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Conversations With Prostate Cancer Experts


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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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Clinical Trial: Free Genetic Testing

Dr. Heather Cheng is an Assistant Professor at the University of Washington and Fred Hutchinson Cancer Research Center, and the Director of the Seattle Cancer Care Alliance Prostate Cancer Genetics Clinic.

Prostatepedia spoke with her about a clinical trial she’s running that looks at inherited genetics of men with metastatic prostate cancer.

What attracted you to medicine?

Dr. Heather Cheng: There are a couple of things I love about medicine and especially oncology. One is getting to know patients, finding out what’s most important to them as people, and using that information to help guide discussions and decisions about their treatment in a way that is true to what is most important to them. These days I guess you call this shared decision-making. That’s the most rewarding part about what I do.

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

Dr. Cheng: I have a lot of patients who fit those criteria. My interest in this area started when I was a first-year Hematology and Oncology fellow. I was in the clinic and it was when we were at the beginning of this wave of new exciting drugs that prolong survival, such as Zytiga (abiraterone) and Xtandi (enzalutamide).

I met this patient who was 43 years old; he had new, aggressive metastatic prostate cancer. His disease blew through every one of the new drugs. It was extremely humbling and disappointing because we were so excited about these drugs, but they didn’t do much to slow his disease. And it was heartbreaking because he was so young. He had a family history of cancer but not prostate cancer. He had a teenaged son. We had a lot of discussions about the effect of his disease on his son. I wondered if there was something genetic, something that was making his cancer so aggressive. And then, what could this mean for his son? His memory has stuck with me.

When I think about the work and research that I do, it’s not just for the individual patient in front of me. I’m also thinking about how we can improve things and advance the field so things can be better for the next generation. How can we make progress as quickly and with as much positive impact as possible?

I met another patient who had a great effect on me. He had just been diagnosed with high-risk prostate cancer, Gleason 9. He was planning to get radiation. As part of a research study, we offered to sequence the DNA of his cancer because he had an unusual appearance of his cancer– ductal histology. He was kind and generous enough to volunteer and participate. It wasn’t going to affect his treatment, but he agreed to help us learn more.

In his cancer, we found a mutation in the BRCA2 gene, the one that many people may have heard of because of its association with breast and ovarian cancer risk. There was suspicion that the mutation could be inherited, so we brought him back for dedicated genetic testing for inherited cancer risk. And, it turns out he did have an inherited version of that mutated BRCA2 gene. He was the first person in his family to be found to carry the mutated version of BRCA2. Neither he nor his family would have known until later if we had not looked in his tumor.

After this, some of his relatives had genetic counseling and were also tested. The sister who had breast cancer had a recurrence and was found to carry the BRCA2 mutation. This information was important for her because it offers additional treatment opportunities for her cancer that might not have otherwise been considered. His daughter was also found to carry the BRCA2 mutation and after learning of this, had a mammogram and was diagnosed with breast cancer. She’s still curable, so she’s going through treatment, but it is possible that she might not have known until much later otherwise.

The importance of test results can extend to relatives in a way that might help more than one person, not just the person that I see in the clinic, but other members of their family. I do want to be clear that these mutations are not found in most people— even those with cancer—but for the people who have these mutations, it can be life saving information for their family members.

What will you be doing, and what can men expect to happen, during your clinical trial?

Dr. Cheng: You can learn about the study from your doctor, support group, or by visiting our website, http://www.GentlemenStudy.org. There is information about the study. You can consent online, confirm that you have metastatic prostate cancer, and check that you’re interested in genetic testing for cancer risk.

There is a questionnaire that many take about 40 minutes to complete, that asks about your knowledge of genetics, basic health, family history of cancer, and demographic information about where you live.

You can upload supporting information about your diagnosis, or you can check a box saying you’d like help from the research team to gather that information on your behalf. Because there are strict privacy laws around medical records, you need to give permission to our team to get medical information for the study on your behalf.

To be eligible, you must have metastatic prostate cancer and must live in the United States. There’s one other exclusion, which is that if you have some blood disorders such as leukemia, we cannot be sure that the test results are valid.

If you meet criteria, you will be mailed a saliva kit, a medical-grade genetic test through Color Genomics, with instructions on how to provide a saliva sample. Follow the instructions carefully and then mail the kit back. Results are typically available within 4 weeks. You will have access to a genetic counselor following your results, and you are invited to follow up in person to our clinic if you live in the area. If you don’t live near us, we can direct you to resources to find a genetic counselor for in-person visit or by telehealth.

