NCCN Guidelines: Advanced Prostate Cancer Testing & Treatment Roadmap

April 27, 2022 Brad Power

Advanced prostate cancer patient Rick Stanton walked through a one-page summary of the NCCN (National Comprehensive Cancer Network) guidelines for advanced prostate cancer and illustrated it with his and Brian McCloskey’s treatment journeys. The NCCN guidelines are the “standard of care” - the evidence-based protocol for deciding on treatments for patients with prostate cancer.

Rick started his summary of the NCCN guidelines after the prostatectomy step since he is focusing on the journey for advanced prostate cancer. From there, most branches in the NCCN decision tree depend on whether the patient’s PSA (prostate specific antigen, a blood test result), is rising or not, and whether their cancer has spread outside the prostate (metastasized).

Rick and Brian’s PSA rose after their prostatectomy, so they switched from observation (“watchful waiting”) and had the next recommended treatment: radiation and drugs (Lupron and bicalutamide/Casodex) that suppress androgen, the hormone that feeds the cancer. This androgen suppression treatment worked for about a year for Rick and Brian.

Brian was doing so well, he and his medical team decided to take a holiday from the androgen suppressing drugs, and then after several months his PSA started rising rapidly. Rick’s PSA started rising rapidly after about a year. At this point for both, with PSA rising, and now both with metastases (cancer in other places besides their prostate), the NCCN treatment recommendation is to try one of several drug options.

Rick chose a next generation androgen blocker (darolutamide). After a few months, it was clear that this wasn’t working for him, so he joined a clinical trial that had two arms: one for chemotherapy (docetaxel) and another with that same chemotherapy plus two other drugs (a PD1 inhibitor and an adenosine inhibitor). Unfortunately, Rick got the clinical trial control arm with chemotherapy only, which he has stayed on until today.

It has knocked down his PSA. Brian chose another androgen-suppressing drug (abiraterone), which he is on now. It is keeping his PSA at a very low level. The first four or five rounds of decisions in the NCCN guidelines are largely not personalized. They depend on whether the cancer has metastasized and the PSA level. It is only in the very advanced stages of prostate cancer that personalization (decisions which draw on genomic tests) enters.

In an upcoming meeting Rick and Brian will continue to talk about ways to (a) enhance the NCCN guidelines to refine this overview of the whole journey - a roadmap for communication between patients and doctors, (b) bring more testing and associated personalization earlier in the decision process, (c) add data on the efficacy of the treatment options, and (d) add a roadmap for steps beyond the end of the current guidelines.

Brad Power: Today we’re focusing on advanced prostate cancer testing and treatment decisions and a decision tree that Rick has been working on with help from Brian. We want to get your feedback on how we can make it better. Some of you may know about the NCCN (National Comprehensive Cancer Network) guidelines. These guidelines are the standard of care for treatment. They are updated every six months.

The NCCN publishes guidelines for a variety of cancers, including for advanced prostate cancer. Given all the learning that we’ve been doing, we thought we might be able to help in advancing the guidelines, and we could use it to illustrate where Rick and Brian have been on their cancer journeys and the decisions they face. Rick Stanton: A little background: when I first got prostate cancer and had my prostate removed, I was at CIty of Hope.

I talked to my medical oncologist, Dr. Lyou, who told me my next therapy steps were going to be completely in line with the NCCN guidelines. ” I didn’t know what the NCCN guidelines were. We are advocating for advanced testing and personalized medicine that help direct patient care. I wanted to know the value of advanced testing. What are these guidelines? Are they good enough? Where do they end?

Rick Stanton: This image says 2020, but the guidelines I will be discussing are from January 2022. This is my interpretation of about a 60-page document. There are two documents. One is for physicians and one is for advanced patients.

Rick Stanton: A shout-out: I noticed (and I didn’t know this before I started laying out this decision tree) that Tanya Dorff, who is guiding me and Brian, is one of the authors, and so is Rana McKay, who is also guiding us. I look across this list of authors, and it’s just about as prestigious as it gets. Rick Stanton: So here’s my interpretation of the NCCN guidelines for advanced prostate cancer. This is a decision tree.

It’s boiling down 50 or 60 pages of therapeutic decisions provided in the NCCN guidelines into one page. I start with “prostate removed” because it’s for advanced prostate cancer. There is more in the guidelines about when to take out a prostate. If your PSA is stable after your prostate is removed, then you’re called “castration-naive prostate cancer” (CNPC) and M0 means that there is no evidence of metastases.

