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Published on December 9, 2020
What Treatment Options Are Available for Non-Metastatic Castration-Resistant Prostate Cancer?
In 2018, patients with non-metastatic castration-resistant prostate cancer (nmCRPC) were watching and waiting. Two years later, there are three novel androgen receptor inhibitors available for the treatment of nmCRPC. But with these new options available, patients and doctors have questions on which treatment is right for them and what to do next.
In this first installment of our prostate cancer Answers Now series, prostate cancer experts discuss these emerging questions around who should use what – plus when, and why! They also give an overview of the disease and the new treatment options. Watch as AnCan Founder Rick Davis and AnCan Prostate Cancer Moderator Len Sierra guide this discussion along with Dr. Tom Beer, Chair of Prostate Cancer Research at OSHU in Oregon, and Dr. Eleni Efstathiou from MD Anderson Cancer Center in Maryland. They are also joined by Patient Power co-founder Andrew Schorr.
This is Part 1 of a 3-Part series. Part 2 and 3 coming soon.
This program is sponsored by Bayer. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.
Transcript | Prostate Cancer and Making Sense of nmCRPC Treatment Options
Andrew Schorr: Welcome to this Answers Now program on prostate cancer. I'm Andrew Schorr with Patient Power. This is the first in a three-program series, so we're very excited about it, very excited about our partnership with AnCan, which provides support group discussions for men dealing with prostate cancer. Let's start with you, Rick. Take it away.
What Is the Difference Between Non-Metastatic and Metastatic Prostate Cancer?
Rick Davis: The first question, and we're going to pose this to Dr. Beer, and then maybe Dr. Efstathiou has some ideas, is that we wonder if there is truly a clinical difference between non-metastatic and metastatic prostate cancer or is this just a manmade discrete distinction for FDA purposes? Is advanced disease really a graded progression and should men talk about advanced prostate cancer rather than non-metastatic and metastatic prostate cancer?
Dr. Beer: I think that it is undoubtedly a human-made condition and it really started to be that way when we started using hormone therapy in pre-metastatic prostate cancer. There was a time when that was not commonly done many, many years ago. If we start treating folks with hormonal therapy for a rising PSA, then naturally we create a non-metastatic, castration-resistant disease state that didn't use to exist. It's also a reflection of the sensitivity of our imaging. And so we know that, as we introduce more and more sensitive imaging, we discover metastatic deposits that were invisible with conventional imaging. It is a bit of an artificial distinction. Having said that, it does have a well-defined prognosis and it is a useful construct for advising patients about what they can expect from their disease and for making decisions about treatment.
Rick Davis: And Dr. E., what's your take on this distinction?
Dr. Efstathiou: I would fully, fully agree with Tom. I think it's more of an administrative, let's call it, currently at least, term because, back in the day when it was coined, sure, as Tom mentioned, we did not have this advanced enhanced imaging and now we do. But my concern is that now the term becomes very confusing, and I tend to use a term that you said, advanced, because once you speak, especially to patients, and say, "Hey, non-metastatic," immediately, if you're the patient, you don't have to know that it's administrative, it's FDA-based, you're just thinking it's non-metastatic, but it might very well be when you do your enhanced imaging. For sure, this is now not just a part of being administrative, but it's also confusing. I would agree.
Now I would also agree with Tom that we should see the disease as a linear progression, and you mentioned, Rick, clinically different. One could argue that if you have a high volume, more advanced disease, that you can obviously see on old-school bone scan, more than likely you have symptoms or just a few. It's a little bit of a different stage or, let's say, advancement of the disease, but there are so many parameters that come in that have to do the person, the patient himself, that, again, we should not just put labels. Advanced would be a good way to start, in my opinion.
Rick Davis: I think about my own situation, where I was diagnosed T3, but a term that was frequently used, and is still frequently used, is micro metastasis, which is one level before non-metastatic, and then there are all kinds of ramifications about micro metastatic treatment.