The testing for this study is not recreational testing. It is not the same as Ancestry.com or 23andMe. This is clinical, medically appropriate testing if you have metastatic prostate cancer.

Do you share this information with their doctor, or is it up to them to share the information with their doctor?

Dr. Cheng: We strongly encourage participants to share the results and information with their doctors, but our ethical board does not allow us to do this for participants without their specific consent.

Are there any fees for patients?

Dr. Cheng: There is no fee for the patient.

It sounds similar to the process for the Metastatic Prostate Cancer Project, except I don’t think they share their results.

Dr. Cheng: Yes, it is similar to that project. The difference is that the patient or the participant gets results that apply to them individually. The Metastatic Prostate Cancer Project, which is fantastic and an important and innovative study, is de-identified, and the patient doesn’t get individual-level results back.

Their goal is to amass as much data as they can for research.

Dr. Cheng: Correct, yes.

Are you also cataloging the information that you collect?

Dr. Cheng: Yes.

What will you do with the data that you collect?

Dr. Cheng: We’ll be looking at demographics, the proportion of people who have mutations (pathogenic variants), information about family history, and validated measures of knowledge, distress measures and satisfaction with testing.

If patients consent to re-contact, they will be contacted at the conclusion of the study. If there are other follow-up studies, they can opt to learn about those. There will also be an invitation for those who agree to subsequent studies, like treatment studies or PARP-inhibitor studies, for example.

We’re still learning about certain genes, such as ATM mutations and CHEK2 mutations. As we learn more, we may want to update participants on what the field has learned. There are still many important questions that the field needs to answer, and patient engagement and participation will make this happen more quickly. There will be opportunities for those downstream studies.

How many patients are you looking for, overall?

Dr. Cheng: The plan was for 2,000. We have sent kits out to over 350. We still have room for participation!

Join us to read the issue and learn how to participate in Dr. Cheng’s study.

 


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Clinical Trial: Zytiga, Lynparza, + DNA Repair Defects

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 about a clinical trial she’s running, BRCAAway, that looks at Zytiga (abiraterone) and Lynparza (olaparib) in metastatic castrate-resistant prostate cancer (mCRPC) patients with DNA repair defects. (The trial has a ClinicalTrials.gov Identifier of NCT03012321).

What can you tell us about the trial that you’re running looking at Zytiga (abiraterone) and Lynparza (olaparib)?

Dr. Maha Hussain: In prostate cancer, and specifically in mCRPC, data emerging from multiple resources, including the Stand Up To Cancer initiative from a few years ago, indicate that greater than 20% of mCRPC cancer harbor DNA repair pathway aberrations. These types of defects in the tumor will allow the patient to potentially be a candidate for PARP inhibitors. In this regard, PARP inhibitors have had a track record in ovarian and breast cancer.

They’re currently undergoing multiple clinical trials, including Phase III clinical trials in patients with advanced disease and in different settings of the disease.

A couple of years ago, we published data from an NCI-funded clinical trial where patients with mCRPC underwent a biopsy of their metastatic cancer. The patients were then stratified by the presence or absence of ETS gene fusion and randomized to Zytiga (abiraterone) and prednisone with or without a PARP inhibitor called veliparib.

As part of that study, we also looked at other tumor genomics when extra tissue was available. We discovered that the patients who had tumors with DNA repair defects seemed to respond much better to treatment with Zytiga (abiraterone) with or without veliparib as opposed to the patients who did not have that. This is not something that anyone knew before. After we had published our data, the Johns Hopkins team published data they had on patients who had undergone germline testing and who had received Zytiga (abiraterone) or Xtandi (enzalutamide). They reported similar observations.

This leads me to the current trial, which we call BRCAAway. BRCAAway is a prospective clinical trial for patients who have developed mCRPC for which they have not yet received any specific treatment. Patient will undergo a biopsy, unless they have previous tissue available from either the primary or metastatic disease, and the tissue will then be evaluated for the presence of specific DNA repair defect alterations. Per the US FDA guidance, patients who have BRCA1, BRCA2, and/or ATM are randomly assigned to either Zytiga (abiraterone) + prednisone, Lynparza (olaparib), or combination Zytiga (abiraterone) + prednisone and Lynparza (olaparib). Any patient whose tumors have other DNA repair defects (not BRCA1, BRCA2, or ATM) are enrolled into an exploratory arm where they will receive Lynparza (olaparib). Lynparza (olaparib) is provided by the study. The patients who are randomized to the arm of the Zytiga (abiraterone) or Lynparza (olaparib) can cross over to the other treatment if their cancer is progressing; i.e., if a patient who is randomized to Zytiga (abiraterone) and prednisone and then develops progression of the cancer is interested and his physician deems it appropriate, he can switch over to Lynparza (olaparib). The same is the case for patients who are randomized to Lynparza (olaparib) if they progress on frontline Lynparza (olaparib), they can switch to Zytiga (abiraterone) and prednisone per standard-of-care.

