-effect profile is fairly similar between them.

Because of some technical details of how clinical trials are designed and how the FDA approval process works, the approval labels on the two drugs are slightly different. They both target the same population. That is, men with castration-resistant prostate cancer whose tumors have specific mutations in these genes involved in the PARP pathway.

For my part, this was a long time coming. We have been doing this research for years when we started doing genetic research. We knew 

 was a good target. We knew this target was in prostate cancer. We knew that in breast cancer and ovarian cancer they’d already shown that these drugs worked. So much of what had to happen was convincing everyone—regulators, the industry, and ultimately patient advocates and patients—that this concept had to be brought over to prostate cancer, that it wasn’t just a concept that worked in breast and ovarian cancer. Ultimately that happened. This is an international effort from researchers in Europe, in the United States, and throughout the world to make this happen.

What’s really exciting in prostate cancer is that the pipeline of ongoing research of other drugs of other concepts and other modes of attack is brimming. There is a full pipeline of new concepts, some of them trying PARP inhibitors in other ways, moving them earlier in the disease course. There are two other PARP inhibitors being tested, some concepts that are completely different—the radiotheranostics and lutetium.

My goal as a medical oncologist is to put myself out of business. We want to cure prostate cancer so that no one has to deal with this again or ever go through this again. The great thing is that in prostate cancer, the pace of change right now is gangbusters. We’re seeing a couple of new approvals every year. The thrill, the happiness of every drug approval, never wears off. We are moving this field forward.

When you started on rucaparib, John, why did I recommend it for you? Obviously, it’s because it matched your genetics. I had a high degree of confidence that it was going to work.

Based on our conversation, what did you feel about the likelihood that this was a good move for you? As you go into a study, knowing that you’re an early adopter—that because it’s a study, by definition we don’t know exactly what’s going to happen—how do you think about defining success? And what was most important to you in that decision-making process?

 As the patient, not the doctor, not fully understanding the mechanics of this type of treatment, I relied on my discussions with you, but the people should know that when you’re volunteering into one of these researcher trials or studies, you’re coming in on a fairly regular basis for blood tests—extensive blood tests—bone scans, and CT scans on a three-month basis, much more frequent than would be normal for a patient with this type of cancer.

My concern was that with the earlier chemotherapies and pill forms of drugs, I was always watching. I couldn’t wait to see what my PSA [prostate-specific antigen] level was. Is it still low? It was almost at a point that it’s not negligible. You almost can’t even discern that it’s there, but with the other modalities, yes, it would start to rise back up. The conclusion would be, “Well, I think the cancers found an immunity to the drug.” This was a totally new concept. I wasn’t sure how I could identify whether I thought it was a good thing, a bad thing, how it was working for me. I relied on waiting to see what my blood tests were and what my scans were.

In a matter of three months of being on this PARP inhibitor, the increased size of my abdominal lymph glands shrunk down to normal size. The cancer was no longer visible in any of the soft tissue areas of my body where they were before. That to me was total success. I could tell that this treatment was working well for me.

The beauty of it all was far fewer side effects of taking this type of treatment than all the others prior to this. No loss of hair, no nausea, no general fatigue, no mood swings, no other things that would come and go with the other treatments. They were gone. I can tell you that I’ve been a full year now with virtually no symptoms and taking a drug that has totally kept my cancer at bay.

I am so encouraged by it. I want to encourage everybody out there to investigate it if in your process of where you are with your cancer, you’re ready for this type of treatment. Because there are some things that you must do prior to getting into a PARP inhibitor type of medication.

 That’s right. The FDA label talks about prior therapies as well. Indeed.

PARP Inhibitors in Recurrent mCRPC

Let’s discuss treatment options. In your case, John, we’ve been through a number of treatment options, first-line hormonal therapy with Lupron, you got the Provenge, the sipuleucel-T, next-generation hormone therapy with pills, and then chemotherapy ultimately and now rucaparib.

That list represents much of the diversity, almost all the diversity, of systemic therapies for prostate cancer. There are other drugs in these categories—we haven’t necessarily used them all—but in broad terms, the combination of hormone therapy, chemotherapy, next-generation testosterone targeting, immunotherapy, and PARP inhibitors are just about all the categories, the last one being the IV [intravenous] radiopharmaceuticals like radium Ra 223 dichloride.

