Prostate Cancer Lab: Personalized Treatment with Advanced Diagnostics

•Brian McCloskey: 56-year-old tech marketing executive; diagnosed 5.5 years ago; on abiraterone; sees the challenge of personalizing his treatment as hinging on data and analytics; wants to bring cutting edge diagnostic data and integrate it to understand his disease and guide his treatment.

•Rick Stanton: bioinformatician with many years in the pharmaceutical industry, including at Human Longevity, Inc., and Amgen; Stage IV; on chemo; wants to bring emerging research diagnostic technologies to his treatment decisions. CancerHacker Lab founder Brad Power moderated and shared an overview of the Cancer Patient Lab and its purpose.

•Building on the hackathon for advanced prostate cancer patient Bryce Olson in 2021.

•Lab process: attract patients, gather data, analyze data and find treatment options, define treatment strategy.

•Have attracted diverse companies and individuals willing to help: diagnosticians, bioinformaticians, treatment matching, patient advocates, and clinicians.

•Focus on accelerating the use of cutting edge diagnostics (RNA, proteomics, single cell, spatial analysis), which are currently “Research Use Only”, for clinical decision-making. Several of the participants introduced themselves, including:

•Nik Schork: of TGen, an organization bridging between health data and clinical guidance - has developed a protocol, approved by an IRB, to grant patients access to research data about them.

•Rick Davis: leader of AnCan, a community of cancer patients - clarified treatment options.