) At this point – if there is no evidence of metastases and you are “castration naive”, which means you have not yet gone on androgen-deprivation therapies, and your PSA is stable – then you wait. Brian and I were both unstable. 6. 2 and above is the definition of recurrence. Right after I had my prostate removed I was not stable. My PSA was going up. I fell into this next category: my prostate is removed and my PSA is rising.

So now, what do we do about it? This is Guide 9 in the NCCN guidelines. There are two choices here. Again this is castration naive prostate cancer and M0 (no evidence of direct concentrated metastases on the imaging), but I did have a rising PSA. M1 means that there is evidence of metastases. The guidelines say, and this is what Dr. Shen (UCLA) told me, put me on apalutamide. The bold is the NCCN “preferred” options.

Within these options there is a lot of bold. In this depiction, both Brian and I shared the first step, which is shown in purple. In the second step, we deviated. I’m in red. Apalutamide is an androgen-deprivation therapy. Lupron is another. Lupron is a shot. ). Lupron is meant to knock down the androgen feeding the cancer, and Darlutamide is a pill that blocks the adrogen receptor on the tumor cells.

This should look very familiar to many advanced prostate cancer patients. Saed Sayad: Do you have any statistical information about the success or failure rate at each stage? Brian McCloskey: I was surfing yesterday with one of my dear friends, Ryon Graf, of Foundation Medicine. In between catching waves we were talking about how to improve the NCCN guidelines. He has his hands on tons and tons of data.

And that’s one of the directions we want to go. We discussed bringing more data to the guidelines. I’m getting to the punch line here. This is such a rudimentary guide, and we think there are opportunities for us – I’ll keep it high level here – to bring more data into this, and response data is part of what we would love to add.

Ryon could help us tremendously in that effort by looking at real world evidence to determine what the response rates are for each of these different scenarios. Saed Sayad: And also if we can find any genotypes for success or failure? Brian McCloskey: He’s the guy. He has a lot of information. We need to peel the onion on that to understand exactly what genomic information they do have.

But, at a minimum, it’s going to be a great place for us to start. Rick Stanton: As we go across this chart, from left to right, you’ll see that the rightmost is the second line therapies, and within the NCCN guidelines that’s where genomic indications first come into the decision-making. It doesn’t kick in until you are castrate resistant and metastatic and at the second line.

For example, taking pembro, which is a PDL1 blocker, is based on genomic information. We’ll get there. Both Brian and I got external beam radiation therapy (EBRT) as our next step, called “salvage” radiation (radiation given after a prostatectomy), and I also had SBRT (Stereotactic Body Radiation Therapy). We were hopeful that this would clean things up and confine this to the pelvis area. But it didn’t for us.

After we left this box, we were told, “You have an incurable disease. ” For me bicalutamide and Lupron lasted for about a year before my PSA started rising. Brian: How was that for you? Brian McCloskey: It was about the same for me. It was a little hard to tell because it overlapped with the radiation. Which was providing the benefit? It was a little muddy. Rick Stanton: After a year, after the radiation, my PSA started going up fast.

It was clear that the bicalutamide was not controlling my disease anymore. And then we go to the next box. This is Guide 10. Now I’m castrate resistant because I’ve been exposed to androgen deprivation therapy. My PSA doubling time was less than ten months. It was like three weeks. This was very scary. It was very aggressive. These are the three preferred options: apalutamide, darolutamide, and enzalutamide.

I was told that darolutamide was the newest generation androgen blocker and with the least side effects. So I went on darolutamide. If I had been stable, I would have just been in observation. But the decision was that I needed to go to the next step, which was darolutamide, which unfortunately didn’t work very well for me. I only stayed on darolutamide for four months, and my PSA was higher than when I started. I didn’t get a benefit.

Brian, I’ll let you weigh in on your apalutamide experience. Brian McCloskey: I got about 15 months of benefit. Then I decided with my medical oncology team that I was going to take a holiday from all androgen deprivation. When you’re on apalutamide, you stay on Lupron. I took a complete holiday from both.

Unfortunately, within about three months my PSA went from undetectable when I ended apalutamide, it began to skyrocket, to a doubling time of two- to three-weeks, so very aggressive. Rick Stanton: This was not good for me. At least you got a little time. Darolutamide wasn’t working for me. I had some PSMA (Prostate Specific Membrane Antigen) scans, which check for metastases. My PSA was skyrocketing, so something was going on.

I had gone from M0 (no detectable metastases from a scan) to a PSMA scan showing 4 or 5 lymph nodes that lit up. So now I graduated to “nodal positive”, M1. This was a scary time for me. I felt as a cancer patient I was falling, and I needed a parachute. This transition didn’t seem proactive. It seemed reactive. My oncologist was surprised that I didn’t respond very well to darolutamide. What do we do?

