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Conversations With Prostate Cancer Experts


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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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Frontiers In Prostate Cancer Genomics

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Who are the lead investigators on these two trials?

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

Is there anything else that patients might want to consider?

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

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

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

Dr. Feng: Yes.

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Prostate Cancer Genomics

This issue is devoted to the genetics and genomics of prostate cancer, which is one of the most promising and exciting areas of prostate cancer research. Already, this line of investigation is having a major impact. For example, by better defining the genomics of patients entering clinical trials, there can be a marked reduction in the number of patients needed to reach statistical significance. This can potentially reduce the costs of drug development dramatically.

Research into the role of genetics and genomic alterations in the biology and treatment of prostate cancer are still at a much earlier stage than it is for breast cancer. While laboratory studies have discovered a wide range of genes that might act to determine prostate cancer behavior in the clinic, proof that these changes actually determine outcome in the clinic are rather limited. There are even fewer examples where drugs attacking these changes have been FDA-approved for the treatment of prostate cancer.

The PD-1 inhibitor, Keytruda (pembrolizumab) is at present the only example. In 2017, this drug was approved to treat cancers that show mismatch repair or microsatellite instability. These mutations are found in a small proportion of prostate cancer patients.

There are a number of mutations targeted by drugs that are in advanced testing, so this list may expand rapidly. One of the more promising targets is BRCA2. Mutations that alter the function of this gene are known to be involved in breast and ovarian cancer. Cancer cells with these BRCA2 mutations become dependent on the protein, PARP, for their survival and drugs that inhibit PARP can be effective therapy. Studies on patients with advanced prostate cancer show that altered BRCA2 is found in 10-30% of cases. PARP inhibitors have shown significant activity in early clinical trials. Randomized controlled trials needed for FDA-approval are in progress.

Genomic information can also be used to determine how likely prostate cancer is to behave aggressively. This can help identify patients who are likely to do well with active surveillance or to be at low risk for recurrence after an initial attempt at curative treatment.

While genomics promises to revolutionize the treatment of prostate cancer, this revolution requires support from the patient community. The key studies can only be done if patients elect to participate in these trials. For this reason, we made sure to provide you with information on how to become involved in this process.

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How You Can Participate in Genomic Research

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

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

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

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

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

Camp Kesem is still around, right?

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

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

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

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

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

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

What is the goal of the Metastatic Prostate Cancer Project?

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

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

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

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

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

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

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

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

The project is basically unending, right?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Genomics, Predicting Side Effects, + Clinical Trial Design

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer.

His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about genomics, predicting side effects and the future of prostate cancer clinical trials

Can genomics predict who will have certain side effects?

Dr. Feng: There have been a number of studies that have used single nucleotide changes within DNA sequences, called single nucleotide polymorphisms (SNPS), to predict who will be most likely to experience side effects from radiation therapy for cancer.

In general, the signal from these toxicity studies has been weaker than the signals from biomarkers that predict responses to particular therapies, like the ones that I mentioned earlier. This may be reflective of the fact that radiation acts through a variety of mechanisms, so any single biomarker may not work well. Even when you cluster biomarkers, it may not account for the heterogeneous manner in which radiation causes a biological effect.

What should patients know about how genomics is impacting treatment?

Dr. Feng: Many of the clinical trials being developed nowadays incorporate genomics. We have clinical grade assays to look at genomics. We have strong biological rationale for why certain genomic biomarkers may identify subsets of patients who can respond to specific therapies. Because genomics is routinely used to personalize treatment in the context of diseases like breast cancer, colon cancer, and melanoma, it’s only expected that genomics will have a major role in prostate cancer going forward.

Will incorporating genomics into clinical trial design accelerate the speed of innovation?

Dr. Feng: I think it will. If you look at metastatic castration-resistant prostate cancer, for example, a number of therapies have been approved by the FDA over the last decade for those patients, including agents like Zytiga (abiraterone) and Xtandi (enzalutamide), next generation taxanes, Provenge (sipuleucel-T), and Xofigo (radium-223). All of these agents extend survival by just a few months.

