Alicia Morgans: Hi, I'm excited to have here with me today, Dr. Wassim Abida, who is a medical oncologist at Memorial Sloan Kettering. Thank you so much for being here.

Wassim Abida: Pleasure to be here.

Alicia Morgans: Wonderful. Wassim, you have really pushed the boundary of our understanding of germline and somatic mutations in advanced prostate cancer and we've been really excited to see your data really just come to light and really affect, I think, clinical practice with some impending therapeutic implications as different medications become approved in the setting of prostate cancer. But as urologists and medical oncologists around the world are trying to integrate our understanding of germline and somatic mutations into our clinical practice workflows, I think there have been some challenges that we need to overcome in just figuring out how to most effectively get this data from our patients, report it back to our patients and use it as we make those treatment decisions. How do you think about the first steps in terms of understanding, gathering somatic genetic material or genetic data for your patients in your clinical practice?

Wassim Abida: I think a lot of people push the boundary recently and I would argue that the genomic landscape of prostate cancer, at least metastatic prostate cancer, has been well established. And one of the key questions, as you mentioned Alicia, is, how do we integrate this into practice and how useful is it been? And I would argue maybe it doesn't apply to most patients in terms of clinical applicability, but I think it will be. And so we're learning more and more about it.

The first step is actually identifying those subsets of patients who we already know benefit from targeted therapies. I would say that the clear population where testing applies is patients with metastatic prostate cancer. And so a patient with metastatic prostate cancer according to the NCCN guidelines should have genomic testing performed ideally on tumor. We do recognize that certain alterations are identified in a more recent tumor, so ideally on a new tumor biopsy. But in the absence of that, we've got archival biopsies which are of various utility because obviously men with prostate cancer can recur many, many years later, so your archival prostatectomy specimen could be 10 years old. And as well as cell-free DNA technology, which is improving. It's not quite at the level where the tumor is yet, but I think it's getting there.

I think given the indication for pembrolizumab for men with MSI-high prostate cancer, that is a clear indication to do genomic testing in men with metastatic prostate cancer. It's a small subset, three to 4% of patients, but the actionable, the targetable proportion is going to increase. The next approval we think is going to be PARP inhibitors for rapid deficient prostate cancer. That's another 10% of patients roughly speaking. And there will be more coming down the pipeline. And so I think that at least doing tissue-based testing when available is the starting step to identify those patients who at this point benefit, let alone down the road as we get more clinical trials.

Alicia Morgans: Absolutely. Ideally, these patients would have a new biopsy, which actually could be useful, particularly if you think that this patient is a rapid progressor and perhaps could have small cells or neuroendocrine differentiation, but you would send that for next-generation sequencing to understand better whether that patient may have a BRCA1, 2, even ATM, PALB2 et cetera type mutations, CHEK2, and then also to do tissue-based testing to look for microsatellite instability. Pembrolizumab is already approved for patients who are MSI-high.

How do you make this happen in your clinic? You see a patient, do you do it when you see a metastatic hormone-sensitive patient? Is this patient a rapid progressor after initial treatment? Is this a patient who is at, has been through multiple lines of therapy and now is looking for new options or clinical trials? When do you do this testing?

Wassim Abida: In my practice, any patient with metastatic prostate cancer. It's good to have the information upfront. And so any patient that I see in the clinic who has metastatic prostate cancer, I feel meets the indication to identify actionable alterations. This is true for pembrolizumab approval, which I typically think of as appropriate after at least one line of next-generation hormonal therapy. After abiraterone and enzalutamide, that's usually when I start pembrolizumab for MSI-high patients. Although the indication, the FDA approval is not specific to prostate cancer, so it's not that granular. Everyone has different practices, but certainly, the indication is metastatic. From a billing and reimbursement perspective, I think that's the appropriate indication. There can be some indications to do it earlier if you feel like the patient's progressing rapidly and you want to have the information upfront. But certainly in the metastatic setting would be time to really think about doing tumor genomic profiling.

Alicia Morgans: So hormone-sensitive or castration-resistant. It doesn't actually make a difference, metastatic disease is the right time. The other nice thing about that is that you have that information when you need it. You don't have to rush and rushing can take weeks for a lot of these tests.

Wassim Abida: There is a failure rate of testing as well, so you do want to have the information upfront, particularly the hormone-sensitive patients essentially given that a lot of patients are getting abiraterone upfront. When they're progressing, they're already castration-resistant but also resistant to your first line of next-generation hormonal therapy so they're appropriate for consideration of these targeted therapies.

Alicia Morgans: Absolutely. Besides somatic testing, tissue-based testing, which just to remind everyone, if you can't get another biopsy, going back to the primary could be an option. Just knowing that there may be limitations, particularly if this was tissue that we had a long time ago. What do you do in terms of germline testing in your practice? How do you optimally integrate that knowing that these are actually two separate things that we have to do for patients to understand the genetics and genomics of the tumor.

Wassim Abida: No, absolutely. Germline testing is a part of this as well and this is a key complicating factor, which is a lot of commercial tumor-based tests out there do not distinguish between somatic and germline alterations. They report all alterations and so if you see an alteration in BRCA or any mismatch repair gene, the patient could be a germline carrier. And so there definitely should be reflex germline-specific testing for those patients where you identify a tumor alteration on a test that doesn't distinguish between both. And in the absence of that, I would say the indication for all men with metastatic prostate cancer is to at least discuss germline testing.