There are three major points. One is the journey of treating advanced prostate cancer is best viewed in total. We’re never talking about one treatment at a time but rather how we combine all these treatments to get you the best cumulative result. Right? Because there’s an interaction. Whatever you do first affects what you do second, and we always want to get the best combination and think in long-term terms, not just short term. But we also talked about the importance of focusing on your goals, how you define quality of life, and what your priorities are, so that we were really choosing therapy in a way that met your expectations. Every patient is different. We always emphasize in clinic that I never want to dictate to the patient what needs to happen. My job as your physician is to understand you, understand who you are, what you want, what’s acceptable to you and what’s unacceptable, and then give you the best option that I think fits what you want.

Perhaps with all those concepts in mind, did you feel like you understood the options along the various steps as we talked about them? You already told us that your daughter also always played a key role as the health care professional in the family in helping you work through it. What advice do you have for patients as they’re trying to have these conversations with their doctors?

 It takes a lot of introspection. You have to soul search. Things that are important to you that you might be willing to let go of—it’s better for your health if it makes sense because of the disease you’ve contracted. My journey on this started when I was 60 years old, and just last month I turned 71. Through those 65-plus, last five, six years, I’ve noticed a lot of changes in just aging in myself. What’s important is not struggling with aging. I used to go out and work out at the gym five days a week. Maybe you have some fatigue from the treatments or whatever you’re having but allow yourself to cut back, to let go of a couple of these things. Rather than being beneficial because you’re out there and maybe you’re missing one or two days a week of your physical exertion, you’re saving on the other side not stressing out about what it might do without being able to do that, that I’m losing my manhood. There’s a myriad of things that go through your head.

The important part is you just want to do the best thing for your body while you’re on treatment and extend your life. That to me was the sole objective here. I also felt because I got into participating in the human trials side of it, you would be excited about some of the results that were coming out of it. I felt I was doing good for everyone else. You need to find something that makes you feel good about where you are and how you’re going through the treatments. You’ve got to let yourself accept the disease, and then hopefully your caregiver and your family also accept the disease that you have and are just supportive of you, that they’re not trying to tell you, “Don’t do this. Don’t do that. Don’t listen. Go to a naturopath.” There are a million different directions you can go, but I’m here to give a testament to following the protocols that are out there today on the more advanced research techniques that are available to people with our kind of cancer. I swear by it 100%.

 It’s inspirational to hear you talk about it. There’s no question. The future patients, patients watching this now, owe you a debt of gratitude. You have absolutely changed the field with your participation in studies. Being one of the men who took the risk to say I believe in this concept, I want to take the chance—obviously it’s paid off for you personally, but of course you don’t know that when you sign up. You don’t know in advance that this is the one that’s going to work for you. Of course, it’s my job to make sure that it is, and that’s what I’m trying to do. Right?

Without question, every decision we make has risks and benefits. There’s always a certain gamble at some level or another. Thank you for your courage. Without question, the physicians and the patients with prostate cancer, we all owe you a debt of gratitude for having that courage to make these decisions.

Treatment Options Available for mCRPC

 We should tell the audience you went on rucaparib on the TRITON2 study because of the 

 mutation. In fact, that is the study that led to rucaparib being approved by the FDA for the treatment of prostate cancer with 

 mutations. You’re one of the men who decided to take that chance after we talked and contributed to bringing this drug to market for everyone else in the country. You’re still on the therapy. The drug is approved, the study is done, and it’s still working for you.

Yes, I am so pleased. The drug is manufactured right outside Denver, by Clovis Oncology. Being part of the study was interesting because there’s a lot of information on the internet about rucaparib. It lists the potential side effects that could take place. I absolutely did have one or two of the more common side effects that over the period here of 14 months, the dosage level of my drug would be reduced a little. It was getting to be hard on my kidneys, but finally, I got to the point where we found a balance, where my kidneys could tolerate the drug and I virtually got from slight symptoms the first two or three months of nausea to for eight months now I have not had a nauseated day, period. I wouldn’t even know I’m taking a chemotherapy drug on this, particularly rucaparib. I swear by it. It’s done wonders for me so far, and I’m still on it. I hope it continues to work for me for a long period of time.

