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Andrea Miyahira: Hi everyone. I'm Andrea Miyahira and I'm the senior Director of Global Research and Scientific Communications at the Prostate Cancer Foundation. Today I'm joined by Dr. Heather Cheng. Dr. Cheng is a medical oncologist and expert in prostate cancer genetics. She's the director of the Prostate Cancer Genetics Clinic and Associate Professor in the Clinical Research Division at Fred Hutchinson Cancer Center and also Associate Professor in the division of medical oncology at the University of Washington School of Medicine. Dr. Cheng is also a 2015 PCF Young Investigator. She's the lead author on the paper, Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer that was recently published in JCO Precision Oncology. Thank you Dr. Cheng for taking the time to join us today.

Heather Cheng: It's a pleasure to be here. Hi everyone. I'm really delighted to be able to highlight the work that is just published recently in JCO Precision Oncology and as Dr. Miyahira here said, it's Internet-Based Germline Genetic Testing for Men With Metastatic Prostate Cancer. And so the objectives of the study are to determine whether an internet-based research, cost-free genetic testing program would be feasible for interested patients and could provide clinical genetic testing for patients with metastatic disease by removing the barriers of access and cost. And I'll just step back and say by way of background, when this study was first conceived, which was around 2015 and 2016, right around the time when this first standup to cancer data suggested that there was about 25% of tumors with metastatic prostate cancer that had DNA repair mutations. And then the second follow on was 2016 when we found that one-tenth of them were germline, meaning they were inherited.

That really sort of prompted this study, which is basically to say, "We know." We knew at the time that this was going to be really important for men for their families. PARP inhibitors were not yet FDA approved, but we sort of had an idea that they were likely to be of great interest. And so the challenge was before insurers and providers and kind of the entire medical system could rally and make this possible for patients, how could we sort of shortcut the system so that patients who have advanced disease have access to genetic testing? Because prior to this, and up until recently, coverage of genetic testing was really based on a family history of breast and ovarian cancer and really had not been done to any meaningful extent for prostate cancer patients. But of course, that's changed. So this was kind of our first four-way into that.

So this is the GENTleMEN study and here are the patients and the methods. It opened in 2016 in September and the goal was to test up to 2000 participants with metastatic prostate cancer. And the important thing is, because this was the first iteration of it, we really didn't know how the best way was to find patients. But we knew that if there were interested and motivated patients, we really wanted to make sure they had access and that cost was not going to be a consideration. So the recruitment was really through a variety of different mechanisms through their medical provider such as their medical oncologist. I offered it to my patients in clinic through patient support groups such as like UsTOO or ZERO and our local for kind of patient support groups, prostate cancer newsletters, social media. PCF, I think, featured the THINKU.. UsTOO, I think, featured... Or sorry. UroToday featured it at the time.

So we really wanted the community to sort of know that this was available. And one thing that was... Due to the IRB constraints, the study materials were only available at the time in English. Hopefully that's going to be changed soon. But here's the schema. Basically as I mentioned, patients would find out about it through a variety of different methods. They would then visit the website and then provide consent or not. And so that's in this sort of flow chart here. They would be eligible if either they uploaded the information that said they did have metastatic disease or we could assist them with that on the research team side. And then due to the sort of workflow, then the patients would then get a test kit code issued and we sort of have drop... You can sort of see some of the drop-off at the different stages.

But ultimately, 678 patients were issued a code of which 567 were activated, meaning they used the code to get a kit. And then 559 returned a saliva kit, I should have mentioned it with a... They get mailed a saliva kit, they provide a sample and they mail it back. And then 551 received a result of germline genetic testing. And just to emphasize, this is a medical test, this is not... This is CLIA certified and used as one test in our genetic counseling kind of panel of different germline genetic tests that are for medical use. And then of that, and we'll talk about it more in some of the other slides, there were no pathogenic or likely pathogenic variants reported in 503 patients. So the majority did not, but about 48 of the 551 did have a pathogenic or likely pathogenic variant. Okay. So we also did... Because this was kind of our first foray into introducing genetic testing by sort of a patient driven web-based method, we wanted to have an understanding of what the understanding of patients were.