Dr. Efstathiou: Yeah, you're absolutely right, and that term micro metastatic, again, and, Tom, your thoughts on that, is loosely used because one could have used it also in the non-metastatic CRPC setting. And when we speak to each other, we tend sometimes to not be as, let's say, scholarly, precise on our terms and that may further create confusion and, hence, like in breast cancer, we should start considering terms such as advanced.
Dr. Beer: I couldn't agree more. I think, in many people's minds if you say non-metastatic, that sounds like we know there are no metastases, which is actually almost certainly untrue. The vast majority of folks with non-metastatic castration-resistant disease, if you use sensitive enough imaging, you find the spread of cancer in the majority if not the overwhelming majority of patients. What we're really saying is without detectable metastases by conventional imaging. But, again, because our clinical evidence was built using those definitions, I wouldn't want to completely forget about them because there's a lot that we understand about how to take care of patients that we've learned from studies that use that definition. As we broaden our definitions, we still need to be mindful of what data we have and how we might use it even as we change our imaging and learn more.
How Does Quality of Life Factor into Decision-Making for nmCRPC Treatment?
Len Sierra: Whether this condition of non-metastatic CRPC is real or administrative or FDA-created, we have to address the issue that there were three drugs approved for this very condition, enzalutamide (Xtandi), apalutamide (Erleada), and, more recently, darolutamide (Nubeqa). And please correct me if I've made an assumption I shouldn't make, but my take on those trials is that there's very little difference with regard to the various endpoints chosen, like overall survival, radiographic progression free survival, among the three drugs, and that there may very well be a substantial difference, however, in side effects of the three drugs and quality of life, one of them being superior, darolutamide. My question is do oncologists have a responsibility to select the drugs with the minimum amount of side effects?
Dr. Efstathiou: Yeah, Len, I think you're absolutely right in saying ... I have to agree with you because what I keep saying is, more than anything, if you look at these three trials that are in this phase of the disease, but also across the board of all the trials that have been done with these more enhanced agents, hormonal agents, you will see that they are very similar study designs. In the case of these three trials, it's almost like they all sat down and copied/pasted each other with very, very minimal differences, and that is good because the results are also reproducible. So, in a way, the one agent's result is supporting the other, so that's good, because if we had conflicting results, we would be like, "Where do we stand?" And it's very, very specific to these hormonal agents, as we see in prostate cancer, showing the value of using them and using them earlier in the disease.
Before I answer your question, I also wanted to go back a little bit to what we were discussing earlier and to point out that some investigators, some researchers, did the following, they took men exactly like the ones who went on the trial and had done this conventional imaging, CAT scan, bone scan, nothing showing up there, and they did PET scans and they showed that 70% of these men had findings on PET scans. Again, indeed, we're looking at a disease that really does have some metastases that we can't see. It's early metastatic CRPC, let's call it.
Yes, efficacy is similar. Based on the data that we have, we have two agents that seem to pass the brain barrier and one that does not, and that is darolutamide. It gives it an advantage, in that sense, absolutely. All three of them are anti-androgens, so they're all three expected to have the anti-androgen impact to a different degree. I would agree that darolutamide has a great advantage there. We've only seen it in one big study and it looks also very promising in the human condition.
But let's go back to your question because I don't want to be like a politician here, which you said, should then physicians recommend the one that has the least side effects? One could say that, yes, but we don't have a lot of experience with darolutamide yet, and Tom knows it better than anyone because he's worked so much with enzalutamide. When we first presented our data on enzalutamide back in the day, in 2009, we didn't see almost any side effect, real big side effect, in the Phase 3 trial because everyone was so super physically fit, we were really monitoring the patients. Later on in practice, we started seeing more side effects. Yes, for now, darolutamide seems to be on top on safety, but we need some more data as we start using it more and more in the real world would be my take.