We are over a year into this, I guess approaching a year and a half into this. I remain entirely optimistic that it’s going to continue to work for us. We don’t have any hint at all that that’s going to change. Again, you’ve done your part throughout in terms of taking care of yourself, healthy living, and working together. We’ve worked together through this with all the various changes we’ve had to make.

 Absolutely. I had to make a couple of lifestyle changes. I used to consume two or three glasses of wine at dinner a couple of days a week. I just stopped drinking alcohol. I’ve never smoked, so that worked to my benefit. But there were certain things that I just knew that I had to do. Whatever I could do—because you’re living with a depressed immune system, you don’t want to do something that’s more damaging to yourself that then works against the treatments that you’re receiving. It’s just smart to do what you can to keep your health better.

John Litten: Participating on a PARP Clinical Trial for mCRPC

 Mr. Litten, could you talk about when we started to talk about genetic testing in your cancer. What were your impressions of that conversation at first? What ran through your head as I started talking about testing the genetics?

I won’t say that I felt like I was going to be a guinea pig in a new series of testing. I certainly was interested, and it was relatively new. I would make sure the listeners understand just how intimately involved you are in the research side of cancer on a daily basis. When you would bring something forth to me, it was truly what I would consider cutting edge. It was the latest and greatest. Because I’ve been through three or four different processes from the initial pill form of chemotherapy to the heavy chemotherapy infusions—losing my hair, going through all of that, going through some fairly serious nausea periods and a lot of fatigue. When we got to the point where you were all over this new genetic testing and the possibilities and the fact that there were some human trials becoming available, you offered that to me. You said I want you to think about this, but I think this might really work well for you because, as it turns out, I did have that missing portion of the gene in my cancer cells, and I was a good candidate to move into the genetic trial of the PARP inhibitors. That’s been the most human trial, and I have been on it for going on 14 months. It’s done amazingly well in keeping my cancer at bay.

I would tell you that I listen to your advice because I had by that time the six and a half years of history of each process that you took me through. Each did the job of pushing my cancer back, reducing the size of my abdominal lymph nodes once it was identified as being there from the CT scans. Each process I went through seemed to work for a period until the cancer found out an immunity to it. Then it was time to move on to something else, so of course I was eager to move into genetic testing.

 That’s right. In this case it was the tumor specifically that had the mutation in the 

 gene, in Mr. Litten’s case. As he said, part of the gene was missing, which was a mutation that we could exploit by targeting it with PARP inhibitors. In your case, the family testing, the germline testing, was negative, so you didn’t inherit this gene. Therefore, you couldn’t pass it on to your kids, but it occurred in the tumor. It occurred in the cancer as the cancer grew up. Did you feel like this was a difficult concept to work through? How did you talk about this with your family?

 I would call my caregiver, my daughter, who’s a trauma registered nurse in Eureka, California. She and I would spend hours on the phone. She would review everything that you said to me, and I gave her access to my patient portal. She’d review everything and look at my scans. Every time she was very encouraging to me about the type of treatment I was getting and that I was going down the right path. [I would] start to get frustrated, saying I don’t think I want to try this. It was similar to people who are currently concerned and are contracting the coronavirus. What do you have to lose? You should try to figure out what the newest is, what the best is. It didn’t hurt me a bit to try it. As a matter of fact, I’ve been amazed at how easy it’s been to be on this PARP inhibitor and not really have serious side effects.

 You’ve certainly done well. There’s no question in my mind that your commitment to maintaining a healthy lifestyle, to having a positive attitude, and to really engage in this with positivity and determination has served you well in all these eight years. You’re certainly an example. I also have no doubt that your daughter has played a big role in this, in keeping you positive and helping you through it.