And so there are some surveys that are in the beginning of the study after they provide consent. So we did need to do some filtering out of spam and duplicate records. And then we did not require everyone to fill out the surveys about genetic knowledge and information, but we requested it. So we did have a minimum survey response to indicate that they had some interest in participating. And that was defined as having just completed one of the six validated survey instruments. So they didn't have to do all of them, but they did have to show that they did at least some minimum. And then we confirmed the eligibility and issued the code. And as I mentioned, we did use the color health or color genomics test, and that's a panel of 30 cancer predisposition genes. So some of the results are shown here in this pie chart, which shows us the composition of the different genes that we identified.

Some of these are ones that have been reported in other studies, BRCA2, CHEK2, ATM, and then the sort of less common ones, NBN, PALB2, BRCA1, PMS2, GRIP1, MSH6. So we can talk a little bit later about the composition of the specific genes that were identified, but we did see a lot of the same genes that we... Or the genes that we would expect. We also looked a little bit at the patients that had variants of uncertain significance, which is sometimes a concern for this type of study because everyone... Oh, I should also mention everyone had access to a genetic counselor. People who had no findings could receive their results by email. And people who had a pathogenic or likely pathogenic variant were required to receive that result with a genetic counselor with the counseling that went with it.

And patients that... Or participants that had a variant of uncertain significance could request that. And anyone who did not have a finding could also request talking with the genetic counselor. So that was something that was available. And we have data follow-up data that will be reported about the frequency of patients asking for that even if they didn't have a finding. So we won't go through this in detail, but in the paper there is a list of all of the specific variants. I think that's often important to be able to look at if people want to do a deeper dive into that. But the specific variants are there. And I'll just call out CHEK2 has 1100 delC as well represented as well as... We did find some other interesting variants in PALB2 and BRCA2 and so forth. So they're more... Maybe more to look into there. Most participants... I think one of the take home points, most participants who'd completed the testing, self-identified as non-Hispanic, white, married tended to have a higher education level postgraduate and professional degrees, and then in higher annual income of over $75,000.

And in some ways, this might make sense because they're the patients who may have more bandwidth to be looking for these opportunities and or maybe have more time to participate in support groups or have access to social media and have time to be looking and follow-up. And so that's something that we can come back to. This is just a graphical representation of trying to deter.... An alluvial plot of which we did look at race as a category and which if there were any meaningful differences in the drop-off rate or people... Or either meeting the criteria, not meeting the criteria and the criteria is mainly confirmed metastatic disease. And then those who activated the code or who didn't activate the code. And we didn't really see a substantial difference in the drop-off within a group. Now we can also talk about the overall representation of who participated, but once they participated, there wasn't... And we can look at that in some of the subsequent tables.

But I think there's some interesting observations that we'll definitely need further follow-up here. So I think the important findings are that web-based genetic testing, is feasible, and it's not necessarily reserved for people with a very strong family history. So people with a personal history of metastatic disease can participate. And this is the preliminary report that we haven't gotten to the 2000, but we did observe that participation was feasible, two-thirds of people who started, completed testing, but that means one-third needed more help or somehow didn't have a follow-up that we might otherwise want to see. It's feasible, it can be improved. And during the COVID-19 pandemic, participants were able to continue to enroll as in a way that they might not have otherwise been able to do because it was remote. So I think we learned a lot of lessons about participation remotely during that time. And it was kind of fortuitous, I guess, that we were still able to continue during... A lot of patients isolating.

Okay, two-thirds completed genetic testing. And why is it two-thirds? I think there was concerns that there may be too much reliance on patient-driven action. So while that's a strength, in some ways, it's also a potential weakness because if people have trouble and they don't reach out for help. And there was a phone-based helpline that if they didn't reach out, we wouldn't be able to help them. And then timing, depending on if they're first getting diagnosed, that's a lot a time in sort of the patient journey, where there's a lot going on, they may be started on chemotherapy, per docetaxel, or they just are sort of grappling with a new diagnosis and that's a lot of information.

And if it's not entirely clear why it's important to them. And at that time, and up until recently, PARP inhibitors weren't really an option that might not be front and center as they were going through some of the other things that... Getting started on their treatment and dealing with potential side effects. The other thing we observed is that the median time to completing the survey instruments was longer than we expected. It was about an hour we have data to track that, and some participants may have gotten frustrated and simply given up because of the time burden. We think that removing the insurance and cost considerations helped some individuals, especially those who are very motivated. But it remains to be seen whether that is the primary reason why people... One of the primary barriers or if we take that barrier away, is it possible that there may be some others, and I suspect there may be other potential barriers that as a system we can kind of work on improving.