Dr. Beer: This is an important area that we need to pay a lot of attention to and I don't think there's a black and white, easy, and the same answer for every single patient and every single situation. Before darolutamide and apalutamide came along, we had these debates about abiraterone (Zytiga) and enzalutamide, and I had the pleasure of debating Dr. William Oh about this at a conference a few years ago-
Dr. Efstathiou: I remember.
Dr. Beer: ... and the audience voted and I thought I won and it was 50/50 in terms of physicians who specialize in this area which drug they preferred to use first, and a lot of it had to do with perceptions of quality of life on these drugs. I think there is still a lot to be learned about that, and while we do have the phase 3 trials that we have, none of them compared the drugs to one another directly. We're doing a study like that right now. It's called a [inaudible] trial where we're randomly assigning patients to enzalutamide or darolutamide and measuring, very carefully, cognitive and physical function, looking at those domains that, based on the phase 3 trial results, we believe darolutamide might have an advantage in, so we're going to get some direct objective data on that, and I think that's going to really help with this topic.
But the other thing I wanted to say is that side effects vary from person to person, and so the most important thing is not necessarily that we recommend that all patients get one drug versus another, but, instead, I think what we ought to recommend is that all clinicians pay very close attention to side effects that their patients encounter and, whatever drug they may start, be willing to make adjustments to preserve and protect the quality of life, be it dose reductions or switching drugs as necessary. Because, statistically, one drug might look better than another, but in a given individual patient, it's not always so. There's quite a bit to do in the individual patient care arena on this issue.
Len Sierra: A lot of patients are curious about what goes on behind the scenes in the oncologist's office maybe with your medical team, going about securing insurance for certain drugs. Let's, again, take the example of darolutamide. If you're trying to prescribe technically off-label, do you have to fight with an insurance company to get coverage or how does that work?
Dr. Efstathiou: Well, listen, let's be honest, at least from my perspective, as I call us physicians at MD Anderson, you're speaking to the Marie Antoinette's, right, because we got this big office in the back with, I don't know, hundreds probably people working on getting those approvals, and that's a privilege that usually physicians' offices don't have. It is usually the moment you prescribe, get an email from the team of pharmacy and the financial clearance office, "Working on it," and, in 24 hours, you'll hear back if there's any issue and that's when you step in. It is rare that I've had to step in and explain, in the case where I'm outside an indication, that I'm switching because of the issue of tolerability. But we've got it really made, I would say, at MD Anderson from that perspective, in the sense that we've all the support. And I have to caution everyone that this can be a real roadblock for practices and extremely time consuming if you do not have that type of support.
Len Sierra: Thank you. And Dr. Beer?
Dr. Beer: Yeah, I think, in the United States, there's been a long tradition of so-called off-label prescribing and so, in my experience, most insurance carriers don't give us a lot of trouble with prescribing any of these drugs for advanced prostate cancer. It is technically true that darolutamide is approved for non-metastatic CRPC, as is apalutamide, and enzalutamide has the broader range of approvals, but by and large, we've not run into significant difficulties in getting these drugs approved. I do typically craft my notes in such a way that anticipates questions, so if there's a reason to switch, I articulate that in my assessment and plan. And, like Eleni, we benefit from a significant level of support from our staff to help manage that.
Of course, insurance is just part of the battle. The other part is patient copay assistance and, even when coverage is provided, there are out-of-pocket costs that can get in the way. That's another dimension that we have wonderful staff helping us with.
Len Sierra: I'm going to go off script a little bit here, Rick, because we just got in an interesting question from one of our attendees which I think needs to be addressed. They want to know which adverse effects are the most concerning with these drugs.