 That’s right. She is a tiger. She isn’t going to allow me to have a down day. She makes sure it’s all squared away before we hang up that telephone. She’s been a great help to me. Likewise, Dr. Bryce, you have too. Everything has always been very positive, very encouraging. Getting the opportunity to try the human trial meant a lot to me. I thought, if others could learn something from me participating in the trial, that would be an honorable thing to do. What did I have to lose? I want to do whatever is the next new thing out there that’s going to give me a couple of more years of life. I’ve always been very positive about this. It’s important for those of you listening who have the cancer to understand there are a lot of doors out there that can be opened for you. You must keep your mind open to listening to what your oncologist says and moving through all the new things. There are new discoveries almost every month of things that help different people with different forms of this cancer. You should be encouraged that there’s so much more out there now than there was eight years ago when I started on this journey. It’s just amazing.

Talking About Gene Testing in Prostate Cancer

 At this point, we want to pivot a little to a detail that ultimately became important in your prostate cancer management. The detail that we think is still underappreciated in terms of how most men are managed and how prostate cancer care is changing in 2020 is genetic testing.

For the patients listening online, genetic testing of cancer involves two different types of tests. All of us have the genes that we inherited from our parents, and these are the genes we could potentially pass on to our children. Cancer by definition is a genetic disease where your healthy cells have mutated to become cancerous cells. What that means, is once you have a cancer in your body, there are two different genetic populations. There are the genetics you inherited and the genetics that the cancer developed. In the last several years in cancer we’ve learned that by looking at the genetics you inherit and the genetics that the cancer has, we can sometimes find treatment options for patients. There can be certain drugs, certain therapies that target certain genetic signatures. It becomes a key question for every patient to talk to their oncologist about when and how we should consider genetic testing.

When we talk about the inherited genes, we’re talking about germline testing. That’s what we call the genes you get from your parents. Of course, half the genes you get from your parents you end up passing on to your children. The other half comes from the mom, since in this case we’re talking about men with prostate cancer. At this point, there are over 50 genes that the American Society of Human Genetics recognizes as being associated with family cancer syndromes.

One of the key things we emphasize when we talk about family cancer syndromes is that you often don’t know that you have it. Carrying a gene doesn’t mean that everybody is going to get cancer. It just means they’re more likely to. Back in the day when families were large and everyone had several siblings over several generations, then taking a family history was probably enough to figure out which families were at risk. But in the modern era, when families have two kids or they’re rather small, maybe someone is an orphan and an only child, you can’t rely on family history to figure out who needs to be tested.

It is now a recommendation in the United States by the National Comprehensive Cancer Network, by the American Urological Association, and by the American Society of Clinical Oncology that all men with advanced prostate cancer should have germline genetic testing. That’s because there’s at least a 5% and maybe up to a 15% chance that every male with advanced prostate cancer is going to carry a family cancer risk syndrome.

For men with metastatic disease, we also test the tumor. The most common gene we find mutated in prostate cancer is 1 called 

. The key point here is most people think of 

 as being associated with breast and ovarian cancer, but it’s also associated with prostate and pancreatic cancers. It’s not specific to women. It affects men and women alike. When there is a 

 mutation, research—including the trials that John has gone on—has proven that we can use a class of therapies called PARP inhibitors to attack those cancers. These therapies can be both highly effective and very well tolerated in terms of adverse effects and therefore extend a man’s life meaningfully with very manageable adverse effects.

This is a part of the journey when we want to talk about it a bit more, because I believe in talking to patients who come to my practice and looking at notes from outside, that the testing is probably not being done enough. We need to get to the point where every man is having this testing done.

Testing for Mutations in Prostate Cancer

 Let’s talk about how it took a few months as you considered your options and thought about what you’d like to do. You talked about the advice you got from a couple of surgeons and their own experience. How did you feel about the nature of the conversations? Were you getting enough detail? Were they too detailed? You must process a lot of information to make a decision like this. What was your process for trying to weigh the various options and the information you were getting?

 It was interesting because when you’re diagnosed with a disease of any sort, it doesn’t take long for that message to get out and get around. I had a couple of friends living around the state who had prostate cancer and had gotten through and were cured, and I had others who had also recently been diagnosed and were doing a couple of treatments. They reached out to me. They found me and said, “This is what I’m doing. If you want to know more about it, I’m happy to tell you.” They recommended of a couple of books to read that were very helpful.