Are you assuming that these patients have already been tested for BRCA1, BRCA2, and ATM, or will you be testing for that?

Dr. Hussain: So long as it was done in a certified and appropriate lab, we can accept the data for patients who have been tested. The study covers a biopsy and the genomic testing for the patients.

Are there any fees associated, or is everything covered?

Dr. Hussain: Anything that’s standard-of-care is billed to insurance. Anything that is a research procedure, as in the biopsy and the genomics testing, is covered by the study. The Lynparza (olaparib) is provided by the study, but the Zytiga (abiraterone) is not because that’s part of standard-of-care. All of these tests to assess the cancer, assess tolerance, and assess the cancer progression in terms of scans, things like blood work or anything for safety assessment, per CMS rules, are billed to insurance.

How many patients have you already enrolled, and how many are you looking to enroll?

Dr. Hussain: In the arm with the BRCA1, BRCA 2, and ATM, we need 60 patients. We’re about halfway there. We have enrolled 40 patients to date. For the exploratory arm, we have expanded our limit, and we’re growing that arm. So far, we have plenty of room to accrue more patients.

How many sites do you have?

Dr. Hussain: We currently have 15 active sites.

That’s a lot.

Dr. Hussain: It’s a lot of sites, but as I’m sure patients appreciate, part of it is that by the time we see an eligible patient, they have to have the specific mutations, whether it’s on new tests or based on previous tissue. When we test, it’s roughly one in five who will likely be positive. Of course, they have to qualify by other criteria, so we have to screen many patients. We’re on track as we forecasted, and we’re hopeful to finish enrollment by a year from now. We also hope to have some important data to share.

Wow! That’s fast.

Dr. Hussain: Of course we need adequate follow-up to assess clinical benefit and its duration. I’m thinking 2020 will be the end of the study, and if there are signals earlier, we will be reporting the data. The Prostate Cancer Clinical Trial Consortium (PCCTC) is acting as the coordinating CRO. The institutional review board (IRB) of record is Northwestern University IRB. If you’re interested in learning more, please visit https://clinicaltrials.gov/ct2/show/ NCT03012321?term=brcaaway &rank=1 or email cancertrials@ northwestern.edu.

Is there anything else you want patients to know about this particular trial or about the context in which it’s occurring?

Dr. Hussain: This and other clinical trials are important options for patients to consider. Clearly, they have access to regular standard-of-care treatment. The hope is that we can do better than standard-of-care. We are also trying to validate earlier observations that I mentioned regarding whether the patients who have DNA repair defects have better response to Zytiga (abiraterone) and how does this response compare to Lynparza (olaparib) versus the combination.

Lynparza (olaparib) is a drug that’s available on the market for breast and ovarian cancer, so there’s a fair amount of experience with it. It is not yet FDA approved for prostate cancer, but we have a reasonable understanding for the potential side effects. Certainly, there are multiple clinical trials that are looking at it and other PARP-inhibitors in prostate cancer.

Zytiga (abiraterone) is standard-of-care and FDA approved. It’s been around for many years. All treating oncologists should be very familiar with it and how to monitor and what to expect.

It looks like an exciting trial.

Dr. Hussain: We are very excited. What is clear from the experience with prostate cancer is that one size does not fit all, this is one of the first examples of precision medicine in front line mCRPC. Our goal is to better personalize care and significantly impact disease outcomes.

The patient is our partner. We cannot succeed and deliver better treatments to patients without their partnership, so we are very grateful to them for their participation.

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Prostate Cancer Dormancy + Disseminated Tumor Cells

Dr. Julio Aguirre Ghiso is a Professor of Medicine, Hematology and Medical Oncology and Oncological Sciences at Ichan School of Medicine at Mount Sinai in New York City. His research explores why and how in some patients disseminated tumor cells can remain dormant for years after initial treatment before reactivating to form incurable metastases.

