Advanced Prostate Cancer: How to Make Treatment Decisions

n. 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 Transcript Brad Power: Today we are going to continue a conversation that we started about the standard of care roadmap for advanced prostate cancer.

Rick shared a one-page summary he had done of the NCCN (National Comprehensive Cancer Network) guidelines, and he identified the place beyond the first few lines of therapy (prostate removed, radiation, androgen suppression drugs) where there was a lot of flexibility or discretion in the advanced stages.

One of Rick’s initial observations was how that could be more structured and guided by testing. We have also talked about bringing testing forward in the guidelines to help people at each decision point. Saed Sayad suggested making it more dynamic and predictive. We've also discussed putting a strategy on top of it.

We spoke with Ryon Graf about embedding more real world evidence in the decisions so that people could understand the outcomes. We have a variety of ideas to enhance the standard of care guidelines. Rick is going to kick it off by sharing where we were before and a couple of ideas he has. Rick Stanton: A quick update on my situation: on Friday I will have my eighth round of chemo.

I am currently stable. My PSA is 2.4, and I have nodal disease. I have four or five lymph nodes in my upper body – neck, middle of my chest, pelvic regions – that lit up on a PSMA scan. The pathologists know where to look, and the interpretation is they aren't growing. My current assessment is stable disease. I will keep going on chemo, for rounds eight, nine, and 10, if possible.

And then what happens after round 10 is what I'm going to discuss. How could we bring some molecular evidence to guide the next treatment?

“Decisions in Advanced Prostate Cancer” (Rick Stanton) [#8] The purple shows where Brian and I have both shared this journey. Where we have diverged, I'm in red, and Brian's in blue. We both had our prostate removed, but our PSA was not zero. We went on hormone therapy, bicalutamide and Lupron, and had radiation therapy (EBRT). Brian is on abiraterone (androgen suppression).

I am on docetaxel (chemotherapy), and Brian has had docetaxel as well. Mike Yancey: When I looked at the NCCN guidelines, I noticed that my situation was hard to find. My prostate was not removed since I was immediately stage four (metastatic). I had to really search to find the starting point in the guidelines that reflected my experience. Rick Stanton: That’s a good point.

I had to pick a place to start. That's the problem with trying to condense 60 pages into one page.

“Decisions in Advanced Prostate Cancer” (Rick Stanton) [#8]

rch to find the starting point in the guidelines that reflected my experience. Rick Stanton: That’s a good point. I had to pick a place to start. That's the problem with trying to condense 60 pages into one page. Here is my second slide:

“Decisions in Advanced Prostate Cancer” (Rick Stanton) [#8] On the left is the same decision tree. And on the right are the guidelines for the steps after that which recommend pursuing clinical trials. The classes of clinical trials available now include immunomodulators, targeted antibodies, vaccines, and other degraders.

I also list above the therapies some of the tests or assays that would support which clinical trial you would want to go on. ●There's IHC, which stands for immunohistochemistry. This is one type of testing that is pretty typical. You can look at whether you have T-cell infiltration into your tumor. It would inform a decision on whether you might be a candidate for PDL1.

If you have T cells in your tumor, they would be able to help kill the tumor if they were not inhibited by the Programmed Death-Ligand 1 (PDL1). ●DNA sequencing will inform decisions on all therapy classes. ●RNA-sequencing can inform decisions on all therapy classes as well. ●Spatial analysis is more cutting edge.

You take a slice of the tumor and analyze it using different techniques, such as immunofluorescence. You tag antibodies to these types of immunomodulators so that you can see the presence of different proteins in your tumor. And based upon that, you would be able to choose which of the immunomodulator clinical trials might be a good fit for you.

“Decisions in Advanced Prostate Cancer” (Rick Stanton) [#8] ●Organoids are cutting edge. You take a little bit of tumor, grow it up, replicate it into, say, 200 little colonies, and query those 200 colonies with different therapeutic candidates to see what kind of response you get. These more advanced assays that people don't typically get might help inform their decision.

We're trying to push the cutting edge. I'm going to go into the assays that have been done on me next and what they mean to me and my oncology care team. This is a screenshot of my genetic testing and DNA sequencing. I have two CDK12 mutations, and they are targetable by FDA-approved drugs, such as Olaparib, for prostate cancer. I have a low tumor mutation burden.

My MSI microsatellite status is stable, and I have a gene fusion. This is the highlight of my DNA sequencing report. I would never have known that I have an FDA-approved drug that might help me, if it wasn't for this DNA sequencing. This is within the NCCN guidelines because they recommend testing for these DNA repair genes and CDK12. My specific mutation is not the same as Brian's.

CDK12 mutations are a poor prognostic. They happen in about 5% of prostate cancer patients. This mutation will create a lot of gene fusions, which can be a target for T-cells. Therefore, I would hopefully be responsive to PDL1.

genes and CDK12. My specific mutation is not the same as Brian's. CDK12 mutations are a poor prognostic. They happen in about 5% of prostate cancer patients. This mutation will create a lot of gene fusions, which can be a target for T-cells. Therefore, I would hopefully be responsive to PDL1. Saed Sayad: Is there any information about using drugs for CDK12?

“Decisions in Advanced Prostate Cancer” (Rick Stanton) [#8] Rick Stanton: There's a fair bit of publications about the outcomes of using this drug, Olaparib. It was more hopeful upon approval, and as more data was released, there has been a weaker linkage to improved outcomes as time went on. This is maybe not the first drug that my care team would consider, but it's something.

When I talked to Dr. Tanya Dorff, she said, “I see Olaparib in your future. You know, one way or another. You could take it sooner. You could take it later. This is a drug that could help you. And when you exhaust other options, you're probably going to try it.” And that's what I know about it.

Brad Power: Given our recent conversations with Saed Sayad, Bob Gatenby, and John Laird all promoting the notion of drug combinations and lower dosages, are you thinking of this as a monotherapy, or are you thinking this might be in a drug cocktail you could try? Rick Stanton: That's a great question. It's not just me who will decide.

Tanya Dorff, who is one of the authors of the NCCN guidelines, at City of Hope, and a well respected leader, told me of a clinical trial at City of Hope that was a cocktail of Olaparib, a PDL1 inhibitor, and a CTLA4 inhibitor. Those are FDA-approved immunotherapies, but the trial is to have the triplet cocktail. She recommended it should be considered.

She felt like Olaparib on its own had a weak response, but in a cocktail triplet it would extend my life.

Brad Power: Building on the discussion we had about the CureMatch report, it would be interesting to see how that cocktail of three would overlap and give coverage to the biomarkers you've identified that are unique to you Rick Stanton: This is going to get very interesting because I would like to give my biomarker analysis to CureMatch.

I gave Ally Perlina at CureMatch my Tempus report, but she told me there were not enough distinctive biomarkers to run their algorithm. She was able to run a report for Brian, but Brian's Tempus report included a section of overexpressed genes which my report didn't include. The bioinformatics team at Tempus said they don't always include it.

I'll do my own assessment of overexpression, with help from TGen, and provide that to Ally. And then we can compare CureMatch’s recommendation to what my care team recommends. Brad Power: Another dimension we've been talking about and you included are organoids. I just listened to a Society for Functional Precision Medicine webinar, where they talked about testing drugs on organoids.

It'd be awesome to test your cocktail with organoids.