Julie N. Graff, MD

 You mentioned some of this before, but the other trial that was a interesting was the ODENZA trial, which is the beginning of a comparison between darolutamide and enzalutamide. Is there anything that you found interesting in what we know, or anything you can share?

 The one we have at OHSU [Oregon Health & Science University] is called DaroACT. We need to wait for the data. I wouldn’t be surprised if we see that darolutamide is better tolerated, but sometimes we get surprised.

 The outcome of that study was that it wasn’t a statistically significant difference in patient preference, with some slight signals one way. But the bottom line is that we have these great drugs. We have a lot of options. We’re at a great time where we need to be aware of all these things and offering them to the patient. You don’t need to just pick 1 and go with it. You have multiple options. The best experience after a time is your own and what you feel comfortable with. We didn’t get a chance to even talk about 1 of the big hurdles, which is financial toxicity and getting stuff approved, because that unfortunately sometimes drives a choice between them. But when we have multiple good options, at least you can feel confident about what you’re using.

 Is there anything else that came out of either the AUA [American Urological Association 2021 Annual Meeting] or 2021 ASCO [American Society of Clinical Oncology Annual Meeting] this summer that you want to talk about? You mentioned some exciting trials about some new agents. Is there anything else on the horizon that we should know about?

 You may not know that I got to do the study that showed that pembrolizumab, which is a checkpoint inhibitor, can lead to profound responses in mCRPC [metastatic castration-resistant prostate cancer] when given with enzalutamide. We’d be remiss not to mention all the immunotherapy studies going on, from primary disease—where people are injecting the tumor and prostate gland directly with immunotherapy—to down the road, where they’re adding a bunch of immunotherapy agents together. I’m interested to see how that pans out. I’m hopeful. For men whose prostate cancer expresses mismatch repair deficiency or is microsatellite instable, checkpoint inhibitors like pembrolizumab can be helpful. But we’re still learning about the other men who seem to respond to it without those features.

 That’s really interesting to have more angles to approach this from the get-go. Dr Graff, thank you for joining us today. And to our viewing audience, we hope you found this 

 video series discussion to be rich and informative. Thank you very much for joining us.

Videos

A recap of presentations from AUA 2021 highlighting next steps using novel therapies as combination approaches to treat advanced prostate cancer.

Novel dual agents for advanced prostate cancer

 Some of the other data that have recently been coming out include real-world evidence out of groups, including mine, on the use of some of the different agents and whether we’re seeing different adherence or persistence on drug. One study we did looked specifically at a large group of patients who were receiving apalutamide while it was approved only for the nmCRPC [nonmetastatic castration-resistant prostate cancer] space. It was looking at a specific population and pulling out the Black patients to see if the PSA response and adherence on drug were there.

Some small studies have suggested possibly even improved responses in population subgroups like this. It was interesting to be able to look at those groups and see that even in real-world evidence in community groups, much like my own, we’re seeing patients who are adhering to the drug at a very high rate and are able to hopefully get the responses that we expected from the trial. As you said, that’s often a slightly different patient population. It’s a little more idealized. Do you glean anything from this real-world evidence? What does it mean for the structure of any future trials or anything else that might come down the road?

 I’m really glad you brought that up, Ben, because 1 of the underlying themes here is that not everyone is represented in trials. One of the questions is, how do we make our trial population more diverse? There’s a lot of work underway to do that. Some of the work is being done at the VA [Department of Veterans Affairs], where we have a much higher population of African American men. We learned through the PROCEED database for sipuleucel-T that cancers in African American men respond better to sipuleucel-T, also known as Provenge, than in their Caucasian counterparts. We have to do much better in diversifying our clinical trial populations. There’s a lot of work underway.

If I may tiptoe onto my soapbox for a second, we also need to improve diversity in our researchers, because not having prominent Black leaders, at least in medical oncology doing prostate cancer, could be discouraging to patients, who maybe won’t join the trial. Real-world data are interesting but not everything. People tend to believe in these data. I just mentioned the PROCEED database. If you read some of the guidelines, they’ll say that if you see an African American man, you should really consider sipuleucel-T. But that evidence isn’t very strong. Based on that, you’d have to enroll in a prospective clinical trial. So interpret the real-world data with caution.

 I really appreciate that. The trials that incorporate more patients, not just from the academic setting but from the community, are often a little more diverse. You can find areas that are more diverse and try to recruit and get better evidence. The partnership there is the important part.

Current limitations of real-world data available that support the use of novel therapies, including androgen receptor inhibitors, as treatment for advanced prostate cancer.

Interpreting real-world data in advanced prostate cancer

 We’re getting a lot of information on the practical real-world experience from use of these agents. There were a couple of abstracts recently presented at the AUA [American Urological Association] 2021 Annual Meeting that recently happened virtually from Las Vegas [Nevada]. One of these was looking at PSA [prostate-specific antigen] kinetic data on the combined TITAN and SPARTAN studies. This was an apalutamide study.

I always think this is an understated necessity of how we look at these drugs. We’ve gotten so used to saying that PSA response isn’t everything and that survival is really important. But when you think about these patients, especially the patients with nmCRPC [nonmetastatic castration-resistant prostate cancer], their entire disease has lived in PSA. Maybe they were treated and then had their PSA rise. They never were proven metastatic. They were put on all these therapies. They failed those and are now going on a new therapy because their PSA is rising again. If we don’t show a profound PSA response, then patient compliance, adherence, and psychology are going to be big issues. We’ll have people coming off the drug earlier than the trial suggested because [they feel] they aren’t getting the response in their entire disease.

