Prostate Cancer: Tests & Treatments for Advanced Disease

•Medical history: Rick shared a table with his PSA measurements and treatment history. His PSA is currently under control, and he is looking to have his next treatment ready to go.

•Treatment options: Rick listed the treatment options that have been recommended to him. Dr. John Laird suggested that trying chemotherapy combinations in the lab of Bob Nagourney at the Nagourney Cancer Institute would have a greater assurance of efficacy (80-90%) than clinical trials (15%). Rick Davis endorsed treatments with more evidence, and recommended that Rick revisit his initial diagnosis, as well as considering Pluvicto (PSMA-targeted radiation nanoparticles).

•Tests requested and analysis desired: Rick has requested IHC stains that will provide indications on his likely responsiveness to immunotherapies. He is offering his extensive medical data to anyone who would like to hack on it. We continue work on “right to see” – finding ways for patients to be able to access data from “research use only” tests run on them. Requests

•Please let us know if you know anyone who might be interested in being a principal investigator, or any potential funding organizations, for an observational feasibility study on providing data from emerging (research use only) tests to patients to guide their prostate cancer treatment decisions (“right to see”).

•If you would like access to Rick or Brian’s data, please contact them.

•Please join our online discussion forum for 24/7 conversation. 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, treatment, product or other course of action that might affect your health. “Tests and Treatments for Rick Stanton” Meeting Notes Brad Power: There are three agenda items we plan to cover in this meeting: 1.An update on our work on “right to see” - the idea that patients should have access to “research use only” data that is run on them. 2.Rick Stanton is going to lead us through his treatment situation, his history, and the decisions that he is facing now, as a setup for the issues facing people like him with advanced prostate cancer. 3.Rick will share the data that we have on him and Brian McCloskey and the additional tests he would like to see run. “Right to See” We spoke with Nik Schork, Peter Kuhn, and Marty Tenenbaum in the past week about various ways to get around the roadblocks to patients having access to data from “research use only” tests run on them. One workaround is to have an IRB (Institutional Review Board), as Nik Schork talked about in our last meeting. Nik described in our last meeting how he helped get an IRB-approved protocol for Rick Stanton. So one path is to broaden or expand that as a template for others to use. Another workaround is to set up an observational feasibility study, which is a research study with a lower barrier to set up than a classic randomized clinical trial, which is prospective, expensive, and slow. We are working to find principal investigators and organizations that would fund such a research activity. If you know anyone who would potentially be a PI or an organization that would want to fund that kind of work, please let us know. Rick is also trying to go through standard channels and a CLIA-certified lab to get the advanced testing he would like through City of Hope, where he is being treated by Tanya Dorff, and where they have access to his tissue. Rick Stanton: TGen is moving ahead with approvals to work with Akoya and Enable. I can’t say for sure because Akoya and Enable don’t want to talk to a patient. They want to talk to TGen, which has the protocol in place. I’m boxed out. I get a little update that things are moving ahead. I’m very excited about that because I would like to be the first of many. I’d like this to be available to everyone who has the means. It’s fairly modest, I think a few thousand dollars. It’s getting closer. Introductions of New Participants Rick Stanton: I’d like to hear from some of the people I see on this call whom I don’t know. Could you please introduce yourselves? “Tests and Treatments for Rick Stanton” Dr. John Laird: An MD focusing on complex cancer patients and integrative treatments, recently relocated to Asheville, North Carolina. Saed Sayad: An MD now focusing on AI, professor in the Computer Science department at Rutgers. Alex Feltus: Biochemist, biomedical, genomics, professor at Clemson, crops, high end computation. Chandra Kota: A medical physicist working in new radiation