None of those suggestions were what I based my decision on. It was a variety of things. I had never had surgery prior to that; that concerned me. On the other hand, I just took with the mindset that if I could remove the cancer from my body, I have one chance to do that, and that’s with surgery. From some of the reading on electron radiation, there’s potential collateral damage, there are seeds you can do. There are a number of different processes available to you. Everyone has to decide what’s best for them.

I immediately put my manhood and my virility on the shelf. I wasn’t going to allow myself to be stubborn about treatment. I was going to try to take the best advice, and once I got connected with you, Dr. Bryce, and the discussions that we had, I immediately found a comfort level in listening to what your suggestions were. I have followed through with every relative suggestion that you made for me to date, as it relates to the human trials I’ve been involved in and to the position that I’m in right now, which I feel totally blessed about.

 I appreciate that, and this is a key conversation for the audience to understand: that process of information gathering, getting that information from people who care about you. Reading what information you can, hopefully this podcast or broadcast is going to help some people as they weigh their options. I know you’re very motivated toward that in terms of educating other people.

Absolutely. An important note to hear is that the conversations that Dr. Bryce and I had initially were very detailed. I expected with so many doctors that I might have a 15-minute session or something with the doctor when I went in and we met face to face. I can tell you we had sessions that lasted well over an hour. Before I would ever leave the office, he would say, “Have I answered all your questions? Do you have more questions? Can you think of anything else that might be upsetting you or that you think you need to know about?” I just encourage gentlemen out there who have prostate cancer to never get up and walk out of the doctor’s office without getting your questions answered. It’s too easy to go home and get into a sense of worry, of “what if,” of “Could this happen to me?” and scare yourself unnecessarily. One of the keys to conquering your disease is to avoid stress and to do everything in your power to relax, take your medication as it’s dished out to you, whether it’s good news or bad news, and then just move through the process without allowing it to overtake your mental concerns and become really stressed about it. You must understand it’s a process, and you need to follow through with it. There are good things that come out of it.

 That’s great advice. I agree completely.

Prostate Cancer: Learning About Treatment Options

John, can you talk about your prostate cancer journey, how it was initially diagnosed by your primary care physician, and what were you thinking as you went through this process?

I had a very fortunate thing right out of college to move to a really beautiful small island in Sitka, Alaska. I lived there for close to 50 years. We didn’t have what I would consider to be the best medical teams available. Annually, I would get a physical, but my doctor didn’t check for the condition of my prostate. It wasn’t until one winter when I was south and I needed to get a prescription refilled and couldn’t do it because I wasn’t home, that I went to a new doctor and said, “I need to get this prescription filled.” He said, “I will, but not until I do a physical.” Well, he checked my prostate and immediately said, “Mr. Litten, you have prostate cancer, and you need to see an oncologist immediately. I’m going to schedule that for you.”

I had no symptoms you could have prior to that point, no urinary problems or any blockages or anything. My emotions ran the gamut from when you’re told you have cancer to be a bit shocked, and even greater was not knowing what to do. I immediately read through a couple of books because there are seven, eight, nine different approaches to how you might treat prostate cancer. I was trying to figure out what the best thing is, what I should do. On advice of a couple of medical surgeons I knew who both had had prostate cancer and had their prostates removed, they talked me into going in that direction.

I flew back to Northwestern University [in Chicago], and I had my prostate removed. That was four to five months after I was initially diagnosed with cancer. At the time of my surgery, the doctor was fairly convinced that the margins were clear, that the prostate was removed. He didn’t recommend radiation or any other treatments at the time. He thought that I would probably be OK after that. Actually, I was OK for about a year and a half. Then all of a sudden, as I had a blood test, my PSA [prostate-specific antigen] level began to climb.

That’s when I came to you to help take care of my medical journey with this cancer. As you initially described all the potential types of prostate cancer you can have, I align with everything you say. I’m at the castrate-resistant, metastatic prostate cancer. Fortunately, because I have been under your direction, I’ve had the opportunity to go through three different human trials.

Most patients start with Xtandi [enzalutamide] and Zytiga [abiraterone acetate]. Those are the initial processes that I got involved with in trying to slow my cancer down. Then it was under your recommendation that I go forward with the Lupron [leuprolide] injection. That is a female hormone injection. They said the side effects that I want to be watching out for were hot flashes, but I don’t know that I ever really experienced that. It was imperative at that point to do exactly as you said, to reduce my testosterone production down to as little as you can.

