Treatment Sequencing in Castrate-Resistant Metastatic Cancer - Mark Fleming

June 9, 2021

In an educational session at the 2021 ASCO annual meeting titled Beyond the Androgen Receptor: New Avengers in the Treatment of Castrate-Resistant Metastatic Cancer, Mark Fleming, MD presented on treatment sequencing in castrate-resistant metastatic cancer (CRPC). In this conversation with Charles Ryan, MD, he speaks to the complex therapeutic landscape and offers guidance in managing treatment sequencing amongst the numerous treatment options in each disease state of advanced prostate cancer.


Mark Fleming, MD, Medical Oncologist, Virginia Oncology Associates, Medical Director, Genitourinary Program, US Oncology, Hampton, VA

Charles J. Ryan, MD, the President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), the world’s leading philanthropic organization dedicated to funding life-saving prostate cancer research. Charles J. Ryan is an internationally recognized genitourinary (GU) oncologist with expertise in the biology and treatment of advanced prostate cancer. Dr. Ryan joined the PCF from the University of Minnesota, Minneapolis, where he served as Director of the Hematology, Oncology, and Transplantation Division in the Department of Medicine. He also served as Associate Director for Clinical Research in the Masonic Cancer Center and held the B.J. Kennedy Chair in Clinical Medical Oncology.

Read the Full Video Transcript

Charles Ryan: Hello from ASCO 2021, the virtual meeting. I'm Chuck Ryan from the University of Minnesota, and I'm with Mark Fleming, a longtime friend and medical director of the GU program in US Oncology and a medical oncologist at Virginia Oncology Associates. Welcome, Mark. Good to talk to you again.

Mark T. Fleming: Always a pleasure, Chuck.

Charles Ryan: So you have an educational session this year at ASCO that you're doing with Dr. Ana Aparicio from MD Anderson and Johann de Bono from the Royal Marsden. And you're talking about beyond the AR, new adventures in MCRPC, and you specifically are talking about treatment sequencing, which really has been a question now ever since we had more than one therapy, to be honest with you. Tell us the big picture story of the educational session and where we are in 2021 with the sequencing of available therapies.

Mark T. Fleming: Yeah, well, what we try to do is lay out for people being an educational session of how you should approach sequencing. I'm going to present a new mnemonic that I came up with called “PM SAGAS”, and it's the way I think about it. And PM SAGAS stands for prior therapies, M being metastatic sites, S being symptoms, A being antigen indifference, which Ana goes into great detail about, G being germline mutations, A being AR signaling defects, and S being somatic mutations. And if you think about those issues, I was a big mnemonic guy in medical school, how should the general medical oncologist approach things? So we think of the prior therapies that happen in the non-castrate resistant metastatic hormone sensitive space, if they're getting docetaxel upfront, if they're getting abiraterone upfront, or enzalutamide, and to think about the prior therapies.

I believe, and there's clear evidence and my talk kind of reveals that disease in the liver is different than the disease in the lymph nodes and bony disease. So, physicians should be thinking about those issues as they think about therapies, because there are some therapies, as you know, that were never discovered with liver metastasis. So were never really truly in level one evidence shown to have a benefit. And so I try to walk the clinician through those issues.

Someone with symptoms is different than someone without symptoms. So, in the pre-chemotherapy space, which as the development of new agents came about, it was really kind of pre-chemo, post-chemotherapy, and drug development. And one of the studies that you led, the Cougar trial, in terms of the patients who are minimally symptomatic. Well, minimally symptomatic means different things to different people. And so it's a way to kind of walk through those issues.

Charles Ryan: Well, first of all, I love the mnemonic, and I think if clinicians are only able to remember after that initial presentation three or four of those components, you will have accomplished your goal of educating them about thinking through the sequencing, because you hit all the highlights. All the things that we should have on our checklist as we approach a patient with CRPC. One of the challenges we have is we just don't really know what sequencing people use in the real world. Give us a little sense as to what we know about the real world evidence of the current sequencing in the U.S. or other places. Do we have much data to go on?

Mark T. Fleming: Yeah, we highlight it in our paper as well. We did a collaborative educational paper, and when you look at real world evidence, people tend to get first-line therapy, but it drops off I want to say to about 50% when patients go to second-line therapy. So it means something, kind of the first opportunity. I don't think that happens in the University of Minnesota. You probably kind of cycle people through multiple lines of therapy. And so, clinicians need to know that there are many kind of life-prolonging therapies.

I think there's not any definitive data, meaning a randomized trial outside of the CARD trial, which I do go into, of what is the right sequence. I tend not to do an AR targeted therapy followed by an AR targeted therapy. I tend to be a switch mechanism type of a person. And I kind of go into the CARD trial, which outlines that if someone has had prior chemotherapy and they've had one AR therapy, what should you do? Another AR therapy, or should you go to cabazitaxel? And it was, I think, a good study. It was kind of convincing study to me that helped kind of justify those of us who believe in the switch mechanism approach from that standpoint.

But you have to apply each patient as an individual and the end of the mnemonic, the SAGAS, in germline mutations, the somatic mutations. I tend not to in the community, do a lot of AR7 testing, but I think it's something important for people to think about in terms of AR signaling defects. I think as the field evolves, looking at somatic mutations, P 10 is just coming as you know, there's just more and more mutations that are drivers of this disease and the clinician who at least thinks about it. And I try to provide a flexible framework that if you're checking germline mutations, if you biopsy at a later point, somatic mutations, you're going to capture the field as it evolves in the future.