treatments. Currently working at Yale and looking beyond my day-to-day job and seeing how I can help patients with advanced radiation treatments. Heather Messerly: At Certis Oncology in San Diego, creating PDx models using mice of patient cancer tumors to test different treatments on them to see which ones work and do not work. I’m not a scientist. Patient manager. Learning by sitting in. Happy to step in and help. Jan Sobieralski: A patient with castration-resistant prostate cancer. I just asked my doctor if I could get Leutetium 177 (discussed in our last meeting), and they said “no”, because I have to be castration-resistant and have had the Taxol treatment, further along in my journey. Rick Stanton Case Rick Stanton: To start with how I’m doing. I just completed six rounds of docetaxel. In my last round I had an 80% dose since I had developed some tingling in my fingers (neuropathy), and I’m a guitarist. When I got my infusion, they also took my PSA, and I learned that my PSA had gone down – not a lot, but it did – from 2.6 to 2.4. The time before that it was 2.4, so I’m bouncing around 2.5. My cancer is being controlled. I expect to get another round of chemo. At the start of my chemo I was advised that I would have six to ten rounds. This is in an Arcus clinical trial. I was randomized to the docetaxel arm, not the arm with a PD1 inhibitor and an adenosine inhibitor from Arcus I had hoped to get. Sandy Liu of UCLA is the leader of this trial and my treating oncologist. The folks at Arcus are my friends from when we worked together at Amgen. They are a very good small molecule company. I hope my decisions will be informed by an IHC (immunohistochemistry) stain at a minimum. This is the kind of test results I hope to get: “Tests and Treatments for Rick Stanton” These are four tumor slices. This is a CD3 stain, that is looking at T-cells: CD4, CD8, and Tregs (regulatory T-cells). The brown pattern in the upper left tells you that this tumor is loaded with TILs (tumor infiltrating lymphocytes), which means it is “hot”. On the right you see that it is “cold”, T-cells are not infiltrating this tumor. On the lower left if you did an RNA-seq, you would think you had good infiltration, but the moat of exclusion means there is immunosuppression. In the lower right you see a low amount of infiltration, though they are there. The reason I bring this up with the four states is that this IHC staining or spatial analysis would influence your selection of an immunotherapy. If you have low infiltration, either you need to do a prerequisite or hope for a miracle. “Tests and Treatments for Rick Stanton” Brad Power: Which do you look like? Rick Stanton: I don’t know. I’m waiting on IHC - this stain. I asked Tanya Dorff to order it for me, and she agreed. I would call this spatial analysis. Akoya, Enable, and NanoString all do very deep queries using advanced technologies which are “research use only”. I want to do this with IHC, which is more standard. I hope that I will be in the upper left. If you’re in the upper right, cold, with no tumor-infiltrating lymphocytes, PDL1 blockade inhibition is not going to work because there are no T-cells to modulate. Dr. John Laird: As you said, with the upper right hand result, it would be a waste to try immunotherapy. Prepping that microenvironment would be key. There is a group, not set up commercially, called Consultative Proteomics at the University of Texas, led by Dr. Robert Brown, that I’ve used. They do proteomics, IHC stains, 20 or 30 on any given tumor. Are you familiar with their work? Rick Stanton: No, that’s beautiful. Dr. John Laird: What they do that’s particularly relevant to this particular slide is assess CD8 cells, which are the ones that are going to be most helpful, from FOXP3 cells that put on the brakes. Anything that is 2/1 or over (CD8 to FOXP3) is considered good. Then they will look at CD163s, which are macrophages, and are also key. Macrophages can be in an M1 stage or an M2 stage, and they transform back and forth. If they are in the M1 stage, that is very positive; if they are in the M2 stage, then that is a brake on the system. We can run the samples and get results, but they are not a high volume shop. It can take six weeks or more to get results back, but they’re very helpful. This look at the microenvironment is something my mentor Mark Breniker had them set up a few years ago. You also get a protein fingerprint to give you a sense of which of these genetic changes are driving the tumor. No