This is invariably what happens when you treat prostate cancer as one disease entity rather than a variety of different entities that are governed by different genomic events. As we become better at selecting therapies based on a patient’s genomic events, we should see longer response times to available therapies and those currently being developed.

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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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Can Decipher Change Your Prostate Cancer Treatment Plan?

Dr. John Gore is a clinician, surgeon, researcher, and educator specializing in urologic oncology and general urology at the University of Washington.

Prostatepedia spoke with him about how Decipher changes the way doctors treat men with prostate cancer.

What is Decipher?

Dr. Gore: Decipher is from a family of genomic tests. In general, it tries to look at some of the alterations in people’s genes associated with cancer or its progression. Decipher attempts to create a panel of genes associated with the likelihood of a cancer coming back. It takes that panel of genes and integrates it with clinical information to calculate the risk of developing spread of cancer to sites that could be detected clinically, like the bones or the lymph nodes, within five years after prostate cancer surgery.

When is a man likely to encounter this test? After that initial biopsy when he is first diagnosed? After his prostatectomy?

Dr. Gore: The most common scenario would be after surgery. If a man has his prostate removed and the pathology shows that he has a cancer that by all accounts seems to have been successfully treated with the surgery, Decipher may not be the right test for him.

If he has some high-risk features— his cancer is potentially encroaching on the shell of his prostate, he has a positive surgical margin, or there is involvement of the seminal vesicles that sit behind the prostate—then he might benefit from Decipher.

That way we can ask if—in addition to knowing that he had some high-risk pathology features—he appears genomically to have a high-risk cancer?

What do the results look like? Do they change how a man is going to be treated post-surgery? How?

Dr. Gore: The actual report that a patient or doctor gets tells them the probability, or percent risk, that he will have clinical metastases within five years of having his prostate removed for prostate cancer. In general, those numbers tend to be in the single digits to low teens. It’s not a common event.

For most people, prostate cancer surgery successfully treats their cancer. That is why this is best used on higher-risk individuals.

In our study, we looked at a cadre of patients who were either found to have high-risk features at the time of their prostate cancer surgery, or now their PSA is subtly rising after going to zero after surgery. Those patients should potentially have more aggressive treatment.

We showed that if a patient had the Decipher test, physicians’ recommendations changed. If your Decipher results showed a lower risk score, your doctor was more likely to recommend observation.

Patients with a higher risk Decipher score were more aggressively treated. They were recommended to go ahead and get additional radiation to the area where their prostate was removed, rather than just active surveillance.

The bottom line is that Decipher changes how men are treated?

Dr. Gore: Yes. We have some follow-up data we just presented at the American Society of Clinical Oncology, Genitourinary meeting in February that showed that those treatment recommendations were actually followed 80% of the time.

You said only men who are high-risk should really be tested. Not everyone getting prostate cancer surgery needs a Decipher Test?

Dr. Gore: That’s right.

Is Decipher widely accepted in the medical community? If a man in rural Minnesota goes to his local urologist or local community oncologist, will he likely be offered the Decipher Test? If not, should he ask his doctor to order it?

Dr. Gore: I think it’s definitely worth requesting it. One thing that has come up is insurance payer coverage, not just for the Decipher Test, but also for other tests like it. The bar that some of these companies have to cross to get their test approved is fairly high.

Some insurance companies are asking if the test not only changes treatment for patients. The trial they’re looking for will compare patients who got the Decipher Test with patients who didn’t to see if the decisions that were made impacted cancer outcomes. If, for example, your Decipher results say you’re high-risk, and you get radiation based on that information, was that the correct decision? The challenge is that prostate cancer is immensely slow-growing. Even when it’s high-risk, even when it’s aggressive, we’re talking about clinical outcomes that take years and years to manifest. It imposes an irrationally onerous burden to prove that these tests are the right thing.

You could wait 10 years to find out if the treatment decisions were correct. Meanwhile, time is passing and these men need to make choices…

Dr. Gore: Absolutely.