Charles Ryan: Yeah, that's really important. You know, I think of some of the somatic mutations that we're detecting now as really managing expectation mutations. In other words, they don't really say do this therapy, but they say, get ready for this therapy to not work all that well. And while some might say that that's not altogether useful or actionable, I disagree because I think one of our jobs with our patients is to have a clear sense of what we're actually treating. And a post enzalutamide CRPC case can be many different things based on those somatic mutations. So again, love that idea. You know, you and I have talked before about the relative under use of chemotherapy in particular in US medical oncology practices. Speak to that again, if you would a little bit and tell us again, what the CARD therapy, what the CARD study showed and how it can potentially bolster our enthusiasm or our confidence in the use of chemotherapy.

Mark T. Fleming: Well, it showed that, this is patients post docetaxel, but it showed that chemotherapy is a viable option and cabazitaxel, I found it to be well tolerated. And you have to think about, unfortunately, we're not going to cure these patients at this point in time, but you want a therapy that is life-prolonging but is well tolerated. And I think it showed that it delayed time to progression. It's just a good set that in my mind, chemotherapy is a viable option. I don't understand why that clinicians don't use chemotherapy enough. It'll be very interesting. The data that Mike Morris presented regarding the vision trial PSMA, which was post-chemotherapy that trial. But chemotherapy has a role. I like to use an analogy of, you want to use as many things in the salad to make the salad good as possible. So if I can add chemotherapy, I can now add a radiopharmaceutical. I think that is very beneficial.

Charles Ryan: Yeah. And you could even argue based on the CARD data that if a patient has had AR targeted therapy, a second AR targeted therapy is not in life-prolonging therapy, right? The AR targeted therapies, we call them life-prolonging therapies because of what they did compared to the control in the various studies that were done, which wasn't in the second line AR targeted therapy setting. So I like that term, we've used that term for a long time now life-prolonging therapy, but it doesn't apply to the therapy, it applies to the therapy in the sequence. Right. And so I think that's, that's a key thing. It will be interesting to see speaking to the vision data. It will be interesting to see what lutetium availability does to the use of chemotherapy. But as you point out, it's not necessarily there to replace it. It's there to be another piece in the sequence. And that might be something that we look at.

So moving forward and your colleagues on the panel discussed other arenas in CRPC that are worth following androgen, indifferent, prostate cancer, et cetera. What's your advice to the clinician out there, anywhere in the world, really, in terms of how they should approach your mnemonic, which maybe you want to repeat for them one more time and integrate it into their practice.

Mark T. Fleming: Yeah. So the mnemonic is PM. Our prostate metastatic, or it's really stands for prior therapies, metastatic sites. SAGAS, and the SAGAS are symptoms, A being androgen indifference, the G being germline mutations, the other A is androgen receptor signaling defects. And finally S, the final acts of somatic mutations. So if you think of it as a checklist, I actually like your term, the checklist. If you walk through those things for people to think about, this PSA isn't very high, but someone has liver metastasis. Hmm. This might not be as simple SOT kind of a patient and Dr. Aparicio in her talk really outlined very well of the evolving issues related to are we driving these kinds of new mutations? And so we're really a way for the clinician to think about it. And so I think you and I commonly think about it because we see it clinically. It's just a way to kind of remind ourselves to think to think about those issues.

Charles Ryan: Yeah, it's a great point. And thanks for repeating it. And it'll probably be showing up on a future PowerPoint presentation given by me at some point at somewhere. So you'll be sure to get credit.

Mark T. Fleming: Oh perfect.

Charles Ryan: The other thing that, just to put out another layer of your mnemonic is it's implied that we're continuing to acquire tissue, right? Resistant liver metastasis, as you pointed out, may have different mutations in the prostate head. And one of the areas that we need to think about integrating your mnemonic into clinical practice is the use of cell-free DNA, repetitive tissue biopsies, I as well as you most likely like to get liver biopsies, if we can, because it can tell us a different story than what the prostate can tell us. And so, could you speak to a little bit of that as far as how that's being integrated into practice, if you have any data on, on that and biopsies.

Mark T. Fleming: Yeah, I didn't speak to that in my talk, but I think that if you have a place to biopsy in the community, I think one of the difficulties is getting bone biopsies, that processing. But in terms of, if I see a lymph node, a knew site of disease, lymph nodes, lung, liver, I'm definitely biopsying it. And that's the whole point of the somatic mutations, is that what you get from somatic mutations? I tend to use less kind of a circling tumor cell type of cell-free DNA kind of biopsy. I do less of that Chuck, but I think what you want to remind the clinician is you should be always testing, the cancer evolves. And so the diagnosis of prostate cancer in 2006, it's not the same prostate cancer in 2021. And just as most oncologists know, that's where oncology is going, mutations. And you have to commonly test for these things.

Charles Ryan: You can summarize that in a quote from The Art of War, "know your enemy". Right.

Mark T. Fleming: Know your enemy. Exactly. I like that. So we'll combine that.

Charles Ryan: Put that on your future slide. Yeah. Well, Mark, great to catch up with you again and congratulations on an excellent presentation at ASCO 2021 with a couple of great colleagues, Dr. Aparicio and Dr. DeBono final words for us, Mark Fleming medical director of GU at US Oncology.

Mark T. Fleming: When you approach your patients with advanced prostate cancer, think of PMSAGAS prior therapies, metastatic sites, their symptoms. Make sure you rule out androgen indifference, check out the germline mutations, make sure you know about the AR sibling defects and finally, somatic mutations, continue to biopsy, continue to biopsy. Know your enemy.

Charles Ryan: And watch your talk on virtual ASCO.

Mark T. Fleming: And watch my talk on virtual ASCO.

Charles Ryan: Read the written component. All right. Thank you, Mark.

Mark T. Fleming: Thank you always a pleasure.