Dr. Efstathiou: As I mentioned earlier, there's a difference in the impact in the crossing of what we call the brain barrier between the two drugs, enzalutamide and apalutamide, and darolutamide. Essentially, based on studies that were not done in humans, but they're supported by what we saw in humans, the two drugs get in the brain at different concentrations when you give them, whereas darolutamide does not, and it has a different chemical structure. The main difference and the most concerning, of course, side effects come from that entering the brain. And we saw then, back in the day that, as Tom mentioned, we were studying the drug for the first time in humans, with enzalutamide. We started going up, up, up in doses. We were giving it every three patients and, all of a sudden, boom, we get at a high dose. It was, I think, about 300 milligrams, and then all the way to 600, we were getting seizures. That's the most offensive, but it's very rare. We peeled back and went to that dose that we're using now.
A similar thing happened with apalutamide, but we knew what we were looking for when apalutamide was starting to get studied. That's the most, most concerning. And, of course, any impact on the brain that could be debilitating would be, for me, the most concerning. That includes fatigue. Now if we leave out the effect on the brain, which can be very variable there are other effects that can happen from the class of agents, which is being an anti-androgen, which is blocking what we call the androgen signaling. It's more the impact on the male body from a sense of physiology, the bone density, the muscles, the general sense of weakness, but there are ways to dissipate and many more that we probably don't have the time to discuss. But that should apply across the board for agents that are strong and efficacious as the ones Rick is describing.
Dr. Beer: I would just quickly add that cardiovascular issues are a concern, and the reason I want to bring them up is that you don't feel them until they happen, they are abrupt events, and so keeping in mind management of other cardiovascular risk factors is something that we also need to be doing as we pay attention to the fatigue, the cognitive issues, and all the more common and more obvious side effects.
Andrew Schorr: We do have some of the gentlemen on who were not part of the AnCan support group, so they haven't gotten as smart as these guys, and so they just want to make sense of all this. You've talked about shutting down the testosterone, if I've got it right, and then these different drugs and where quality of life comes in, right? And so the discussion with your doctor about which drug or combination of drugs and how you live as well as you can while trying to keep the prostate cancer at bay. Eleni, did I get it right?
Dr. Efstathiou: You got it absolutely right. Okay, I don't want to use the word poison, but you're using medication, regardless of what you're doing, so you've got to pick the one that's going to get that balance that we call therapeutic index, maximal outcome, minimal, minimal side effect. If you were going to do it right, it would be what Tom said, just very personalized to yourself, "We're going to get there, but right now, we have to go based on our clinical criteria," and then very good interaction with the patient just getting all the information out and being very, very honest and persistent about what you want in your life.
Andrew Schorr: And, Tom, just to you to underscore this point for our audience. The man who might otherwise just say ... you say, "How you doing?", he says, "Oh, I'm fine," and you can look at all the test results, but if they're not fine or if the wife or partner speaks up, has to say, "You know what? He's really having some confusion," or "He's got a lot of fatigue," or he's got this or that, you need to hear that, right? They need to be honest with you.
Dr. Beer: Yeah, absolutely, Andrew. One of the things that drives me bananas is that about half my patients when I ... I always open with, "How have you been since the last visit?" Half my patients say, "Well, you tell me," which what they're really saying is, "What's my PSA?" And I really want to start with a question about how they're feeling and I don't even want to get to the PSA until I understand how they're doing as a human being. And it's critically important and I'd encourage the participants to really share with their physicians how they're really doing and not be afraid to bring of quality of life and to consider treatment adjustments, carefully and thoughtfully, but I know a lot of folks who, once their PSA is where they want it, they choose to put up with side effects that maybe they don't need to, maybe they can achieve the same cancer control with a better quality of life if they're only willing to share that with their physician and allow a little bit of adjustment.
And this is not a disease where, if we take the foot off the brake a little bit to test a lower dose, that we just lose control and can never get it back. It's not like that. It's okay to make little adjustments, switch drugs, lower the dose to achieve what Eleni was talking about, which is maximum benefit with the least toxicity and cost to quality of life.
What Are the Treatment Options for nmCRPC if Drug Resistance Occurs?