And as I mentioned, we did... The participation was largely non-Hispanic, white, married, highly educated, and from a higher income bracket. So we need to really be thinking about how to increase education outreach to a more diverse population and help them be aware of the importance of the genetic testing, understand why they may be reluctant if they do have reluctance. And I guess finally, the proportion of men that we identified to have pathogenic mutations was similar, a little bit lower perhaps, that 9%, than prior studies. And I think there's some potential explanations for that. It may be that people who have a very strong family history are more likely to directly be really referred to genetic counseling and rely less on a clinical trial to get that information back. Next steps. So this is also some... This is a schematic of ways we think might improve what we learned.

And I think one of the things that we're... So currently, enrollment is paused because of the finding that we had. And one of the things we want to do is try to improve the workflow for the patient and the patient experience based on this information. So for example, now that we have a fair amount of baseline survey instruments, we don't think it's necessary to make them do that survey that took some people as long as an hour. So that's now moved to... We could move that to the backend and make it optional after they've completed the test. So we remove that as a potential barrier. And then there's other dedicated education and outreach to diverse communities and maybe an automated invitation if it's within a medical system, having a paper-based option if people are less comfortable on the web, having a follow-up phone call, really trying to understand the concerns that patients may have tailored the workflow.

And one understanding, if some of the declines, maybe because of the timing and the intensity of treatment in the upfront setting if they have a new diagnosis of prostate cancer and more active study team help. So these are all ideas that we have and we're working on, when we sort of reopen, we hope to have these in place. Then we may be able to make some comparisons of uptake before and after. So I think that concludes, I'm happy to sort of talk further and see what question there might be, but thanks so much for your attention. Forgot to mention this. There's two follow-ons that I think of might be of particular interest. One is where we look at the denominator. So in other words, we look at all patients who have a new metastatic cancer diagnosis and invite them to participate. And Dr. Hiba Khan reported that at ASCO, some of our findings there.

And then I also want to showcase the TARGET study, which Dr. Veda Giri and Stacy Loeb. And I was fortunate to be part of it, but was led by them, a way in which we can further help educate patients using the internet and web-based tools to help facilitate better patient experience and understanding as they go through this. So that's PCF Challenge Award and also has the PCFYI as well.

Andrea Miyahira: Awesome. Thank you, Heather, for sharing all of this. So I guess as far as the study, looking forward, what is the target recruitment number for the new study flow and when do you expect it to start?

Heather Cheng: Yeah, I think part of the issue is that we may reconfigure it and I think it might hopefully be around a thousand, but I think we really have to... So it might be an opportunity to talk about the GIFT study, which is what I mentioned, which is... This study was patient driven. So we would expect to have... And we saw I think mostly motivated patients, but what we really want is to ensure that everyone has access to the information and doesn't get left behind. And that includes, for example, people whose oncology... Maybe they're getting their care very remotely and they have a diagnosis, but the center that they're being treated at doesn't have genetic counseling and maybe their doctor is really busy and doesn't have the capacity to think about it or offer it. We want to make sure we're not missing those patients.

And so I think that is what I think about when I think about the next iteration, is an automated invitation to people we know might be eligible, whether it's in a medical system or whether it is through our cancer registries and then inviting them. And we do have some preliminary data there. So that, I guess, to answer your question would be the next iteration is to improve and be more systematic and deliberate about the outreach. And we're still working on the design of that, but the overall idea would still be to try to improve, educate, and give access where it isn't right now.

Andrea Miyahira: Has the color test that's being used changed over time? Are there more genes now that are being looked at?

Heather Cheng: Yeah, it's a great question. So I think NBN has actually been removed from the current commercial panel, but they're also working in... There's discussion about incorporating something called PRS, which is polygenic risk scores. That's investigational, at least to my understanding right now. But I think it's going to be kind of interesting and exciting to look at how that unfolds moving forward because I think there's a lot of possibilities there too.

Andrea Miyahira: I think another question I have just as this study evolves, we're learning a lot more about what the genetic variants actually mean for prostate cancer risk.

Heather Cheng: Yeah.

Andrea Miyahira: So I guess what have we learned about that and how has it changed, what's being tested for?

