How to Evaluate Multiple Prostate Cancer Treatment Options

•An androgen receptor (AR) degrader (ARV-766) which destroys AR expression, not just inhibits it, available through a clinical trial from Arvinas identified by Massive Bio. (Prostate cancer is driven by the hormone androgen. Many treatments for prostate cancer inhibit androgen production. This drug attacks androgen reception.) Brian’s genomic analysis shows high AR expression.

•An Antibody Drug Conjugate (ADC) targeting B7-H3. This is available through a Daichi clinical trial. Brian’s primary and met tumor RNA seq analysis (done by Rick Stanton with Tempus data) shows very high expressions of B7-H3. An ADC is a monoclonal antibody chemically linked to a drug. The monoclonal antibody binds to specific proteins or receptors found on the cancer cells, and spares healthy cells.

•Pluvicto, the newly approved radioactive nanoparticle drug that binds to Prostate Specific Membrane Antigen. Rana McKay has seen very strong responses to this drug among her patients. There are challenges with access right now.

•Cabazitaxel, a standard of care drug for men with metastatic castration-resistant prostate cancer. It is a type of chemotherapy called a microtubule inhibitor. Bipolar androgen therapy, a treatment tailored for a patient who has become “castration- resistant” (deprived of androgen through drugs, yet PSA is rising), is also something Brian is considering. It has been very effective for his friend, advanced prostate cancer patient Bryce Olson. Emma Shtivelman, PhD, Cancer Commons Chief Scientist, a molecular biologist who has much experience in making treatment recommendations, weighed in with her opinions about Brian’s treatment strategy and tactics. She was attracted to pathways that are different from the androgen receptor pathway, which has been drugged for Brian several ways already. She feels that CAR-T is a potentially valuable treatment option, as is PSMA targeting (Pluvicto), but that they are farther off in Brian’s future. Therefore, she favored the Antibody Drug Conjugate attacking B7-H3. She also liked the trial sponsor, Daichi, which is a leader in the field of making good Antibody Drug Conjugates. The drug combination options were a concern for Rana McKay, due to toxicity and quality of life risks. Brad Power and Saed Sayad recommended lower dosages for each of the drugs in a drug combination. Brian wanted to see evidence for lower dosages. Brad said that is in the domain of experts (not clinical trial evidence), and suggested we tap a dosing expert. Requests

•Do you know anyone who is an expert on dosing, especially as a way to reduce toxicity concerns in drug combinations?