As you’ve explained to me in other discussions, it’s impossible to completely eliminate your prostate production because it can come out of other organs. But you have to stop feeding the cancer somehow. That was my initial journey in getting to your office. Then at that point, I have followed all your recommendations.

I can remember our first conference. At that point, people that were in my condition said that you probably have a fairly secure three to five years to live without it taking your life. That was eight years ago. I feel blessed in the treatments I’ve received to date.

 The journey is difficult. Everything you’ve gone through in terms of the education and the emotional evolution, you really took the bull by the horns to say I need to take care of my health. Right? You did a lot of research. You sought out different doctors. Also, credit that to the primary care physician who did the physical exam and found the cancer when it was still relatively early at least and before you were in trouble with it at the time. It clearly emphasizes how important it is to do that kind of screening.

 Absolutely. You should be screened annually. Every physical that you have, your prostate should be checked because it can change quickly in a year, from normal feeling of no cancer to finding a lump. That typically is your first indication to a doctor that it’s time to do something, that and potentially your PSA score.

Receiving a Prostate Cancer Diagnosis

Hello, my name is Dr. Alan Bryce. I’m an oncologist at the Mayo Clinic [in Phoenix], with a practice specializing in prostate cancer. I’m here today on 

® with my patient and friend, Mr. John Litten. John has been a patient of mine for several years. We’ve been treating his prostate cancer, and he has become a passionate patient advocate and educator and has volunteered to be with us today to talk to you about prostate cancer. 

My name is John Litten, and I’ve been a patient of Dr. Bryce’s through the Mayo institute for eight years. I don’t know how often human trial research is available to the viewers who have the same type of prostate cancer. It’s been an incredible journey so far. Fortunately, because of my connection here with Dr. Bryce, he has led me down the path of a variety of treatments up to the one I’m on right now. I guess we would start from when I first came in and got started with you.

 Let’s begin with a general overview of prostate cancer. After we introduce that, we’ll discuss the general terminology and classification of prostate cancer. We’re going to talk with Mr. Litten about his journey with prostate cancer, how the diagnosis started, and his insights on what it’s like to be a patient starting down this path.

In terms of an overview, prostate cancer remains the second-most common cause of cancer-related death in U.S. men. It’s the most common nonskin cancer diagnosed in U.S. men and affects about a quarter of a million men a year. About 85% of those men are going to do very well, but roughly one in eight will develop life-threatening disease, and about 30,000 men a year will die of prostate cancer in this country. Oftentimes it’s thought to be a disease that moves slowly, and men will die with it, not from it. In fact, it’s still a major public health problem and something that requires a lot of work for us to solve it to make sure that we’ve cured this and reduce the death rate.

In terms of aggressive prostate cancer, we consider prostate cancer to be advanced. If it spreads beyond the prostate and reaches the lymph nodes or other organs in the body, at that point we call it metastatic prostate cancer. That’s the form of prostate cancer that can be life-threatening. In the early stages, we’re going to treat that kind of advanced prostate cancer first with hormonal manipulation. The reason we do that is because prostate cancer cells in the early stage are much like the normal healthy prostate cells.

The prostate, of course, is a male organ. It develops in the embryo when the fetus gets exposed to androgens, such as testosterone and related hormones. Even throughout development in adult life, the prostate continues to be stimulated by testosterone. One of the most effective ways to treat prostate cancer in the beginning is to take that testosterone away. That’s what we call actual chemical castration. That usually works well in the beginning until the cancer starts to become resistant to that and grows despite low testosterone, and that’s what we call castration-resistant disease.

Prostate cancer can cause a variety of symptoms. In the early stage it’s often urinary obstruction because the prostate sits right under the bladder. The urethra passes through the middle of the prostate, and if a cancer is growing in that space, it can cause pure mechanical obstruction of the urine flow. But if the cancer starts to spread, it can cause a variety of symptoms. If the prostate cancer becomes bulky, then it’s an organism—it’s a parasite if you will—competing for the man’s energy, so it can cause weight loss or fatigue. If it starts to show up in organs like the bones or the liver or the lungs or places like that, it can start to cause pain or obstruction or other symptoms based on its size or location.