Heather Cheng: Yeah, I think that's a really good point, Andrea. And I think that we are still learning about that, and that being sort of the particular risk that's conferred by specific genes and then also by specific variants within a gene. So here, I think in this study in GENTleMEN, it's not necessarily going to be the best cohort to sort that out. And the reason is because everyone has metastatic disease. So to the answer the question about risk, we would need... And I think there's efforts ongoing to identify people who don't have prostate cancer, who have those risks, those same variants. Maybe they're relatives of people who have metastatic disease, maybe they don't have a family history of prostate cancer, but it requires kind of a more population-based identification of the cohort and then follow up of who develops prostate cancer. That's going to take some time.

There's ways in which we can infer that information, like for example, is the variant more enriched and metastatic compared to localized, compared to people who don't have prostate cancer? And I think for a lot of these genetic variant, the answer's yes, but that doesn't sort out which factors put you at risk for prostate cancer versus which ones might potentiate aggressive potential or could be associated with aggressive potential rather than the development of prostate cancer. So there's definitely a lot more that is important to learn about and makes it really, I think, exciting to be looking forward to those new kinds of questions.

Andrea Miyahira: Cool. And are you able to follow these patients and of the patients that you determined that were carriers of alterations, did they cause any change in treatment planning and if any families that underwent cascade genetic testing afterward?

Heather Cheng: Yeah, that's an excellent question. I think... So for this first pass, it was really, did they do testing or not? And then we have invited them, but in another study that is related called the PROMISE Registry, and that one is more designed for long-term follow-up of treatment response and asking questions about cascade testing. So we tried to do it, but this study was really kind of the first path. We just want to see if... Is it even feasible to do? And I think the answer is, it is feasible, we can try to make adjustments to make it more effective. And then PROMISE is underway right now, and we're really trying to engage patients long-term for those very questions that you just asked, what is the treatment response of the different types of commercially available treatments as well as targeted treatments? Do they respond better to... We think they're going to respond better to PARP inhibitors, but what's the response to lutetium, for example, or Pluvicto, that's going to be... I think a lot of us are thinking about that. That's really kind of...

Lutetium is a DNA damaging drug, and so it might make sense that some of those cancers that arise in the setting of those mutations might be more effectively treated. We don't know yet. And then also the question about cascade testing, which is really, really important. And it's often something I think about which is, "Well, can we make sure the family members know?" And then if they want to know, and then will they have those opportunities for reducing their cancer risk? And do they follow through on that? And to what extent does that happen more for women because there are more interventions in place compared to the men, who historically may not have been thinking about their own prostate cancer risk. Those are all very important questions that I think we also need to be thinking about. And lots of really motivated colleagues in the field through... That we've been connected through PCF and UroToday are thinking about that together.

Andrea Miyahira: I guess going back to feasibility, you're able to identify a lot of barriers to even a process that's remote and free for patients, but still, what do you think are the most significant barriers remaining as we move forward to tests being covered by insurance and being used to select treatment and also all changes in guidelines?

Heather Cheng: Yeah, that's great. Thanks for asking that question. I think one of the weaknesses in some ways... Or I guess it's not a weakness, it's... For this particular study, is that it was a very heterogeneous population. And in some cases we had... I personally had relationships because they were my patients, and I think like at our center, we had that therapeutic relationship, and in some cases we didn't. In most cases we didn't. Most cases the patients were not ones that we were personally taking care of. So I think that actually goes a long ways, I think that's one, is really having the provider, the physician, the urologist, the medical oncologist, be able to explain to the patient why it's important to them, why it might be important to their family. Also, now that there are PARP inhibitors in clinical trials and have targeted therapies, there's that piece that is more tangible than it was at the time, right?

Because at the time, we didn't have those necessarily as robustly as we do now. And then I think there is something about the cultural context and the patient context of what are their concerns and are we really addressing them or do we think we're addressing them? And that's a lot more difficult to get at. And I think we've had in the... In the GIFT study, we've had phone interviewers that have called and really followed up and tried to understand, but if people don't respond, we don't really know. We can only guess if they don't tell us why they're not going to do it. And sometimes, I think in clinic, there's enough of a power differential that patients won't really tell us if they don't want to do it, they may nod their head and say yes, but then they just don't follow through. Right? And so that might be a little bit of the absence of follow through if there's either a mistrust or a discomfort or something that's giving people pause.

