Metastatic Prostate Cancer: Current and Emerging Treatments

Jonathan Starr and Brad Power June 19, 2023

Prostate cancer is not curable for most patients once it becomes metastatic. Advanced prostate cancer patients find themselves trying treatments that work for a while until they fail, then moving on to another therapy.

They are continuously worrying about the effects of their cancer and treatments on their quality of life, especially bone metastases and the side effects of hormone deprivation therapy, which leads to bone density issues and muscle loss, among others. Prostate cancer, like all cancers, is unique to each patient, with some patients receiving molecularly targeted therapy, and some patients responding to immunotherapy.

New drugs, such as those which use a radiopharmaceutical are now coming to market. Patients might also consider experimental combination therapies, for example combining a radiopharmaceutical with a PARP inhibitor or immunotherapy. Alpha and beta particles can also be combined experimentally, as well as alpha or beta particles with radiation sensitizers, modulating the way the drugs alter DNA.

The importance of lifestyle and prevention of complications in advanced prostate cancer is another concern. A. Oliver Sartor, MD, recently moved to Mayo Clinic, is uniquely qualified to review this complicated landscape and discuss research on immunotherapies, radiopharmaceuticals, and combinations in prostate cancer.

His research has mainly focused on translational science and clinical research trials of advanced prostate cancer since 1990, and he is recognized as an expert in that field through his contributions to the practice and the publishing of over 500 peer- reviewed articles and numerous book chapters and reviews.

He has been PI or co-PI on pivotal trails that have helped to change the landscape of advanced disease including radium-223, cabazitaxel, and Pluvicto (PSMA-617 Lu-177).

(lightly edited) Brad Power 0:02 We're very honored to have Dr. Oliver Sartor with us today. Dr. Sartor, you'll remember that part of our connection is through Jeff Hoffman, who was a classmate of yours at Tulane back in medical school, and Jeff is my cousin. Jeff pointed me to Dr. Sartor, and Dr. Sartor has been very helpful in providing advice to a number of the patients we've had, especially, Bryce Olson, on some of the choices that he faced.

A number of patients in our community have requested to have a conversation with Dr. Sartor. He's moving from Tulane to Mayo Clinic. Does that mean a physical move for you? Oliver Sartor 2:03 Yes. I realize as I pull up the slides, that it shows me still at Tulane. I'm at Mayo now. I'm happy to give you my email and stuff like that. Let me let me put that in the chat. But yes, I'm physically at Mayo.

There's a request that you focus on castrate resistant prostate cancer patients who are beyond hormone sensitive prostate cancer so that we get kind of skinnier branches of people that are more advanced, as much as you can. Oliver Sartor 3:09 I’m at Mayo Clinic right now. I’ve been involved with advanced prostate cancer for a long time.

And I think first of all, you have to have some feeling for where the field is before you can understand the rest. This particular slide encapsulates all the phase three trials that have been shown to have an overall survival advantage. All of these are in the New England Journal, except for one. That's the TROPIC trial. And we have a variety of things that I think are sort of noteworthy.

So first, I'll make a comment that when you look at the overall survival benefit, I think the first thing that you would conclude as a patient is that this is pretty unimpressive. And I think it is not as impressive as we would like. But that's just the reality. And there are a variety of reasons for this, some there may be crossover and but nevertheless, these are factual data that I think is important for people to know.

A couple of other things. The field has really been changing since the early trials showed a benefit for things like Sipuleucel-T, that's Provenge. I don't know how relevant it is today. The same is probably true for radium. Sipuleucel-T was FDA approved in 2010, radium FDA approved in 2013. And there's really been a wholesale change since then, if we want to look at clinical decision making, and I can spend an hour on this, but I won't.

You have to kind of think about, first of all, what is available and what is affordable. And that's not always so clear, a lot of these things are very expensive now. So that's really a problem. There are a lot of therapies that may not be suitable for everybody, you know, performance status, age, comorbidities, laboratory assessment symptoms all sort of dictate how we think prior therapies, response and resistance and duration of prior therapies.

I just spoke to a patient today. He underwent chemotherapy with no response. I’m probably not going to give him another chemotherapy. Oh, it's an intolerance of prior therapies burden of disease, I'll go mass not only go BAT. Where's the disease located? Bone only, liver, pelvic lymph nodes only – – makes a big difference, particularly liver. The liver is a bit of a challenge. What about the pace of the disease, is it rapid or slow?

And it's very different for different people, that this progression is a systemic progression or focal progression for the phenotypes. You know, we talk about adenocarcinoma, like it's the only thing that there is, but it's not true there. anaplastic Sydnor integrins.

Their molecular biomarkers rock up being a clear one image based biomarkers like Pitts May and FTG, clinical trials, options, you know, what's out there, what's not out there, advertisement profiles and patient preference. So all of these fit in imaging is important. genetics are important. Histology is important prior treatments. All of these are really critical.

When we begin to look at the current landscape, the novel hormones are all going up front so everybody gets a novel hormone. And that could be Abiraterone, Enzalutamide, darolutamide apalutamide. Everybody gets a novel hormone and it typically is even before you get to be metastatic CRPC What's your mistake CRPC.

There's our conventional things, and then there's PARP inhibitors, and pembrolizumab fits man with tissue and radium that are specific for certain populations. This is from the NCCN guidelines 2023 You can sign up and get them. The sequence matters. If you have not had any of the novel hormones and all you've had maybe as an omen, androgen something like Byculla mine, then I will use Abiraterone or Enzalutamide typically, in that setting.

If we're going to be looking at the host into deprivation and docetaxel, a little bit of an older patient, I'm still looking for the hormone. So I'm looking at Abiraterone Enzalutamide typically as my number one and number two options.

If you've had an androgen deprivation therapy and a novel AR pathway inhibitor, that's the patients who have Abiraterone, Enzalutamide apalutamide darolutamide then, you know, docetaxel is currently category one that may change, but docetaxel is sort of category one.

And “The Current and Future Landscape of Metastatic Castrate Resistant Prostate if you've had both, then probably say both I mean docetaxel and a novel AR plus ADT, of course, then we're probably looking at Pluvicto or Lutetium 177 PSMA 617 as being the path forward, but you also have to understand that genetics are real. There are a variety of things. These are our molecular image based markers.

We have amongst recombination repair genes like BRCA2, BRCA1, PALB2, RAD54L, etc. PARP inhibitors can be effective, particularly for those who have BRCA2 mutations. BRCA2 PARP inhibitors can really be quite important, probably block one lb two by three pour out a lot of the other ones not so much. Mismatch repair genes and there are 4 of them, but there are two that we understand a little more than the others: MSH2 & MSH6.

and here we have pembrolizumab as an FDA approved options are important and then Pluvicto for patients who may PSMA positive. When we look at these biomarkers that can be either tissue or circulating tumor DNA base, there are a variety of DNA repair defects that are noted if you look at the tissue base genetics, but we have things like olaparib that have prolonged survival in individuals with metastatic castrate resistant prostate cancer.

But not all the genes are created equal. It's very, very important that genes that seem to be particularly sensitive BRCA2, probably BRCA1, RAD51B, maybe RAD54L. It turns out that you don't need to have tissue, you can get tissue, but you can also use circulating tumor DNA, and that's pretty accessible. Here's the efficacy, comparing tissue tissue and circulating tumor DNA per olaparib. And basically, you can see there's no difference.

So circulating tumor DNA is a good way to go.