One of the most important aspects of prostate cancer management and decreasing the burden of this disease in American society is screening. We prefer to catch cancers early when they’re most curable. This remains a controversial topic in U.S. medicine. How do you appropriately screen for prostate cancer? It’s a topic that makes a lot of men uncomfortable.

Metastatic Castration-Resistant Prostate Cancer Overview

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.

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.

FDA-Approved PARP Inhibitors for Prostate Cancer

 What impact would a mutation have on a patient? If you find out that they have a germline [mutation], that means that they inherited it from somebody. And that they could potentially give it to their children, and that their brothers or sisters, uncles and aunts may also have that mutation. Therefore, they need to inform their family that that gene exists in the family. I remember one of my patients had a FANC gene, and he had given me an unusual history of a cousin who had leukemia and an aunt who had a brain tumor.

And then I discovered that he had the Fanconi anemia gene, FANCC. Then all of a sudden the world opened up, and his cousin with leukemia discovered that she had the gene and it’s an autosomal dominant, and then all of a sudden his kids had to know. It became important for his family to know about that gene. Some people can’t find their family. I had one guy with three daughters. He had a BRCA1, and he doesn’t know where his one daughter is. They got estranged during a divorce, and he’s tried to get a hold of her and can’t. This is the social side of this testing. On the other hand, if the patient has only a somatic [mutation], that means they cannot transmit it to their children and it was not inherited.

Because the Food and Drug Administration has approved two drugs for these genes, rucaparib and olaparib. Both called PARP [poly ADP ribose polymerase] inhibitors. There are other genes now that we need to know about, because those include Lynch syndrome, which can occur in prostate cancer. That’s what we call MMR gene mutations. We never do just one gene, we always do a whole panel of genes. But if the patient is found to have a BRCA gene and they have advanced cancer outside of the prostate, that means that they would become a candidate to be treated with either rucaparib or olaparib. These two drugs are FDA approved for BRCA mutations. Now, olaparib is approved for a few more genes than rucaparib. But those are relatively minor distinctions.

Most of the patients with prostate cancer are going to have either BRCA1 or BRCA2, for which both drugs are approved. The approval was given based upon big studies, research studies. For rucaparib, this was TRITON, that was the name of the study, TRITON2 and TRITON3. And for olaparib, that was approved based upon PROfound. All of these were research studies. And based on these studies, the FDA approved the drugs for treatment in these men. These men have to undergo other treatments first. Right now there is no recommendation to give these drugs as the first line of treatment.

We’re working on that. We’re working on giving it earlier. It may be more effective earlier. But right now, we’re giving it after hormone treatment has failed. Usually two types of hormone therapy must fail before we’re allowed to give either of those drugs.

Impact of BRCA Mutations in Prostate Cancer

 About 25% of patients with prostate cancer, maybe less dependent on where their age falls or what their grade group is, have mutations that cause prostate cancer. The most common genetic mutation causing prostate cancer is called the BRCA gene. It is commonly called BRCA2. There is a BRCA1 that is less serious. And then there are about a dozen or more other genes that, when broken or mutated, can also cause cancer. These genes are commonly inherited from the parents. The BRCA gene can come down from either your mother or your father’s side. The BRCA gene may cause breast cancer in women. It also may cause ovarian cancer.

In other cases, pancreas cancer or uterus cancer. Any one of those cancers could be caused by a BRCA gene. Now, the FDA [United States Food and Drug Administration] and what we call the guideline group, NCCN [National Comprehensive Cancer Network], recommend that all patients get BRCA tested, or at least genetically tested if they have a family member with one of those cancers or if their father or brother had prostate cancer, or if they’re particularly young. Frequently we do genetic testing on men who have a four or a five [grade group]. Typically, we don’t do genetic testing on one or two grade group cancers. Sometimes on a three, if their family history warrants it, or if they’ve had another cancer. There are a variety of reasons why you would do genetic tests.