oncologists are going to make any treatment decisions based on this, but looking at the microenvironment terrain can often help in the off label environment. Rick Stanton: I feel like going 20 deep in the IHC. Are these different slices of tissue, or are you able to stain and wash? Dr. John Laird: They end up with 20 slides. They need a block. Offline I can help get you set up. Rick Stanton: Are you acquainted with Akoya and NanoString’s spatial efforts? Dr. John Laird: I’m not. “Tests and Treatments for Rick Stanton” Rick Stanton: You’re going to love them. It’s immunofluorescence, like an IHC. You’re able to do it on one slice of tissue. Immunofluorescence allows stain and wash. You are tagging the fluorescent molecule some color, typically red, green, or blue, to an antibody. You can go in three at a time with the three colors. You could pick CD3, CD4, CD8 and iteratively build up to their high dimensional, up to 100 plex. I know they’re operating at 35. This is both Akoya and Enable. It’s like what you said, except it’s on one slice. NanoString enables even deeper querying. In the slide on the lower left, you could query boundary areas. Dr. John Laird: What was the extent of your disease and previous treatment? Rick Stanton: Here is a one-page chart of my history and treatment considerations with my state, tests, treatment guidelines, and therapy options being considered. From row 20 to the bottom is my PSA and the treatments I have received from my diagnosis in 2019. You can see I had Lupron, Casodex - which held me stable for 8 months, Darlutamide - which didn’t do much, and now Docetaxel - which took me from 3.6 to 2.4. Brad Power: Dr. Laird asked about the extent of your disease? You’re metastatic? Rick Stanton: I have nodal disease, 4 lymph nodes from my neck to my pelvis. These are picked up in a PSMA scan and confirmed in a CT scan. I am at nodal, Stage 4, castrate resistant. Lines 3 through 9 are my next therapy options. “Tests and Treatments for Rick Stanton” When I talked to Tanya Dorff, what evidence would influence her recommendations? CDK12 opens a lot of neoantigen fusions. She is advocating for this clinical trial which combines a bispecific PD1 and CTLA-4 with olaparib. Olaparib has been approved for CDK12 mutations, but subsequent data maybe shows not that great. It’s more for a BRCA-1 or BRCA-2. So I asked why she would recommend it. She said she wouldn’t recommend olaparib on its own, but in combination with the PD1 and CTLA-4, she thinks it might be a good fit for me. Rana McKay gave her recommendations, including a PSMA-targeted CAR-T. Why would she add PSMA? There are three evidence notes on why it would be a fit for me. It fits from population studies. It was also confirmed in the RNA seq. I am a super high expressor of PSMA, and so is Brian. I light up. Rick Davis added Pluvicto in our conversation last week. Dr. Laird: Are you familiar with the work of Robert Nagourney down in Long Beach? Rick Stanton: No. Dr. Laird: Bob Nagourney in the 1990s started doing chemo sensitivity testing. He took live tumor tissue and exposed it in a test tube to multiple chemotherapy agents. There were many other people doing the same work at the same time. Some of the work was crappy, and the whole field was discredited. Nagourney has done good work over decades. In the test tube you can test various combinations. In general, if he finds that a tumor is sensitive, that will be borne out 80% of the time clinically. If he finds that a chemo is ineffective, that is borne out clinically 90% of the time. Nagourney is one of the smartest oncologists around. He is world class. He has a tough ego. He’s gotten a lot of hits from the profession. But his work has led to standard of care combinations, such as cabazitaxel and gemcitabine. The larger point is that trials are a crapshoot, and the percentage of success is maybe 15%. It would therefore be rational for my patients – and usually I don’t give any advice to patients unless I have reviewed their files for four or five hours, and I don’t really know your case, but this is a wide-open conversation – to go the Nagourney route, because you’re looking at 80% or 90% effective treatments vs. 15%. I would go that route first and get his assessment. He doesn’t care so much about genetics. He looks deeply. He’s more like Harrison Ford in Indian Jones who is confronted by a guy with swords and knives, and he pulls out his gun and shoots him. Nagourney cares about whether the treatment will kill the