Rick Davis: But I want to ask you another question because we get this a lot of times, men get very concerned about what treatments are available to them down the road, and particularly when these second-line anti-androgens that we've discussed, like enzalutamide, apalutamide, darolutamide, abiraterone, stop working, stop working meaning they're no longer controlling the disease, we're seeing more growth on scans, maybe we're seeing a difference in the PSA. What categories of treatment are available for these men once the second-line anti-androgens stop working?
Dr. Efstathiou: A great, great, great thought and question, Rick. We didn't have the time to discuss it today, but things are changing in our field and that's a great thing. It essentially started as of last year when we got, for the first time, the real data that say that, if you've got a target, you go after it, and we have to prove that it works to go after that target. And when I mean target, I mean another event in the cancer, a mutation, what you want to call it, a change in the cancer cell that would, if you target it, lead to a remission of the disease. That's what we call more targeted therapy, and it was very elusive for prostate cancer for a lot of reasons. But now we know that, going back to what Tom said about individualizing, you need to look carefully at that cancer and at the person to decide what further you have to use to address the cancer growth.
It is beyond just the androgen signaling or the old-school chemotherapy approach now. We are getting more and more of these targeted agents. Now that creates another part of the work that your team is doing, which is take some of those cancer cells, potentially look at your genetic background, and try to find if you have mutations that led to this cancer or if the cancer itself has some mutations that are not pertinent to you and can be addressed. That will be the future that will decide what are the rest of the treatments that we have. We already have two drugs approved this year to do that, it's for a subset of patients, but, you see, this is now moving fast. It was just the beginning last year and we got another data set, just came out in June, that may lead to another breakthrough with just a matter of time.
And the third part is also that there is a subset of patients where immunotherapy worked. We know that's elusive, again, in prostate cancer, but we need to keep on looking for those targets. It's a very, very complex world that we're going into, but it's extremely exciting because it will give us answers that we need.
Rick Davis: Dr. Beer, what would you add beyond immunotherapy and precision medicine as other alternatives when second-line hormone therapy, stops working?
Dr. Beer: If we think about agents that are currently approved and available, when androgen receptor blockers, like the three drugs we talked about, quit working, unfortunately, the probability that another conventional hormonal drug will work is relatively low. Abiraterone after enzalutamide or apalutamide or darolutamide works in a small minority of patients. What we have available is chemotherapy, and I know that has a bad brand, if you will, but we should remember that chemotherapy can be very effective for many men and can be quite tolerable for most men. We have radiopharmaceuticals, radium 223, for folks with bone-predominant disease, and we have PARP inhibitors for those that have DNA repair mutations that we can detect either through a blood test or through a tumor analysis. And for a small subset of patients, we have PD-1 immune checkpoint inhibitor therapy. That's about one or two or three percent of patients, depending on the molecular features of their cancer.
That's the standard armamentarium. We definitely, for most patients, view that window between progression on enzalutamide or darolutamide or apalutamide and the need for chemotherapy as a window of opportunity to try new things because we know that chemotherapy is on the shelf, we can deploy at any time with 24 hours’ notice, we're ready, but that's where we're testing novel immunotherapeutics, novel targeted agents, and novel radiopharmaceuticals.
I'm sure Eleni participated in the effort to develop lutetium-177-PSMA-617. It's a novel radiopharmaceutical that moves beyond the radium 223 to target radiation therapy to prostate cancer. That's a phase 3 trial that's completed accrual. We're all awaiting results from that, but I'm cautiously hopeful that that'll give us another whole category of agents, and the really attractive feature of that is not only that it's a different type of therapy, so it's likely to be useful when other therapies are not, but the other thing is that PSMA is expressed probably in 90% of prostate cancers, so it's not going to be one of those tiny 10 or 20% segments of patients that are eligible. Most patients should be eligible. That's another area I'm keeping an eye on.
And then there are other targeted drugs that we won't even probably get a chance to talk about that are in development. Some will fail, some will succeed, but as Eleni said, the pace of progress is really remarkable and so I'm very hopeful for the future.
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