Prostatepedia spoke with him about his research and about a clinical trial testing his findings that is currently looking for prostate cancer patients.

To  learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us or download the issue.

Why did you become involved in cancer research? What is it about cancer research that has kept you interested?

Dr. Julio Aguirre-Ghiso: When I was an undergraduate student, I was looking for challenging problems to solve in biology. Serendipitously, I started working and volunteering for a cancer biology team in Argentina, where I trained. I became very interested. I was working on tumor immunology. Then I became very interested in the cell biology of cancer cells. At some point, I realized that it didn’t really matter if it was cancer or Alzheimer’s or some other basic biological questions on other organisms; what I really was curious about was solving tough problems and answering questions. This was a good mix where, if I were able to do it, I would also be helping people with cancer in the future.

Focusing on cancer would give me an opportunity to apply my curiosity to something that is relevant for people. That was the original intention. Since I was not an MD, my curiosity was about mostly biological questions. This was a fitting problem to go after.

Let’s talk about the concept of disseminated tumor cells. Can you explain to us how that works and how it is related to the development of metastasis?

Dr. Aguirre-Ghiso: Patients usually present with what’s called a primary tumor. That’s the first cancer lesion ever found in that patient. At that time, doctors will do certain tests on that primary tumor to understand if it had gone through certain changes that would make it able to spread. When cancer cells grow, they may acquire certain abilities that allow them to spread from that primary site—from, let’s say, the prostrate or the breast—to other parts of the body.

The disseminated tumor cells are these cells that have spread throughout the body. They have disseminated from the primary tumor to other organs in the body. Those could be the bones; the liver; the brain; or the lung. When they arrive to those organs, they’re not immediately able to grow. Since they’re usually solitary cells–that’s how we find them in the patient samples and in the mouse models that we’ve used—we call them disseminated tumor cells. They’re not yet metastases, but they’re not in the primary tumor. They’ve left and arrived to other organs. That’s the definition of these disseminated tumor cells.

Why are they important? We and others have provided compelling evidence that these cells are the source of the metastases. Those are the cells, not all of them, but some of them, that are able to eventually grow into metastases that affect the functioning of the organ, and sometimes systemically, the functioning of the patient. That’s what leads to death. That’s why these cells are important.

Do all disseminated tumor cells eventually grow into metastases?

Dr. Aguirre-Ghiso: No.

How do you know which disseminated tumor cells are going to grow into metastases and which are not?

Dr. Aguirre-Ghiso: Well, that’s been a major challenge and a major push from my program: to try to get in early and identify those disseminated tumor cells so that we have some idea if a patient carries disseminated tumor cells that are not going to do anything and the patient doesn’t have to worry, or if the patient carries some cells that look like they’re switching and they’re going to form metastases.

That has been our goal. It’s not yet a clinical test, but that’s why we have pushed the boundaries of our research to get to that point as fast as possible because we think that instead of waiting and not doing anything or treating blindly and then waiting until those metastases grow, we can intervene earlier. We would like to be able to say that this patient has only dormant cells and they don’t look like they’re going to reactivate based on certain markers or gene signatures.

That patient would then only need to be monitored, but new treatments may allow eliminating even those cells. If another patient has a mixture of cells some of which are fully dormant and some of which look like proliferative cells, we would treat him in a different way.

We have provided data for this from our mouse models and from clinical patient samples in prostate cancer. We published two papers in 2014 and in 2015 on this.

Not all cells are going to grow.

In fact, if you look at early lesions in breast cancer, for example, disseminated tumor cells are found in the bone marrow of 13-15% of women with ductal carcinoma in situ but only a small fraction of that 13-15% will develop metastases. It’s not a given that if these cells are there they’re going to grow, but if they are there, there is a higher risk of metastases. That has been proven by large population studies that have been published in The New England Journal of Medicine. This is true for not only breast cancer but for other cancers as well. The goal and the challenge is to have enough information to be able to predict accurately what those cells are going to do when you detect them.

Where we are in the timeline of being able to predict which patient is carrying potentially dangerous disseminated cancer cells and which is carrying dormant disseminated cancer cells?

Dr. Aguirre-Ghiso: We have different areas of research into these disseminated tumor cells. Why they are dormant? Why do they sleep in the body for a long time and then awaken? We discovered a marker in 2015 that could distinguish these deep-sleeping cells in both prostate cancer and breast cancer models. If the cells had this marker, they would behave in this dormant way, and if they didn’t have this marker, they would look more like a proliferative or an about-to-reactivate cancer cell.