It shows from my journey, I went onto docetaxel. My medical oncologist told me, “You’re falling fast, and we need to hit you with something that is going to catch it right now. ” I also was able to sign up on a clinical trial, as advocated by my medical oncologist team, led by John Shen at UCLA, that included docetaxel, a PD1 inhibitor, and an adenosine inhibitor. This clinical trial was being run by Arcus Biosciences.

Some of you may recall that I worked at Amgen for 17 years, and I worked with Terry Rosen, who is the CEO of Arcus. I actually reported to him at Amgen. I know the science. I know his rigor. I suggested this trial, and Dr. Shen agreed - my care at UCLA transitioned to Dr. Sandy Liu who ran the Arcus clinical trial at UCLA. Unfortunately, I got the docetaxel-only arm. That was a bummer, to say the least.

I was hoping to get the docetaxel and immunotherapy arm, which would have a synergy. But those cards didn’t fall my way. Other options as shown on the chart are: (Abiraterone, Enzalutamide, Sipuleucel-T, Docetaxel, Radium-223 – bone, FParticle abiraterone, Other hormone. ) I didn’t have any evidence of bone metastases, so radiation (radium-223) treatment wasn’t indicated. I am on docetaxel currently. I’ve just finished seven rounds.

It has held my disease progression in check. I wish it would have shrunk more, but at least it is stable. Right now, stable is wonderful. Brian, what is your story? Brian McCloskey: If you go back to the prior box. Rick was on darolutamide, and I was on apalutamide. 77. So just blazing fast. 02 level in March, and within three months I had six metastatic lesions identified by whole body MRI, PSMA PET, traditional CT scans, etc.

We decided that we would do surgery. My mets were entirely in soft tissue. ) They were in my peritoneum (the membrane covering the abdomen), underneath the belly button area. 05 in August of 2020 when I had my surgery. After surgery my PSA dropped from 2 to 1. We knew we didn’t get all of it. They removed 6 lesions, but there weren’t clean margins. And I also knew that I had some caking in the peritoneum that they couldn’t surgically remove.

I knew we were going to have to have some kind of systemic therapy. If you look at the box with CRPC M1 from NCCN Guideline 111, my systemic therapy choice was docetaxel, similar to Rick, but they added pembrolizumab, because my DNA suggested that I had one targetable mutation (PBRM1), and we thought that we could hit it with Keytruda (pembrolizumab) and with docetaxel.

I did 6 rounds of docetaxel, and finished the docetaxel in January of 2021 and continued with pembro until October of 2021. The reason I stopped was because my PSA began to rise. That gets us into the next box, NCCN Guideline 12. After my PSA began to rise, we decided to go onto abiraterone. I started in November of 2021, and I am currently on abiraterone. I’ve got 5 or 6 months under my belt. 45. I’m going to get some labs today.

We’ll see if I’m still responsive and stable. After abiraterone, what do we do next? You can see on the chart that there is still a family of drugs that we could go after. There is additional chemo. One oncologist recommended that I try darolutamide, even though there is evidence that would suggest that the transition across second line hormone therapies is not terribly effective.

Another option is Pluvicto, a radioligand which recently got FDA approval. And there are others. Brad Power: Clustering the treatments in broad strokes: after the prostatectomy and radiation, you hit it next with androgen deprivation, in the first and second boxes. Then chemo (docetaxel). Then there are immunotherapies (PD1, PDL1). Pluvicto is a different treatment methodology, using radiation to attack unique prostate-specific antigens.

Some of these drugs are similar in their attack pathway? Rick Stanton: That’s correct. Prostate cancer is a hormone-driven cancer. So shutting off androgen is the first step. When that is running out, there are still some other treatment options, like chemo, which kills all fast-dividing cells. I don’t know where Pluvicto fits. It’s not in the NCCN guidelines yet. It was recently approved. It is a tremendous hope for me and Brian.

This is a radioligand (a radioactive biochemical substance) that targets and attaches to PSMA, a surface marker antigen unique to prostate cancer cells, to deliver the kill. Saed Sayad: This is a very useful decision tree. But it seems branching only depends on the PSA. Rick Stanton: That is correct. I tried to faithfully lay out the NCCN guidelines. This is only PSA- based decision-making. Saed Sayad: It’s good as a base.

But it leaves a lot of room for improvement. Brian McCloskey: There are actually two decision-points. One is if you are metastatic or not, and the other is PSA. It’s two-dimensional. Rick Stanton: In the left 3 boxes, there is no personalized medicine going on.