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Differences Between Prostate Cancer Genomic Tests

Eric A. Klein, MD, is an international leader in the biology and management of prostate cancer. Dr. Klein serves as Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.

Prostatepedia spoke with him about the differences between the various genomic tests available to prostate cancer patients.

Dr. Eric Klein: These tests measure the expression of genes in prostate cancer. That’s what they’re designed to do. They predict the likelihood of your having higher-grade cancer or cancer that penetrates the rind around the prostate (called extraprostatic extension), or cancer in the lymph nodes or seminal vesicles. These tests predict that better than biopsy or plain old Gleason grading. This gives us a leg up in deciding who is a good candidate for surveillance.

If your biopsy only shows Gleason 6, but you actually have higher-grade cancer in the prostate, or you have some cancer that’s through the rind or in the seminal vesicles, you’re not a good candidate for surveillance. We know that from decades of doing radical prostatectomies. These patients are at highest risk for progression and that’s what these tests measure.

They also tell us whether a pure Gleason 6 cancer is one of the 5-10% that has molecular features of high-grade cancer.

These are biopsy-based tests. For example, if a patient has a biopsy that shows Gleason 6 cancer and otherwise favorable features, such as a PSA below 10, and a PSA density below 0.15, we wonder whether he’s a candidate for surveillance. We always do a confirmatory test after a first biopsy. Decipher can also be used after the prostate has been removed to help decide on the need for additional treatment.

A genomic test like this is appropriate in some patients. An MRI of the prostate is appropriate in others. Sometimes it’s appropriate to get both. We don’t have enough experience to know which is the best test for which scenario, although I have some ideas about that. Then, once we confirm that the patient has a low-grade cancer that lacks molecular features of high-grade cancer, we feel confident in putting him on surveillance.

The results can do two things. They can confirm that the patient is a candidate for surveillance. Sometimes they can convince a reluctant patient that surveillance is the right thing. We don’t want to over-treat people who have low-grade cancers that aren’t going to kill them because the side effects of treatment are worse than the likelihood of his dying of cancer. Sometimes, the results can convince a physician that surveillance is the right thing. If you look at the criteria for putting people on surveillance, it’s mostly patients who have just a minimal amount of cancer–low-grade cancer, a Gleason 6 on a biopsy.

We published a study in the Journal of Urology recently that showed that even among patients with high-volume

Gleason 6 cancer in multiple cores— four or five remove cores—many have no molecular features of high-grade cancer. In the past, they haven’t traditionally been considered good candidates for surveillance, but based on the biology of their tumor, they are good candidates for surveillance.

You may have someone who has a couple of cores of low-grade cancer, maybe a PI-RADS 4 lesion on MRI.

You’re not sure if they’re a good candidate for surveillance or not. If a genomic test confirms the absence of molecular features of high-grade cancer, you can put the patient on surveillance. That is the kind of information that genomic tests provide. They have their nuances.

Oncotype and Decipher are good for patients with very low, low, and favorable intermediate-risk disease. Prolaris is best validated for patients who have intermediate risk disease. It doesn’t have good discriminatory value for low-grade cancers. Generally, they all measure gene expression and they’re all are used in the same way.

These tests help determine whether or not someone is a candidate for surveillance. At the moment, we don’t use these tests based on biopsy to determine which treatment to give a patient, but that’s coming. Post-prostatectomy, Decipher can help tell us that.

There are challenges to active surveillance. Say we put someone on surveillance and he starts out with 1 core of Gleason 6 cancer. A year later, he is re-biopsed and has 3 cores of Gleason 6 cancer. We don’t know whether that’s true biologic progression that requires treatment, if all that Gleason 6 cancer was there in the beginning and was just not sampled by biopsy, or if the patient grew some new Gleason 6 cancer that doesn’t have any biologic potential.

This isn’t established yet, but I believe we can use these tests for what I call serial biologic monitoring, meaning you biopsy patients a year or three apart. These tests, for the very first time, allow us to measure true changes in biology as opposed to just changes in what we see on biopsy, which may underestimate what’s going on in the prostate. This is a new paradigm.