•Lea Ann Biafora: oncology nurse, founder of Beacon Associates; Jason Sager: pediatric oncologist; Stacy Hurt: patient advocate, colorectal cancer survivor; Jeff Waldron: healthcare community connector; Jan Sobieralski: advanced prostate cancer patient. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatm treatment, product or other course of action that might affect your health. Meeting Notes Brian McCloskey: I’m a 56-year-old father of three and husband. I was diagnosed five-and-a- half years ago. I have been on an interesting journey since. Professionally, I spent the better part of 25 years building personalized consumer experiences in e-commerce and high tech, and most recently managed marketing for the largest healthcare staffing firm in the country, AMN Healthcare. My background is very data and digitally oriented. When I was diagnosed with cancer I realized there were some opportunities in how we used data to better personalize the experience, and hoped to use my background in approaching my cancer. The essence is trying to understand my cancer before we move onto treating it. It’s the same as when we used lots of data to personalize consumer experiences. I haven’t seen anything that tells me that that analogy doesn’t hold in medicine. There’s a long way to go in medicine, and that is what this is about. How do we use data to more intelligently treat us? My passion is surfing. I live in San Diego. I passed it onto my kids. Rick Stanton: I’m a surfer as well, though not as good as Brian. I have two kids and a wonderful wife. My daughter moved to Hawaii to surf. I’m Stage IV. I’m on chemo. I have gone through multiple rounds. My prostate cancer was discovered after noting a jump in my PSA at a yearly checkup. I had no symptoms. It turns out I have a CDK12 mutation, which is aggressive, but opens up some therapy options. My goal is like Brian’s. There are about 1,000 clinical trials going on for advanced prostate cancer. They are targeting roughly 25 or 30 molecular targets of the immune system or in the cancer cell. I and Brian are at or nearing the end of the standard of care for NCCN guidelines. The standard of care includes androgen (hormone) blocking drugs, and then you go on chemo. I am on my fifth round of chemo and need to know what to do when it fails. You can’t stay on chemo forever. I’m having tingling in my fingers. My hope is to help Brian, myself, and patients to come to decide what the next best therapy is after the standard of care as we push into immunotherapies and combinations of conventional, targeted, and immunotherapies. I have 3 or 4 doctors, so I am getting multiple counsel. Different doctors have different clinical trial options. I’m finding that none of these treatment options are defined by my state. RNA seq is typically not used. Mutations are used, e.g., my CDK12 mutation is being used to guide my therapy. Tumor mutational burden is used and some basics. I’m hoping to get guidance on which trial or therapy to try next, to either manage my disease well or find a cure. Brad Power: Any more details on your medical history? How has your PSA responded to different treatments? Rick Stanton: I was diagnosed in late 2019. My treatments have been salvage radiation, Lupron, and Casodex, which controlled my PSA for 13 months. Then I went on darolutamide, which is a next-generation androgen receptor blocker. That didn’t do so much. I was on that for 4 months, and my PSA started rising to 3.6. My doubling time was about a month. It was not being controlled. It was determined I should go on docetaxel chemo, which I have been on since December. It brought me from 3.6 to 2.6, so only a marginal drop in my PSA. I have a nodal disease. I have 5 or 6 lymph nodes that have cancer in them, from my neck to my pelvis, as shown in a combination of CT and PSMA scans. I’m currently at a PSA of 2.6. My largest lymph node is about a centimeter, in the middle of my chest. I requested IHC stains from my primary tumor, which might guide my TILs and predict responsiveness to my tumor. Brad: You might have noticed implicitly that Rick is a bioinformatician by background. Brian McCloskey: Here is a graphic that describes my journey of treatments and responses: Exhibit 1: Biomarker/Treatment Overlay - 8 Key Decisions I was diagnosed in 2016. I had a radical prostatectomy. My DNA mutations are in the blue box: TP53, PBRM1, and TMPRSS2-ERG. I went on a number of different treatments: hormone therapy, radiation, a second line hormone therapy with apalutamide (decision number 4). Then I went on a holiday, and as soon as I went on a holiday, my disease came roaring back. My Gleason is a 4.3, with a tertiary grade 5, which would largely explain the aggressiveness of the disease. I have 6 metastatic lesions in my peretenium. That was discovered in July of 2020. I had robotic surgery in August of 2020. We determined that my DNA mutations were the same as from my primary tumor in 2016. Rick did an amazing job of quarterbacking an RNA seq analysis with Tempus. There were a lot of findings from that; of note: expressions of CD276, CD357, TD02, and FOLH1 (PSMA). TILS 0%. Definitely some challenges in terms of a very immunosuppressive environment. After my surgery, since we knew we didn’t get it all, I started on systemic therapy with chemo and pembrolizumab (Keytruda) in October 2020. 6 rounds. Then I remained on pembro until October 2021. Then my PSA began to rise and lesions re-appeared. I had “no evidence of disease” shortly after my surgery. I started abiraterone in November of 2021. My PSA was at .91, and it has dropped to a .45. I am currently responsive to abi, which is great. But I don’t know how much mileage I’m going to get on this. I know that the likelihood of becoming hormone-insensitive is high. My objective is to determine what is going to be the next best therapy for me. Here is a quick snapshot of my journey in terms of the sheer number of medical visits: Exhibit 2: 205 Cancer Visits over 5.5 years Office visits (dominant) - 33% Lab - 25% Radiation (a big part early on) - 20% Imaging – 10% Here is my table of treatment options: Exhibit 3 - Treatment options I want to get much smarter about which treatments I can rule out, and which treatments are going to be most relevant for me. Today the way that decisions are made is largely based on the stage of the disease (e.g., metastatic), hormone-sensitive or not hormone-sensitive, and the medical history and relate that to clinical trials and mass treatment response rates. I believe we can do better than that. We found some interesting insights from my DNA analysis. We had some interesting results from the RNA seq analysis. I wonder what else we can find if we continue to look from a genomic perspective, from a cell perspective, an extracellular perspective; look at my immune system, and maybe other factors, and help me do a better job to rule out treatments and prioritize those that will provide the greatest response. My mission is to live as long as I can. Exhibit 4 - My mission is to live my best life, as long as I can. I am grateful for the amazing care I’ve had, and the advancements and the support I have received. I also see there is a chance to accelerate the pace of translational medicine. I’m thankful to have Rick and Brad on this journey. I believe we are trying to better use the insights that exist in the lab and bring them to treat our diseases more effectively. I have conversations every day with so many amazing doctors, scientists, and researchers about how those improvements are happening. I want us to take a different approach. This prostate