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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