Another common scenario is a man who has a low-grade cancer on initial biopsy (1 core, Gleason 6) and a year later has a little bit of Gleason 3+4 with 5% pattern 4 and 95% pattern 3. In the past, that would always trigger treatment. But it’s my belief, based on what we’ve learned from these tests, that this is probably not correct. Many of those men can still stay on surveillance.

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Genetic Testing + Counseling

Ms. Merel Nissenberg is the President of the National Alliance of State Prostate Cancer Coalitions, a nation-wide organization comprised of state prostate cancer coalitions dedicated to saving men’s lives and enhancing the quality of life of prostate cancer patients and their families through awareness, education, and the development of a public policy network.

She talks to Prostatepedia about guidelines for genetic testing in men with prostate cancer.

Much has been written or suggested about the genetic component of some prostate cancers. For example, a family history of prostate cancer can increase a man’s risk of such a diagnosis. There have also been articles about the genetic component of certain breast cancers: BRCA1 and BRCA2 have historically been strongly implicated in the familial pathway for that diagnosis. What is more recent is the now more-firmly established connection between certain mutations like BRCA1 and BRCA2 and prostate cancer. However, guidelines for genetic testing in men with prostate cancer have been limited.

Recently, the Journal of Clinical Oncology published a special article entitled “Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017” following the Prostate Cancer Consensus Conference held in Philadelphia on March 3-4, 2017. Members of the panel strongly agreed that men should engage in shared or informed decision-making on the issue of genetic testing.

Panel members emphasized the strength of the inherited predisposition of prostate cancer, noting higher risks with BRCA1, BRCA2, and HOXB13 genes. The panel noted that prostate cancer patients with BRCA2 mutations have poor prostate cancer-specific outcomes. We now consider the link between prostate cancer and DNA mismatch repair (MMR) gene mutations to be stronger than we suspected, adding a specific opportunity for treatment. In fact, up to 12% of men with metastatic prostate cancer have inherited genetic mutations, mostly with BRCA1, BRCA2, and ATM. And targeted agents for these specific mutations confer better outcomes for these patients.

The panel concluded that: “Identifying genetic mutations of inherited prostate cancer… has implications for cancer risk assessment for men and their families, for precision treatment of metastatic disease, and is being incorporated into guidelines for individualizing prostate cancer screening strategies specifically for male BRCA1 and BRCA2 mutation carriers.”

Unfortunately there are no generally accepted standard guidelines for genetic counseling and genetic testing in prostate cancer, or standards on how to fully interpret results of current panels with multiple gene testing. The information discovered through genetic testing not only informs treatment for the prostate cancer patient himself, but is also an aid to other members of his family, including women who may have a genetic disposition for developing breast cancer. As for the patient, not only does the information potentially help guide prostate cancer treatment, but it also makes both him and his clinician aware of the potential for additional cancers.

The results of the Philadelphia Prostate Cancer Consensus Conference can be read in detail in the Journal of Clinical Oncology 36, no. 4 (February 2018), 414-424. Their considerations included the following:

  • which men should undergo genetic testing for prostate cancer;
  • which genes should be tested based upon clinical or family scenarios;
  • how the testing results should be used to inform screening for prostate cancer; and
  • how results should be used to inform treatment of early stage (localized), advanced stage (high-risk), and metastatic prostate cancer. Genetic testing done thoroughly and properly can help guide screening and treatment decisions.

The National Alliance of State Prostate Cancer Coalitions strongly endorses the use of genetic testing and genetic counseling for prostate cancer, and urges clinicians to read, consider, and follow the scientifically sound suggestions of the 2017 Philadelphia Prostate Cancer Consensus Statement on the Role of Inherited Prostate Cancer Risk. NASPCC will be presenting a Webinar on Genetic Testing and Genetic Counseling in Prostate Cancer on May 9, 2018. It is supported by Myriad Genetics. (Visit https://naspcc.org/index.php/may-9-2018-naspccwebinar to register.)