cancer lab represents an opportunity to take a unique approach to do that. Jan Sobieralski: I want to compliment Brian on his flowchart. This could help in any diagnosis. It’s a great way to present your case. Brad Power: Prostate cancer is lucky in a way – it has a PSA as a measure of the aggressiveness of the disease which allows monitoring. Patients can effectively run experiments on themselves. For example, they try a drug, and it knocks the PSA down. Stacy Hurt: Do either of you have any glaring comorbidities that would exclude you right off the bat from any clinical trials? Brian McCloskey: Unfortunately, I’m a pretty healthy guy. I exercise all the time. It’s one thing I can control. I know Rick does too. You would look at me and not know I had cancer. Rick Stanton: Same with me. I try to work out a lot. Swimming every day and lifting weights. Rick Davis: Do we have any genitourinary oncologists on the group? Rick Stanton: My primary care medical oncologist is Dr. Sandy Liu out of UCLA. Even though she couldn’t make it, she is very supportive, and she will be tracking our progress asynchronously as much as she can. Tanya Dorff at City of Hope, John Chen at UCLA, and Rana McKay at UCSD are my medical oncologists. I think they are awesome, they guide clinical trials, and are knowledgeable about options. Brad Power: We have gotten commitments from six or eight clinicians who have committed to work with us but will not be on these calls every week. Rick Davis: What are they each saying about where you are in your treatment, and what are they recommending that you do? Rick Stanton: Dr. Liu is my primary medical oncologist because I am on an Arcus-6 clinical trial. Unfortunately I was assigned to the docetaxel chemo arm only. The clinical trial is run out of Arcus Biosciences. I know the CEO. I used to work for him when I was at Amgen, where I worked for 17 years in discovery research. I know the Arcus team very well. I used to consult to them. I saw the adenosine PD1 and docetaxel clinical trial as something that I wanted to explore. The trial is reaching its end. I contacted Dr. Dorff for a second opinion. I’m trying to be proactive. She recommended a Xencor trial, which is a bispecific PD1 and CTLA4, along with olaparib. I am also trying to get IHC stains for CD3, CD4, CD8, and PDL1. I’m waiting for that result. Rick Davis: Do you have any markers for a PD1, or for olaparib? Is there any indication that those drugs might be suitable for you? Rick Stanton: Only population statistics at this point. Rick Davis: I’m asking because I get very concerned that guys who come to us are not used as lab rats. You’re getting a little bit of neuropathy, but that not unusual after five sessions. What about reducing the dose? Sticking where you are? Looking at what shows up right now on an NGS? What about adding a platinum if something unusual shows up? And in the meantime, science is moving so quickly. A year from now there could be something clear. Olaparib will do horrible things to your blood counts. Docetaxel is keeping you in check for now. Rick Stanton: All of my doctors recommend that I stay on docetaxel for as long as possible. They are in complete agreement with you. They are very conservative. By the way, I think you’re amazing. I have attended a number of AnCan meetings, and I see what you’re doing for the patients. Many are less informed. Brian McCloskey: Rick [Davis], you may recall you were actually part of my last decision. When my PSA began to go up, we looked at abiraterone, enzalutamide, apalutamide - where I had an amazing response, and derolutamide. I’m being treated at UCSD, and Rana McKay is my primary onc. She is incredible. I’m so fortunate to have her. I have many other medical oncologists that I speak to on a regular basis. We decided to go down the abiraterone route. The primary reason was that there were some clinical trials with a lot of success. We considered abi plus chemo. I had just come out of chemo, so that wasn’t the greatest fit. This is where it is part art and part science. Where I want to focus this effort is not necessarily jumping to treatment decisions. I’m fortunate that I am responding to abiraterone right now. I have discussed all of the treatments on that list that I shared with Rana and my doctors. For example, I just spent some time yesterday with Tanya Dorff, and we talked about when it would make sense to do a CAR-T. I had an amazing conversation with Saul Priceman on my way home from City of Hope, and we talked about some really great opportunities to do some cutting edge diagnostics. Right now, where I am in this honeymoon period, I don’t know how long it is going to last, I want to get a better handle on my disease. I want the data to speak. I’ve seen it in my professional career so many times. It’s like the cardinal sin of marketing: if you think you know who your customer is, you are wrong. You need to let them speak. You need to let the data speak. Even though the work that Rick did on my RNA seq analysis wasn’t immediately processed by my oncology team, after three months, I got a thank you for it. “This is information that we can actually use for targeting.” Namely B7H3 and CD276. I have a pretty good handle on what my DNA looks like, and a decent idea of what’s going on from an RNA perspective. That’s opened up new doo doors. As we look at the flow of diagnostics, getting into proteomics and other things, what else am I going to uncover within those specific fields? And when you look across them, from a genomic perspective, a cell perspective, an extracellular perspective, immune, etc., how is that going to come together and provide new context for how my prostate cancer and Rick’s prostate cancer has evolved? Hopefully we can identify more meaningful treatment options. I have spoken to many, many people, researchers, oncologists, etc., and I’m very fortunate. For example, Laura Kleiman, who is on this call. I reach out to people and they pick up the phone. It’s crazy. I am more and more convinced that what we are doing here is novel. There is something kind of similar, “PROMISE” [Prostate Cancer Precision Medicine Multi- Institutional Collaborative Effort]. It’s a team of medical oncologists and researchers that are trying to correlate DNA to treatments. But I think that that is dealing with a limited set of information - DNA. How much of that is out there for prostate cancer patients? There is some. Yes: continue on that effort, but we really need to continue to look holistically at a whole range of diagnostic tools that can really shed light on our cancers. Brad Power: Rick [Stanton] has been particularly useful in providing introductions into the new diagnostic area of spatial analysis, which is looking at the tumor microenvironment. We’ve had conversations with Akoya Biosciences, NanoString, and Enable Medicine, and these are all “Research Use Only” at this time. These are amazing tests that are being used to help with understanding the heterogeneity of the cancer and of the microenvironment. We want to accelerate its use for clinical guidance, for Rick, for Brian, and for other patients that would follow. And that will be a key part of this prostate cancer lab that we are launching, to see which of those tests are useful in clinical guidance. Part of our challenge is overcoming the hurdle of tests which are currently for “Research Use Only” and being able to use them for clinical guidance. Rick has been negotiating with these companies to get clinical access. Rick Stanton: I’d like to introduce a wonderful organization, TGen, along these lines. Danielle,