cancer. He cuts to the chase. He’s good to have on your team. If you have nodal disease, he would need a centimeter of tissue that you would have to get to him on the next day. Your tissue would probably be accessible. Whereas the proteomics can be frozen tissue, Nagourney needs fresh tissue. Nagourney Cancer Institute . Rick Stanton: That sounds great. Dr. Laird: He has a TED talk on his website. He is not just a lab, he is an active practicing oncologist. He knows the challenges. It would have advantages to do it onsite. “Tests and Treatments for Rick Stanton” Brad Power: Rick, what are the requests you would like to make? What are the questions you have? Rick Stanton: Rick Davis, you gave the suggestion of Pluvicto. It was shocking to me because three out of three of my clinical oncologists hadn’t mentioned it. I queried them during the week. I got a beautiful response from Sandy Liu, my treating physician under the docetaxel Arcus trial. Her response was, “Yes. Pluvicto would be a very good option for you.” It’s so interesting that until I brought it up, because you brought it up, it wasn’t even on the radar. Suddenly it’s a very good option. The other option is a crossover that I can go to and stay on the docetaxel and the PD1 inhibitor and adenosine. Rick Davis: It’s a pleasure. It’s what we do. Sometimes you can’t see the wood from the trees. I also want to thank Dr. Laird because he’s saying the same thing. We can be looking around and running around in circles up the spiral staircase in the ivory tower and there’s some really good stuff out there. I don’t know how much experience Dr. Nagourney has with prostate cancer, but it doesn’t behave like other cancers. In looking at your chart, something came to me that Dr. Laird mentioned: your disease was strange from the start. It showed up as very aggressive, 4 + 3. (The pathologist looking at a biopsy sample will assign one Gleason grade to the most predominant pattern in your biopsy and a second Gleason grade to the second most predominant pattern. The Gleason score classifies cancerous cells into 5 distinct patterns as they change from normal cells to tumor cells, graded on a scale of 1 to 5, where grade 1 cells resemble normal prostate tissue, and cells closest to 5 are considered “high-grade” and have mutated so much that they barely resemble normal cells.) It was relatively aggressive, but not over 8. I think if your slides ever got re-read might it have a much higher Gleason score? If you had intraductal disease and low PSA, from the outset your disease didn’t behave like an adenocarcinoma disease. There may have been mutations in there from the beginning that didn’t allow you to respond properly. One of the treatments we’ve seen used in that situation is adding platinum-based chemotherapy. I think you’re just getting docetaxel right now. I would be doing a little more work and see whether your cells had a bit of a neuroendocrine aspect earlier? Or even now? If they did, maybe we should add something else to the chemo. This is separate from the PSMA discussion. We go to these docs, and they don’t see the obvious. It makes me a little crazy. Were you properly diagnosed in the first place? When guys come into our group, we often push them back to their medical team to say, “have you done this, have you done that?” There is no one better than Epstein at Johns Hopkins to review those slides. “Tests and Treatments for Rick Stanton” I’m glad that we got you and Brian onto the PSMA path, especially when you say you’re super sensitive to PSMA. And Pluvicto is the best PSMA option. We have a guy whom we hooked into Bryce yesterday. His disease is running crazy – his tumor burden is around 39. He is certainly eligible to start Pluvicto, but he doesn’t want to wait the four to six weeks it would take to start. He is going into the Weill Cornell trial with alpha- plus beta-particles, starting next week, because time is so much of the essence for him. Fortunately, you don’t have that situation. Oliver Sartor thinks that alpha- plus beta- has some merit. But I would start with is tested. I would be interested to hear from Dr. Liu about when Dr. Calais (at UCLA) is going to be able to start to take patients for Pluvicto. On olaparib, these doctors are searching around to see how they can make a cold tumor hot. You have CD12. The problem with olaparib is that in the trial with Maha Hussain (PROfound ClinicalTrials.gov number, NCT02987543), they went for a basket approach and got a basket approval.