•Would you like to join a group to talk about how we could create or find protocols (observational trials) that willing physicians could put their patients in to benefit them in real time, as opposed to 20 years from now, after you collect enough data? 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. Meeting Notes 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. Brian McCloskey: I'm going to be speaking to you about the process that I've gone through to identify treatment options. Many of you have been part of that journey in helping me along the way. I first want to thank all those that have contributed to this. This is an inflection point in terms of how the Prostate Cancer Lab is benefiting me and Rick, and other patients, such as Ken and Mike who are teed up in the process as well. Over the past several months I have had the great pleasure of working with three companies to help me identify potential targeted therapies for me to consider and to take to my doctor. The process has been really straightforward and very simple. It consists of two components. One is data gathering. As many of you know, I'm being treated primarily at UC San Diego Health. I'm also at The City of Hope and the Larry Ellison Institute for Transformative Medicine. Over the course of the past six years, I have a pretty long rap sheet in terms of my medical records. My medical records from UC San Diego are long and illustrious. The other data input is my genomic profile. I have five separate genomic reports. Some relate to my primary tumor, some relate to my metastatic tumors, and then liquid biopsies along the way. In total, there were nine different documents that went into the analysis that I've shared with three different companies. The first is CureMatch. Ally Pearlina has provided concierge, white glove service to me in terms of taking in all of my information and integrating that into their treatment matching process. The second company is Massive Bio. Their process is a little bit different, and similar to xCure’s, where all of those nine different documents were uploaded into their portal. Then they reached back out to me to make sure that they had everything. They worked directly with UCSD to capture all of my medical record information, imaging, et cetera. That was basically the same for xCures – a combination of online document uploading and white glove service where they worked directly with the healthcare provider, and then made sure that they had all of the information. Once those three companies have all of the information, they then run it through their matching algorithms. Depending upon their focus, they provide treatment options. For example, CureMatch is very focused on combinatorial approaches that are targeting my specific molecular targets. Massive Bio does something similar, but they're really not focused so much on drug combinations, although that is part of their solution. They focus on clinical trials. How do you find the right treatments? Based upon the profile of the patient, their history, medical records, molecular profile genomics, et cetera, and then find those trials. xCures is similar to Massive Bio in that they are using the same information for their matching. They consider clinical trials as well as standard of care and some off-label drugs as well. Across all three vendors, you have a pretty rich group of different options to choose from. It's interesting that across each of these three vendors, I received 17 different treatment options, and there was no overlap in any of them. That's kind of nice because they were complementary, I have more options. But on the other hand, it raises the question: can we do better in terms of having the right information upfront to have more precise treatment options? Brian McCloskey’s 17 Treatment Options Therapy OptionTargetsRationale and Expert Input SourceDrug Access 1Antibody Drug ConjugateCD276 (B7- H3)Primary and met tumor RNAseq analysis shows very high expressions of B7-H3 relative to pan cancer and prostate cancer cohorts. Tempus/ Stanton BiosciencesDaichi 2CabazitaxelUnspecifiedSOCxCures/ Cancer CommonsN/A 3177Lu- PSMA-617, PembrolizumPSMAIf eligible for a clinical trial, consider the combination of 177Lu-PMSA-617 and the immune checkpoint inhibitor xCures/ Cancer Commonshttps:// www.clinica ltrials.gov/ abpembrolizumab. Trial located at UCSF. The Phase 3 VISION study reported a 38% reduction in risk of death and 60% reduction in risk of radiographic disease progression or death in men with PMSA-positive mCRPC who received 177 Lu- PMSA-617 plus best standard of care as compared with standard of care alone. (https://www.globenewswire.com/ news-release/ 2021/06/03/2241602/0/en/ Novartis-177Lu-PSMA-617- significantly-improves-overall-survival- and-radiographic-progression-free- survival-for-men-with-metastatic- castration-resistant-prostate-cancer- in-Phase-III.html).ct2/show/ NCT038055 94 4Cabozantinib , AtezolizumabUnspecifiedIf eligible for a clinical trial, consider the combination of cabozantinib and atezolizumab. Trial has multiple locations in CA. A Phase 1b trial of cabozantinib and atezolizumab in advanced solid tumor patients reported, in 132 patients with mCRPC, a partial response rate of 15% and a median overall survival time of 18.4 months (https://www.targetedonc.com/view/at ezolizumab-combined-with- cabozantinib-shows-efficacy-in-high- risk-mcrpc)xCures/ Cancer Commonshttps:// clinicaltrials. gov/ct2/ show/ NCT031709 60 5Degarelix, Enzalutamid e, TrametinibBRAF, AR, MAP2K2 over expressionConsider the combination of AR inhibition with the MEK inhibitor trametinib. Targets the BRAF, AR, and MAP2K2 overexpression. Mimics part of