At that time, it was correlative between just two groups of patients. Last year, we published a paper on breast cancer where we used the same marker detected in tumor cells disseminated to the bone marrow of breast cancer patients. We were able to show that if patients had this marker they were much less likely to relapse with bone metastases than if they didn’t have this marker. In 2015, we’ve published the original finding where we just said this is probably a good marker; we understand how it works in mouse models. In 2018, we showed that the presence of the markers can distinguish retrospectively how patients behaved. Now the challenge is for people to start using the markers prospectively to see if it helps them make decisions on how to treat or monitor patients. We are very much at the early stages of applying the information that we have generated and bringing it into the clinic.

On the other hand, in that same 2015 paper, we were able to show that if we use two drugs that are FDA-approved and combine them in sequence, we can turn on these dormancy mechanisms in different types of cancer cells—i.e. breast, prostate, and head and neck cancer cells. Because these drugs were available—and there are independent studies showing that when prostate cancer patients are treated with hormonal therapy and anti-androgens, they turn on this marker of dormancy that tells you the cancer is deciding to go into sleeping mode— we wondered if we could repurpose those drugs and treat prostate cancer patients at risk of developing metastases to see if we could delay the onset of metastasis and keep the disseminated tumor cells in a dormant state.

To read the rest of our conversation and to learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us. Or download the issue.


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Clinical Trial: Combining Erleada (apalutamide) with Zytiga (abiraterone)

Dr. Eleni Efstathiou is an Associate Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas.

She spoke with Prostatepedia about her clinical trial combining Erleada (apalutamide) with Zytiga (abiraterone).

What is the thinking behind your trial combining Erleada (apalutamide) with Zytiga (abiraterone) in men with metastatic castrate-resistant prostate cancer? Why this combination as opposed to another?

Dr. Efstathiou: Here is the idea. There is a large trial on combining Zytiga (abiraterone) and Erleada (apalutamide) for all patients who have failed original Lupron (leuprolide) injections or standard androgen deprivation therapy. This trial is for men with metastatic castrate-resistant disease; it compares that combination to just one of the agents alone. I’m part of the steering committee for that international trial.

The trial that I just initiated here at MD Anderson is a smaller trial. This trial is trying to identify and confirm a subset of men who harbor cancers that are going to be exquisitely sensitive to the combination and may need no further treatment for years and not just an average of about a year

This all started with my first trial, now 11 years old. That specific trial was characterized by the fact that the men who received Zytiga (abiraterone) underwent biopsies of their bones while on treatment so I could study what was going on in the cancer realtime. It showed me that 70% of the men would respond. There was a reaction in the cancer cell while the androgens were dropping and they were undetectable. Their androgen receptors were going up. The next trial that I did used a drug that is very close to Erleada (apalutamide) called Xtandi (enzalutamide). That trial showed exactly the inverse, that as you gave that drug the receptor was switched off, but the androgens went up. All of this is in the tumor cells. This means there is some feedback happening, but does this feedback contribute to resistance? Could the combination actually help these men who get both drugs survive longer and get better responses?

But there is a caveat. I looked more carefully to find the characteristics in the tumor samples taken prior to treatment and found that there were specific molecules that, if expressed, were associated with a benefit. It made sense to me to focus on those specific characteristics in the cancer and try to combine.

I then did another trial where I combined Zytiga (abiraterone) and Xtandi (enzalutamide) and looked to see if my theory made sense. It did. It looked like the men who had these molecular characteristics responded better on the combination than those who didn’t.

But that was all hypothesis. The next thing you need to do when you discover something is test it. Then you need to confirm it to validate it. I used a 180-patient trial to test it. The next step would be the validation if testing looked promising. A validation means you have preset the parameter of the research trial; you’re trying to become agnostic to the outcome so you’re not biased in any way.

The testing also panned out. The trial we’re now discussing is the validation. Patients who come in the door accept to undergo a biopsy. We don’t need to do the old-school bone marrow biopsies anymore. We have great radiologists who go in with very fine needles and take several samples so the patient has no pain, just the discomfort of the process. Then we look at the cancer cells to see if they have these characteristics. I would tell you that about 30% of the cases have these characteristics that would make them eligible for the trial. The men who do have these characteristics in their cancers start treatment. If my hypothesis is correct, the validation will be that 90% of these men should respond in an outstanding and protracted fashion. I’m trying to hone in on who would be the ideal candidate for a combinatorial trial. The way the field is going, we’re throwing all the drugs at all patients; that helps a lot of people to a degree, but on the other hand, it causes a lot of toxicity, especially if you combine two rather than one agent. That is the main gist of this trial.