And I don't think we have a good enough yet understanding of that, but I suspect that's going to require really kind of careful and deep listening and may require other avenues to understand that and address it better. And I think we need more patient advocates to come forward, but also community members that don't think about this and maybe have a different perspective on people's impressions of what that really means, what genetic testing means, because I think we can only see our side of it. We don't always have as much as we might think we do, understanding of patient's perspectives. And I think that's good. I think that's going to be really important.

Andrea Miyahira: Yeah, when I think about the design of this, it's free, it's remote, so that seems like it would be a really great opportunity to address disparities. So what sort of plans are you guys activating for... Trying to reach out to patients from underrepresented backgrounds?

Heather Cheng: Yeah, I think... And we're not the only ones thinking about this, I think, across the field and a lot of at GU ASCO and at ASCO and PCF and PCCTC and many groups are thinking about how we do this more effectively. And I think that... Honestly, I think we really need community leaders, not necessarily medical people in the field to potentially also do not on the foot outreach, outreach to barbershops, to churches, to community groups, and listen carefully and try to understand the barriers, but also try to bring our hopefully enthusiasm and excitement. And I think there's opportunities to leverage with families. So oftentimes, genetics is much more... I think women tend to be the sort of bearers of healthcare information and advocacy in the family, so that there's a way to kind of leverage that. But I think there's... I don't have an easy answer except for that. I think we have to try and we have to keep doing it, and it's really important.

And I think getting into the communities and then finding out. Because sometimes we say, "Oh, well, maybe internet access isn't as readily available." But I think that's actually not necessarily true. A lot of patients, even in our safety net hospitals have smartphones. So there may be other things that we can do, perhaps it's better education, like maybe doing more videos. And that's something we've talked about using the Helix tool that Dr. Gary and Dr. Loeb and I worked on with PCF to sort of help educate, but not just educate, but maybe understand both, there's a education and then a sort of assessment of comprehension, but maybe those formats could be further improved. So I think those are things that I'm thinking about in terms of how we do better.

Andrea Miyahira: I was wondering about some of the questions that your survey asked. Were you able to ask questions, like why? What was the motivating factor for patients getting genetic testing? I'm wondering if like for instance, younger age or any family history with other cancers would come up in sort of motivating factors.

Heather Cheng: Yeah, I think we don't have all of that data analyzed or reported yet, but it's underway. And actually, we have a genetic counseling student who's working on that right now, analysis along with one of my colleagues and collaborators, who does... That's her expertise, Dr. Sarah [inaudible 00:28:41] and Sunny Ren. And so I think that will be important. But I do think as much as that will be interesting to look at, I think that we... Again, we don't know. We only know the response of the people who are engaged. We don't have responses to the people that didn't. So it's going to be a little bit of a biased view. It's still important, but we have to remember that too.

Andrea Miyahira: So I just wanted to talk a little bit about telehealth. The GENTleMEN trial was initiated before the pandemic and that whole necessary move towards telehealth that the pandemic sort of pushed us towards. And I guess there's some serendipity there for your trial. So you said the pandemic, you didn't see any pauses in enrollment. Did you see any increases in enrollment? And have you found that since the pandemic and the expanded use of telehealth that this remote genetic testing and counseling platform would have even greater utility now?

Heather Cheng: Yeah. Thank you for that question. I think it's a little bit... We didn't see major drops in enrollment. I don't know that we also... We necessarily saw increases either. But I think the fact that it was steady and did not decline tells us that unlike some of our therapeutic studies, it was much more... This was a strategy that could occur despite the pandemic. And I think part of that is the convenience factor. Patients often might be very motivated, but they look for logistical reasons, transportation, elder care, childcare, can't always meet the same schedules that therapeutic trials require. But this type of study and registry studies might be more feasible for them. And I think that that's something that we are seeing with some of the other registry studies like PROMISE and IRONMAN, that they are more compatible.

So I think it's a nice opportunity, and it does make me think a lot about, "Well, what are the opportunities that we could leverage with variations upon standard of care that could be delivered to patients wherever they're getting their care?" Maybe there's a way to do that if it's not completely just... We can't do that for phase one trials, but could we do that in other contexts? And I think that's really exciting to think about.

Andrea Miyahira: Okay. Well, thank you so much. I think this trial was a force of nature and very forth looking, so I'm excited to see where you guys go with this and also hear about the results from the other ongoing trials that are looking at genetic testing in patients. So thank you for joining us, Dr. Cheng.

Heather Cheng: Yeah, thank you so much for having me. Thanks everyone in the audience for your participation.