This is getting a little off-track as far as why for the patient. Do you have any thoughts on that, Julie? To me, PSA data are still critical, although we don’t want to overemphasize that.

 I’m glad you’re bringing this up because, as you know, we have treatments that don’t decrease the PSA, like sipuleucel-T and radium-223. It’s funny because patients are wedded to their PSA. Then they go on other treatments, and you say, “Forget about it. Don’t worry about the PSA. That’s not the focus anymore.” And they’re like, “What?”

I hear you. First, this idea of PSA depth isn’t new. If you look at SWOG-9346, Dr Maha Hussain wrote a paper looking at the depth of PSA on castration alone and how that resulted in different survival times, where if you got it under 0.2 ng/mL, you did the best. That concept is coming back with apalutamide. It’s not mysterious that if you’re able to wipe out more of your disease, you’re going to live longer.

But when you’re sitting across from a patient whose PSA goes from 30 to 20, then to 18, but then 19 ng/mL, it’s not going to keep going down. It would be foolish to abandon it. I hear your statement that the patient might feel discouraged. Yes, he might. But as providers, we need to say, “We still think this is benefiting you on some level.” You might even look before starting the drug, and maybe the PSA was increasing very steeply and now it’s leveled off. Those are opportunities for clinical trials to ask what we can add to this to get more disease eradication.

In our clinical decision-making, we still think about the PSA, imaging, and how the patient is feeling when we change therapies. I’ve certainly seen some patients who were on enzalutamide for a month, abiraterone for a month, and chemotherapy for 3 cycles. It’s not a race to get through all these treatments. You have to milk them for everything they’re worth. I’d look at these kinetic data and say this is a great opportunity to do research. For these guys whose PSAs don’t get down to under 0.2 ng/mL, what do we need in addition to these AR [androgen receptor] antagonists to help that happen?

In response to a presentation from AUA 2021, Dr. Julie N. Graff considers the role of PSA kinetics as prognostic markers in advanced prostate cancer.

PSA kinetics in advanced prostate cancer

In the last year or so when we’ve all been virtual and unable to go to a lot of these bigger meetings, there have been meetings happening and data presented. Do you want to talk a little about some of the emerging data that have come out recently and what they can tell us as we look to build on our experience?

 Yes, Ben. I have a couple thoughts about it. One is we’re getting all these new agents, but they still fall into existing classes. It was cool when we had enzalutamide and abiraterone. We had these genuinely new agents, and now we have 2 more androgen receptor antagonists. The lessons being learned now are that the more intense the treatment up front, the better, and that if you’re going to go for castration therapy, go for maximal androgen deprivation therapy. There probably won’t be much of a role for androgen deprivation therapy or castration by itself anymore. It’s going to be that plus other more intense hormonal treatments. As I said earlier, the addition of chemotherapy followed by these hormonal drugs will probably become more popular.

An important point for the androgen receptor antagonists is that they have a common mechanism through which they become ineffective. The androgen receptor loses the ligand-binding domain, and the drugs don’t have anywhere to bind. That 

 mutation is the most common one. It also affects abiraterone. As far as newer therapies, although we now have several androgen receptor antagonists, we’re looking more at androgen degraders, androgen blockers that work in ways other than binding to that ligand-binding domain. I hope to see more of those drugs soon.

Yes, that’s very exciting. The possibilities are endless. We’ve spent a lot of time now with—it’s not really in the scope of what we’re discussing today—looking for that subset of patients who might be eligible for PARP inhibitors and other therapies in the advanced state after failing drugs like those we’re mainly talking about. As we learn more from those studies about what’s really happening within the tumors and do more appropriate study of those tumors, right alongside is all the development of hopefully more targeted agents and learning from other cancers and everything else that we can see, just like a PARP inhibitor showed us in coming from early experience with ovarian, breast, pancreatic, and other cancers.

The future is only going to be more complicated. But with these androgen receptor inhibitors, the question is are we ever going to really be done with hormonal-mediated treatments? It’s hard to imagine we’ll find anything that’s as good. We’d all love to avoid it or maybe find a way to create a window where we’re not treating it. But especially now that we know that more intense therapy is better earlier, it’s hard to imagine a world where we walk away from that benefit. Maybe we can delay it or do something else where we continue to put nonhormonal agents earlier. It’s exciting, but more and more we’re going to be doing exactly as you said, which is finding these agents that help us when traditional hormonal-mediated therapies don’t work. Maybe we can still go to the androgen receptor as a target, just in a slightly different way, and that’s what’s exciting.

Most recently, at the AUA [American Urological Association annual meeting], there was a presentation of specific targeted therapies that can get at just what you were saying, the 

Based on long-term data and clinical experience treating advanced prostate cancer with androgen receptor inhibitors, Drs Julie N. Graff and Benjamin H. Lowentritt suggest ideas for future study.

Julie N. Graff, MD

Articles

Novel dual agents for advanced prostate cancer

Interpreting real-world data in advanced prostate cancer

PSA kinetics in advanced prostate cancer

Next steps investigating AR inhibitors in advanced prostate cancer