What can men expect to happen step by- step?

Dr. Efstathiou: You get a biopsy. In about a week, we tell you if you area candidate or not. You start the treatment. Then it’s quite straightforward: we follow you just as you would be followed in your doctor’s office. You come once a month to see me. This may go on for years, if all goes well. I have some patients who have been on treatments like this for years. Sometimes after six months of treatment, apart from seeing us to evaluate toxicity, we also perform imaging again to see what is going on with the cancer.

What images studies will you be using?

Dr. Efstathiou: CT scans and bone scans. We have not included, unless it’s needed for this trial, more advanced imaging such as PET scans. As we monitor these imaging studies, we see how the cancer cells seem to be more quiescent. The lesions become smaller. If, God forbid, the disease tries to progress again, then we would repeat a biopsy Remember, as I’m sure you’ve discussed with a lot of other specialists in prostate cancer, one of the main concerns is prostate cancer’s heterogeneity. When I’m doing biopsies, I’m actually looking at a snapshot of a specific subset of cancer cells. What if there is a cohort of cancer cells in there that is very resistant and expresses completely different molecules?

This clinical experiment gives me the opportunity to see if the way I am assessing things is actually capturing well what is happening with regard to the prostate cancer activity. There are a lot of investigators out there who are huge advocates of liquid biopsies without having done the basics of assessing what is going on in the actual tumor that has grown in the bone, lymph nodes, or liver. I understand that the dilemma for most people is the difficulty of doing biopsies, but if we want to be honest in all other malignancies, that’s how the development of all the targeted agents started. At the end of the day, it is going to be important to not ignore the actual tumor samples and to try and characteristics those well. Above and beyond this specific trial, one of my main efforts is to hone in on a classification of the disease that allows you to appropriately designate specific treatments to specific patients. There was some nice work recently presented in a meeting that supports that idea. Some of the mutations or alterations can be found early on.

If we know which these are, then we can pursue them. If we know that others change over time, then we can do real-time biopsies.

Which tumor biomarkers are you looking at?

Dr. Efstathiou: One of the most important parameters is androgen signaling. I was the one who reported for the first time the association of AR-V7 in the tumor sample with lack of response to these drugs. Right after that came the liquid sample data from the Johns Hopkins and Memorial Sloan Kettering groups who were doing it in the circulating tumor cells.

One of the markers is related to AR-V7, but I went a step further. The androgen receptor needs to be intact. I’m looking at the two ends of the androgen receptor. The one end is the end where the androgens go and attach themselves. The other end is the stable end, the one that never changes. The end to which the androgens attach themselves is the one that is affected by mutations and variants. I measure both ends and then I look at the difference in the ratio between the two. That’s another important marker.

I also look at PTEN, which is a very known marker. I look at RB loss, p53 mutation, and the proliferation index of the cancer.

What are the eligibility criteria?

Dr. Efstathiou: It’s very simple. Patients must have not received previous new agents such as Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide). They must have failed standard hormonal approaches, such as androgen deprivation therapy or bicalutamide. They also have to have metastatic disease. These are the main criteria. It’s very straightforward.

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Dr. Ken Pienta: Chemo For Prostate Cancer

Dr. Kenneth J. Pienta, of the Johns Hopkins University School of Medicine, is an international expert in the development of novel chemotherapeutic agents for prostate cancer. He was the recipient of the first annual American Association for Cancer Research Team Science Award and is the author of more than 300 peer-reviewed articles. He frames this month’s conversations about chemotherapy for us.

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In 2018, chemotherapy for prostate cancer continues to be one of the many options we have to lengthen the lives of patients suffering from metastatic prostate cancer. There are still multiple other therapies that we don’t consider chemotherapy. Second-generation anti-androgen therapies like Zytiga (abiraterone), Erleada (apalutamide), and Xtandi (enzalutamide) are all now standards of care in castrate-resistant prostate cancer. We also have Xofigo (radium-223) as an option for patients with bony metastases.

There are two chemotherapies that have been approved for prostate cancer: Taxotere (docetaxel) and Jevtana (cabazitaxel). Now, the real challenge for patients and providers is when to use those chemotherapies.