This does involve a more detailed discussion obviously because it has implications for family members and that's usually what I discuss with my patients is that I do recommend germline-specific profiling for men with metastatic prostate cancer and men with high-risk localized prostate cancer who meet certain family history criteria. Those are the two populations where I talk about germline-specific testing, mostly looking for BRCAs, that's the most common inherited mutation in men with high-risk or metastatic prostate cancer. This does involve more time in discussing with patients, talking about the risk, anxiety, implications for family members. But it's very valuable because we know that roughly one in 10 men with metastatic prostate cancer will have an inheritable alteration. With metastatic disease, you do not need to have a family history to have that discussion.

Alicia Morgans: Absolutely. And I just want to emphasize that if you find something on tumor tissue testing, say a BRCA2 mutation, you'd actually want to go back if you have not already done it and do germline testing for that patient because you cannot know if that's in the tumor alone or is in the patient's germline, which may have very clear implications for his family.

Wassim Abida: Right, absolutely.

Alicia Morgans: Absolutely. As you think about this and as many urologists and medical oncologists are thinking about this, they may feel like it's a bit of a burden or a challenge that they don't necessarily feel like they have the tools to discuss positive results or even the VUSs, variants of uncertain significance. You have a genetic counselor plus you have an extensive background in this, are there ways if you don't have a genetic counselor that people can communicate these results or feel like they have backup in communicating these results when they don't necessarily feel like they have the education to do it as they wish on their own?

Wassim Abida: Yeah, it is tricky. I agree. And because it creates anxiety. It has a lot of implications, particularly for tests that do report variants of unknown significance. It's a tough discussion to have with a patient to say, "You have a variant, we don't know yet." The bottom line is that a variance of unknown significance is not actionable and it is, it's a conversation that I'm comfortable having with a patient. But I would say that there's always genetic counselors and this is an important enough issue I would say for a referral, even if there's not a genetic counselor nearby to have that discussion.

And so it is important to have a professional talk about the implications of these results. Certainly doing the testing itself, I feel like a trained clinical practitioner. A urologist, medical oncologist, could talk about pretest counseling, but when there is a positive result, it is important to have someone who's experienced in having those discussions and their implications, particularly when it comes to cascade testing, testing of family members, screening on all of those other things. Really it does help to have a genetic counselor to have those discussions, or experienced genetics professional.

Alicia Morgans: Absolutely. And because BRCA2, BRCA1, these have implications and other mutations that one might find on these tests might have implications not just for prostate cancer. We have to remember this can be breast cancer risk, this could be ovarian cancer risk for family members, it could be other cancers, colon cancer, et cetera. We want to make sure that these family members have the information that they need. And even if urologists or medical oncologists do not have access to a genetic counselor, which hopefully many of us would have access, there are chat boxes, there are web-based programs, there are phone programs where different companies that do this germline testing can actually help support the practitioners in their practice and speak directly to patients about the implications of the positive tests, which can be really helpful to them for practices as well.

Wassim Abida: Absolutely. A lot of commercial companies essentially will facilitate this type of information and facilitate testing, cascade testing, family members, since the mutation is known using that test.

Alicia Morgans: Yes. Well and they could help identify, this test worked before for you, we could use it for your family member. Wonderful. Well, as you're thinking about all of this, which can be very complex, but is actually really exciting too, as we think about identifying cancers earlier in before they become cancers hopefully in family members or providing therapeutic options for men with prostate cancer, do you have any sort of overarching message for people as they're thinking about germline and somatic genetic testing in prostate cancer?

Wassim Abida: I would say one of the big questions comes down to utility. How many patients is this helping who have prostate cancer? And is the time worth, is the effort worth all of this time that's expended towards it? And I would argue that we're learning more and more about this. There's certainly a subset of patients who really do benefit from doing the genetic testing. And for those patients, you just don't want to miss that opportunity. And that's really what it comes down to, a durable responder to immunotherapy is, even if it's an uncommon scenario, it's three to 4% of men with metastatic prostate cancer, it's still an important enough case that you really don't want to miss that opportunity. And for me, that's what drives my desire to discuss genetic testing and to do it.

Now I would say in terms of actionable alterations in prostate cancer at this point, I usually tell patients that in about a quarter, in up to a quarter of men we find something that is actionable. It doesn't mean that if there's an approved drug, but we have some targeted trial somewhere that they can go on. But as we learn more and more, as we develop more targeted therapies, that number I do expect will expand as our tests get better. Genomic testing is also changing with time. And so I think it's worth to think about it and to have those discussions with patients and to use the technology that we that can identify patients who can benefit so far.

Alicia Morgans: It's a great message. A message where this is worth it. There are enough patients who would be affected. And as we continue to do these tests in our practices, we as clinicians, I think will become more confident with them. We'll make sure that we have the resources available to correctly counsel patients and will really move the needle for a population of men that needs it and their families. Thank you so much for sharing this information and your time with us today.

Wassim Abida: My pleasure. Thank you, Alicia.