ongoing NCT01990196. A study in a mCRPC patient reported a decrease in PSA of 85% and 93% at 3- and 5-months following treatment with trametinib, and no radiologic or clinical progression for 18 months (https://www.nature.com/articles/s413 91-019-0134-5)xCures/ Cancer CommonsOff Label 61)Apalutamid e, 2) olaparib, 1)AR,2) FANCA via PARP1, CM_006190 BM CureMatch Report 20220418.pdf CureMatch1) FDA approved 2) FDA 3)trametinibPARP2, 3) BRAF via MAP2K1, MAP2K2 MAP2K2approved 3) Off label 71) Carboplatin 2) regorafinib 3) trametinib1) FANCA via DNA damage 2) BRAF TP53 via FLT1, KDR 3) BRAF via MAP2K1, MAP2K2 MAP2K2CM_006190 BM CureMatch Report 20220418.pdf CureMatch1) FDA approved 2) Off label 3) Off label 81) palbociclib 2) regorafinib 3) trametinib1) CDK4 2) BRAF TP53 via FLT1, KDR 3) BRAF via MAP2K1, MAP2K2 MAP2K2CM_006190 BM CureMatch Report 20220418.pdf CureMatch1) FDA approved 2) Off label 3) Off label 91)Apalutamide , 2) olaparib1)AR, 2) FANCA via PARP1, PARP2CM_006190 BM CureMatch Report 20220418.pdf CureMatch1) FDA approved 2) FDA approved 101) Carboplatin 2) trametinib1) FANCA via DNA damage 2) BRAF via MAP2K1, MAP2K2 MAP2K2CM_006190 BM CureMatch Report 20220418.pdf CureMatch1) FDA approved 2) Off label 111) Olaparib 2) regorafinib 1) FANCA via PARP1, PARP2 2) BRAF TP53 via FLT1, KDR CM_006190 BM CureMatch Report 20220418.pdf CureMatch1) FDA approved 2) Off label 12OlaparibFANCA via PARP1, PARP2 CM_006190 BM CureMatch Report 20220418.pdf CureMatchFDA approved 13Carboplatin FANCA via DNA damage CM_006190 BM CureMatch Report 20220418.pdf CureMatch FDA approved 14TrametinibBRAF via MAP2K1, MAP2K2 MAP2K2CM_006190 BM CureMatch Report 20220418.pdf CureMatchOff label 15CCW702 PSMACCW702 is an investigational immunotherapy for prostate cancer Massive BioClinical Trial - Phase 1 16ARV-766ARAR degrader designed to destroy AR expression, not just inhibit Massive BioClinical Trial - Phase 1 17Abiraterone + AbemaciclibAR + CD4/6 inhibitorAdding an targeted to my existing drug, Abiraterone Massive BioClinical Trial - Phase 2/3 I'm not going to go through all of these in detail, but I'm going to hit some of the highlights. First, just a little bit about the transition from getting all 17 different treatment options into the conversation that I had with my oncologist, Dr. Rana McKay, on Monday. I sent Rana this spreadsheet, which you see here. This is a summary of the different reports that I got from each of the three different providers. I also sent her all of the backup documentation from the three providers. She had all of that information prior to our meeting, and she reviewed it in detail. We spent about an hour in the clinical office visit. We spoke first about the particulars of where I am with my health. I'm currently on abiraterone. I've hit nadir with my PSA. I hit that probably about three months ago, I'd say March. My PSA has gone from 0.45 to 0.49. It's now at 0.54. It's gradually moving upwards. We both think that there's mileage to be gotten from my existing drug. We are going to go after imaging, get some baselining, and understand the extent to which my disease is progressing or stable. It's been maybe nine months or so since I've had CT scans, so we're going to do that. And I'm going to have a PSMA PET, which I have not had since June of 2020. Those are just some of the basics in terms of what we talked about relative to my health. Then we got into the various treatment options as we started to plan for my imminent failure of abiraterone. The first one that we talked about was option #1: the antibody drug conjugate which is targeting B7H3. This option came from work that Rick Stanton did with Tempus and myself to identify a target through some transcriptomics, an RNA seq analysis. There is a trial that Daichi is running and Rana feels that this is a possibility. I would mark this green. This is something that we are going to keep on the menu. Option #2 is cabazitaxel. This is a standard of care treatment. It's certainly a possibility. It came from xCures. Option #3 is Pluvicto plus pembro, which is a clinical trial that's being run out of UCSF. The commentary on this option was that it is very interesting. She said that she has seen two patients that early in the cycles have seen complete remission on Pluvicto alone, a radioligand. She likes the idea of combining it with something like pembro. I would not qualify for this trial, because I've already seen pembro in my care. But she is pretty enthusiastic about Pluvicto. Option #4 is cabozantinib and atezolizumab. She thinks that this is a possibility, but a little bit less confident about the response. For some of the other options she has some concerns about toxicity. Jeff Waldron: Going back to Pluvicto, option #3, in addition to getting access through trials, you could consider getting a compassionate use, expanded access program to receive that therapy. Brian McCloskey: Pluvicto is FDA approved. To get access to it is not an issue; rather, the challenge is supply. She said forget about a combination with pembro or any other drug. If you wanted to get this drug in December, we would have to start the process right now. It's a very, very slow process. They've had supply issues, et cetera. But right now, I don't think we're leaning towards that as a next option. Rick Stanton: What is the target in your option #4 of cabozantinib and atezolizumab? Brian McCloskey: This came from xCures, and the target was unspecified. Emma Shtivelman: Cabozantinib is a very powerful drug. It's an inhibitor of multiple tyrosine kinases, and also angiogenesis. Atezolizumab is a PDL1 drug. You are not eligible for this trial, Brian. Brian McCloskey: I’m not eligible because …?