Multiple studies have demonstrated that, when you’re newly diagnosed with metastatic prostate cancer, it may be beneficial to receive a limited number of doses of Taxotere (docetaxel) at the start of hormone therapy. That’s especially true if you have multiple places where the cancer has spread. That’s not correct for all people, but for some patients, it is a good option. More and more physicians are prescribing Taxotere (docetaxel) with a luteinizing hormone-releasing hormone (LHRH) antagonist at the start of therapy.

However, that doesn’t mean you cannot use Taxotere (docetaxel) after other things have failed. If you failed second-line hormone therapy or have failed radium therapy, Taxotere (docetaxel) is still a good option that helps people live longer.

Jevtana (cabazitaxel) continues to be a good chemotherapy option if patients have failed Taxotere (docetaxel).

Thank goodness we’ve seen over the last several years an increase in the number of drugs available to treat metastatic prostate cancer in addition to chemotherapy. Chemotherapy has been around for quite a while now, but there is still a role for it.

Again, the challenge for all of us is: when do we slot them in for you? The chemotherapy we use for prostate cancer is really a single agent chemotherapy, either Taxotere (docetaxel) or Jevtana (cabazitaxel). This is not the multi-agent therapy we use for other cancers, so the idea of major side effects is a bit overblown. For example, nobody vomits from chemotherapy for prostate cancer. The drugs we use to prevent that are too good.

We also have gotten much smarter about limiting the number of doses we use. We don’t necessarily give chemotherapy until it doesn’t work anymore. Often, we just give several doses and then take a break. If you get more than a couple doses of chemotherapy, you will still lose your hair temporarily.

Chemotherapy can make you feel more tired when it lowers your blood count, and it can make you more susceptible to infections, but people are very rarely hospitalized now for an infection from chemotherapy. It’s virtually unheard of that somebody would die as a side effect of chemotherapy.

The major side effect of Jevtana (cabazitaxel) tends to be diarrhea, but again, as we’ve learned about the dosing of that drug, that has become more manageable.

Another side effect of both drugs can be peripheral neuropathy, which is tingling in the fingers and toes. But we watch for that too. If you start to develop that, we tend to stop the drug. These are very tolerable medicines.

The word chemotherapy always evokes images of horror, but chemotherapy in 2018 is a lot different than it was even five years ago. We just know how to give chemotherapy much better. When I started in the field 30 years ago, if you had metastatic castrate resistant prostate cancer, survival was 6 months. Now, with the advent of all these newer therapies, we’ve gotten much better. The landscape of how to treat prostate cancer has changed completely in the last five years. It will change completely again in the next five years. The challenge is in what order are we going to use all these powerfully good drugs rather than having only one drug to give or none at all.

For us as physicians, it’s an exciting time to take care of men with prostate cancer.

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Genomics + Prostate Cancer Care

Dr. David J. VanderWeele is an Assistant Clinical Investigator in the Laboratory of Genitourinary Cancer Pathogenesis at the National Cancer Institute. He is particularly interested in investigating the progression of clinically significant prostate cancer.

Prostatepedia spoke with him about how genomics impacts patient care.

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What is genomics, and how does it differ from genetics?

Dr. VanderWeele: Typically if you’re talking about genetics, you’re talking about an individual gene or a small set of genes. When you refer to genomics, you’re referring to all the genes or a very large set of genes. Genomics usually refers to the genes–the DNA sequence. But sometimes genomics is also used to refer to when those genes get expressed (as RNA), or to other changes to the DNA that don’t change the DNA sequence (also called epigenetics).

What do and don’t we know about why some men develop curable or indolent prostate cancers while some develop widely lethal diseases?

Dr. VanderWeele: A lot of effort has been put into trying to learn more about the genes you inherit from your parents and how that influences the likelihood that you’re diagnosed with cancer. Most of that effort has been unable to identify which alterations in your genes make it more likely that you will get an aggressive versus an indolent cancer.

As many of your readers probably know, many people get indolent prostate cancers. In fact, many autopsy studies have looked at patients who have died of other reasons and have never been diagnosed with prostate cancer. Once men reach their 70s or 80s, it looks like more than half of men develop prostate cancer. Of course, those are relatively slow-growing cancers.

The most information that we have now is that men who come from families with breast and ovarian cancer syndrome appear to be more likely to get cancer and more likely to get aggressive cancer. These involve BRCA1, BRCA2, and other DNA repair genes in a similar pathway. Though there aren’t FDA-approved therapies yet, there are trials suggesting that these patients are also more likely to respond to certain therapies approved for breast and ovarian cancer.

