Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I'm speaking with Brenda Martone from Northwestern University. Thank you so much for being here with me, Brenda.

Brenda Martone: Thank you, Alicia. I'm glad to be here.

Alicia Morgans: Wonderful. And I want to just speak with you about something that is near and dear to our hearts. When we practiced together, we had the opportunity to really, I think, launch and implement on a broad scale genetic testing, germline, and somatic testing for our patients with metastatic prostate cancer. And this is something that is so important for our patients but is something that does take time and thought when we're implementing these procedures at the beginning and when we're really working it into a practice. So from your perspective, let's talk about germline testing first. How do you think about germline testing at least in terms of patient selection when you're really thinking about it just at first steps?

Brenda Martone: So based on the NCCN guidelines, those who have high-risk regional or obviously metastatic disease, they should all be offered both germline and somatic testing. So, when a patient comes in, let's say we're seeing someone who has de novo, so just newly diagnosed metastatic hormone-sensitive prostate cancer, that's on our checkbox. So when we're meeting the patient, we take a very good family history looking for keys and cancer incidents and early diagnosis that might alert us to possibly a germline mutation. We then discuss the fact that the germline mutations will help us for treatment selection currently at the present time, not with this first-line treatment, but with second-line treatment. And then we also have to have an important discussion that what is the cascade effect.

If we do identify a germline mutation, this actually has implications for other family members and children. And so you need to have a conversation and perhaps depending on your practice, you'll have the genetic counselor help you interpret so they can counsel the family member as well as the family. Somatic testing is testing on the tumor tissue itself. So we do know that roughly 17% of patients can have a BRCA mutation in their tissue. And so that's another reason that just because they don't have a germline, you look at the tissue also because again, that would qualify for a PARP inhibitor in a later line of therapy.

Alicia Morgans: So these are such important thoughts and points. And I really want to just focus in a little bit on germline testing and the implications for family, which you mentioned. It's so important for our patients, I think, to recognize that in the metastatic setting, one, all patients with metastatic disease need to be tested, that's regardless of age of diagnosis and that's regardless of family history because the incidence of these DNA repair defect mutations in that population is around 12%. So that in itself meets the threshold for testing everybody, which is really, really important. And family history was not even associated with the risk of actually having those DNA repair defects in a nicely done study that really investigated this in a large population. So, so important.

When it comes to family members though, what I also want to emphasize, and I love to hear your thoughts on this, is that the risk for family members could be in children, it could be in siblings, and that risk actually applies to the risk of prostate cancer in sons or in brothers. But it actually applies to breast or ovarian cancer when we're talking about daughters or sisters. And of course, there's a risk of pancreatic cancer and some other syndromes as well. So it's not just our sons, it's not just prostate cancer, and patients, I think, really need to hear that and be educated around that because the risk for daughters and for sisters is a real risk too.

Brenda Martone: Yeah, I totally agree. And that's the reason that we have these great conversations with our patients, getting them in to see our wonderful genetic counselor. And we do stress that it's not just prostate cancer as you mentioned, there's a higher risk for breast, ovarian, and pancreatic. And I actually had a patient who did have a BRCA germline mutation, and his daughter actually chose to have prophylactic mastectomies and oophorectomies because she was concerned about her risk. So even though sometimes patients who do have a germline can feel a little guilty sometimes but it's not their fault, this patient actually probably saved his daughter's life. And he realizes that and that just brings him such joy.

Alicia Morgans: I agree. I think I know who this patient is and it does bring him joy. And it also, because I think his daughter's a young mother, actually brings her a lot of peace of mind as well.

Brenda Martone: Yeah.

Alicia Morgans: Because it's whole families that we treat when we're doing germline testing and it's so important for that individual and for all of those people in his family. So really, really a great point, and thank you for bringing that up. So, when we're thinking about using this data in later settings, germline or somatic data from the testing that we've performed in our patients, and somatic testing really can happen early, it can happen a little bit later just given the therapeutic implications are not necessarily in the metastatic hormone-sensitive setting at this time, what are the thoughts that you're having about treatments? How does this inform what you're doing in clinical care?

Brenda Martone: If we do see a BRCA mutation or other DNA mismatch repair deficiencies, there are two currently approved PARP inhibitors for this population. One is olaparib and one is rucaparib. Obviously, their mechanism of action is pretty similar. Their FDA approvals or indications are slightly different. So with olaparib, it includes basically BRCA ATM and then the whole other basket I call it of germline mutations, and also olaparib is indicated for those who progress on a second generation AR inhibitor. Rucaparib is approved for those who have just BRCA1 and 2 mutation, either germline or somatic, have received prior AR inhibitor therapy as well as docetaxel. So when you're talking about patients, you do have two potential options. And so you need to make sure that if they have a DNA mismatch repair and not a BRCA, then your option will be olaparib.

Also, if they have BRCA, then you have two agents and you can look at the side effect profiles and find out which agent the patient prefers, because at two things being equal, sometimes the side effect profile while they're similar, they can have slightly different side effects, some may influence a patient's choice. So again, it's all about informed decision making, mutual decision making and making sure we're presenting all the options to our patients.

Alicia Morgans: I could not agree more. So really important to remember the distinctions between the two PARP inhibitors in terms of their indications and then the mutations where they can be used, of course, either can be used in BRCA1 and BRCA2. Olaparib has a broader array of mutations and then either can be used after an AR targeted agent in taxane, but olaparib can actually be used pre-chemo. So really important there. The other thing that we can get from somatic testing that's important to just mention is that we may have a patient with microsatellite instability, high status, or these patients may have MSI high type mutation, MSH2 or 6, these are the most common that may actually put us in a MSI high state in terms of the tumor tissue. This would give us the opportunity to use pembrolizumab. Have you ever used that in your practice?

Brenda Martone: We have, or actually I have. I've used it. And while the actual patient population that has MSI high or TMB high is relatively small, I've had maybe two or three patients that we've used pembrolizumab on and actually, it's been quite successful. But again, just bear in mind different patients have different outcomes so it's not a slam dunk. But I'm pleased that for our patients, they've been responding well and we can see some significant disease reduction as well as control. And we actually have a patient who while we don't want to say is cured, but we talk about him being in a complete remission. And we're so pleased every time we see him and this is ongoing. So this was a great opportunity for this patient for treatment. And if we hadn't had looked for those somatic mutations, we may not have had the same outcome.

Alicia Morgans: And that's what's so important for our patients, doing germline and somatic genetic testing gives options to patients that they would not otherwise have, the opportunity to take targeted treatments that may give them really phenomenal responses that could be durable and could have a tolerable side effect profile for the drugs themselves. So important for our patients and really a win for our practices. So thank you so much for sharing your expertise.

Brenda Martone: You're very welcome. Thank you.