Genetic testing can be done in two ways, and should be done in two ways. Number one, you do the germline. That means that the cancer we suspect is inherited from one of the parents. Or you do somatic, which means that you got struck by lightning and you’ve got the gene, but you didn’t know where it came from. And those may be things like Agent Orange, or external beam radiation, or any number of ways that you can inherit it. We do somatic [testing] on the cancer itself. We do germline on your saliva or blood. There are now ways to do germline on the cancer, and there are companies that will do both on one specimen, which is time-saving, and allows us to get an answer quickly.

If we discover one of these genes that are mutated, we as doctors, begin the process of talking to the family about these genes. It’s a bit complicated. And so that’s where a genetic counselor may come in. Some doctors will refer the patient to the genetic counselor and let the genetic counselor do all the work. That’s what I used to do. Now, I do most of it myself. But when the family is complicated or when I’m not sure about the gene, then I send them to the genetic counselor.

During counseling there are many complexities. Many of them are not known today about what the gene does. We call those the VUS genes, variant of unknown significance. Many times you will find a man who has a mutation of an important gene. Let’s say they have CHEK2, that’s one of the common genes that can cause prostate cancer. Then there comes a report saying VUS. And you don’t know, you literally do not know. For example, I’ve had a variety of patients from Cuba, and I’ve had a number of BRCA1 mutations in my Cuban patients that are VUS. And we don’t know, is that a cancer-causing mutation? Or is that just a carrier mutation that happens to be part of the Cuban legacy? There are many areas in which we don’t know. And usually I will refer them to the genetic counselor for further evaluation.

I’ve done this so many times now that I don’t need a genetic counselor right away.

Genetic Counseling for Prostate Cancer 

: Prostate cancer occurs in between about 200,000 and 250,000 men a year. Prostate cancer comes in five general varieties. We have summarized those, initially in what was called the Gleason score, that was one to 10. That has been contracted down to one to five. They come in five types; one, two, three, four, and five.

There are other types, rare subtypes, and those are dealt with on a separate basis, including sarcomas and small cell carcinomas, but typically we’re dealing with the 5 types. Once a patient is diagnosed, the first thing we want to know is what type you have. The diagnosis is made based upon the PSA blood test, prostate-specific antigen. It’s a blood test that has been used for many years. It is effective for measuring the amount of prostate cancer in the blood. If the PSA is a little bit elevated, that leads to a suspicion that you may be dealing with prostate cancer.

The next step is the rectal exam. That is then followed by either an MRI [magnetic resonance imaging] of the prostate or a prostate biopsy. Based upon the biopsy, the diagnosis is made. The results can range from a little bit of cancer to a large amount of cancer. And it also is a function of your PSA number. PSA can be normal, it can be high, or it can be very high. Everyone is categorized by their PSA number, by their grade group, one through five. And usually, depending upon what the number is, we do what we call staging. This includes the bone scan, CT scan, [computed tomography] and in many patients, an MRI 3T, that’s tesla, 3T, or three tesla MRI, which is specific for the prostate tissue, in prostate cancer diagnoses. At the end of that period we categorize the patient as to what stage they are. 

All patients will be categorized into where the cancer is. There are three basic categories of where the cancer is: localized; regional, that is outside of the prostate maybe in lymph nodes; or metastatic, that is spread to the bones or other organs. There is debate as to whether a lymph node should be considered metastatic. Generally, we call that metastatic, but it’s a different category. My patient today had a PSA of 84 [ng/mL], his grade group was four, and he had it in lymph nodes. He was treated with hormone treatment alone, and then today I recommended that he also have radiation to the prostate, to the lymph nodes, and hopefully will be cured. Each patient falls into those categories, and you must be careful to get it right, because a lot of the patients are curable.

And a lot of the patients, particularly those in grade group one, that have only little bits of cancer in the prostate, don’t need any treatment at all. The treatments vary by the type of cancer they have. If you’re a grade group one, relatively low PSA, good MRI findings, you may not need to be treated. On the other hand, if you’re a grade group three or four within the prostate, you should be treated with radiation or a surgery. If you’re a four and have it outside of the prostate, you’ll need to have the hormone treatment and maybe radiation or surgery.

For those that are spread outside of the prostate in the bones or other, hormone treatment, ablation of the male hormone, testosterone, antitestosterone therapy is indicated. That’s a very broad overview of the field.