This is a pretty small subset of all the men with prostate cancer, but the percentages increase with any kind of measurement of aggressiveness. If you look at people with localized cancer, that percentage increases if you have high-grade cancer versus low-grade cancer. The percentage increases if you compare people with advanced castrate-resistant prostate cancer to those with localized cancer.

If you look at the length of time between a man’s diagnosis and when he dies, that rate increases significantly the shorter that time is. That is just looking at three of these genes, BRCA1, BRCA2, and ATM. If you look at a broader number of these DNA repair related genes, it looks like ten to twelve percent of all patients with castrate-resistant prostate cancer harbor a mutation that they inherited from their parents. It seems likely that for most of those patients, that inherited gene contributed to their prostate cancer.

That has led to some debate about how often we should test for mutations in these genes. Is that a high enough number that we should test everyone with castrate-resistant prostate cancer? Should we still rely on family history to provide guidance for which people should be tested?

Is it really expensive to test those men? Why wouldn’t you just go ahead and test?

Dr. VanderWeele: Depending on how you do it, testing costs have come down quite a bit.

But when you’re testing for genes that could potentially be passed on to your offspring, or that siblings or other family members may have inherited, there are implications for your other family members, not just for you.

Some members of your family may definitely want to know that information and think that more information is better. Others may feel that if they find out that they harbor that gene mutation, they will just feel like they’re waiting for the other shoe to drop. It’s not information that they’d want to know.

Generally, we advise people to get counseling to help them think through some of these issues before getting tested for genes they’ve inherited from their parents.

Do we know why some men respond to certain drugs and therapies and others don’t?

Dr. VanderWeele: There’s a lot of interest in that. There has been some progress made in terms of identifying the biomarkers that might suggest which patients are more likely to respond to which types of therapies. At this point, however, most patients still get treated with most therapies.

There are some genetic biomarker-driven therapies that look like they’re on the horizon. Patients with mutations in BRCA2, ATM, and related genes are more likely to respond to a type of therapy called PARP inhibitors, which are currently approved for patients with ovarian or breast cancer, but not yet for prostate cancer.

There was a single Phase II study that showed that patients who had loss of a specific tumor-suppressor gene called

PTEN are more likely to respond to a certain type of targeted therapy. There are larger ongoing trials to demonstrate that these are indeed predictive biomarkers for response to these therapies.

There are companies like FoundationOne and GenomeDX that look at the molecular features of a man’s cancer. Are those tests useful? What do they tell a patient?

Dr. VanderWeele: The FoundationOne test looks for mutations, deletions, or amplifications of specific genes that are relevant for a wide array of cancers. There are a lot of companies offering this type of sequencing.

Many hospitals offer their own version of it. A FoundationOne type of test can tell you if you have a mutation in BRCA2 or ATM. They should also be able to tell you if you have a deletion in PTEN. When they detect a mutation is present, however, generally they are not looking to determine if you inherited those changes from your parents versus the mutation being present only in the tumor cells.

These genetic tests are more popular in other types of cancers, because for prostate cancer there aren’t yet any FDA-approved therapies that would be given based on the results of these tests. These tests will become more popular as we make progress in demonstrating the benefit of these specific therapies and in our ability to predict which patients are most likely to respond.

If a patient reading this gets one of those tests, is it likely that his doctor is going to know what to do with the results? Will the results actually impact his treatment?

Dr. VanderWeele: There are probably a small number of patients who will have a result that will directly impact their therapy. At this point, the way that it would impact therapy is that it might suggest that they should find a clinical trial testing a specific type of drug.

I see.

Dr. VanderWeele: There are also other commercially available prostate specific genetic tests, like the one performed by GenomeDX, that are mostly aimed at men with localized prostate cancer who are trying to decide how aggressive their therapy should be. Typically, this means whether they should pursue active surveillance or get surgery or radiation.

Sometimes these tests are also used to determine if a patient should get radiation after undergoing a prostatectomy or if he should just continue to follow PSA numbers. The prostate specific gene expression tests are RNA-based tests, which are a little different.

They measure the levels of expression of a few specific genes. Tests like FoundationOne look for mutations, amplifications, or deletions of genes—which means they are DNA-based tests.

Tests like Decipher are more widely used now, right?

Dr. VanderWeele: Yes. They’re probably used mostly by urologists. My sense is that how often urologists order those tests and how heavily they rely on them versus other ways to predict the risk level of the prostate cancer varies quite a bit from urology practice to urology practice.

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