Roundtable Discussion: Morgans Addresses How PSA Levels Affect Nonmetastatic CRPC Treatment

Six months after being diagnosed with stage T2N0MO prostate cancer, a 75-year-old patient showed a 2.1-cm left pelvic lymphadenopathy on an abdominal/pelvic CT. Alicia K. Morgans, MD, MPH, associate professor of of Medicine at the Feinberg School of Medicine at Northwestern University, discussed the case with a group of peers during a Targeted Oncology^TM Cased-Based Roundtable event.

MORGANS: There’s not a therapeutic implication at this time, but because of the patients’ high-risk features on his pathology, the guidelines now say that high-risk localized disease also should be included. However, I’m a medical oncologist, so I don’t see most of these patients. The urologists are the ones who are doing the testing. I just wanted to raise the point that we should keep our eyes on [treatment guidelines], because it’s not for the treatment of this patient, himself, or any of those patients with localized disease. It is because the rate of germline mutation is expected to be over 10% potentially and may have implications for family. But it doesn’t impact his treatment right now, is my understanding from the guidelines.

NUTHAKKI: The guidelines also recommend not only germline testing, but also molecular testing of the tissue in patients with high-risk nonmetastatic disease. So I don’t know. Also, in germline testing, they do the whole germline for [7 or so] genes or just the prostate panel?

MORGANS: I can tell you what I do, but the guidelines are not as clear necessarily. We do a prostate cancer–specific germline testing. We use a particular brand that we happen to have in our clinic. We use invites; you can use whatever you want, but that’s what we have been doing. They’re not always clear, to your point; they recommend additional testing as well. There’s not a treatment implication right now for this patient in terms of somatic testing, but you’re right, they do say that.

CHOWDHARY: We order the germline testing. But we are doing the NGS [next-generation sequencing] panel, as well. The reason for that is, I am a proponent of getting the NGS testing done early on. He does have locally advanced disease. At some point, just looking at the treatment paradigm [the patient is] pursuing, as he’s going to need more systemic therapy in the future. Aside from germline testing, you do want to know what the HRD genetic profile is, what is homologous recombination deficiency genetic—if there are any genetic mutations in that group of genes. Because even that informs us for treatment down the road, so I would do both germline testing and the NGS panel.

MORGANS: I just think it’s phenomenal that there’s such a transition, because that’s typically what we would do, too.…I just wanted to comment that, I think I was in one of these discussions a year ago and people hadn’t yet adopted all these things in their practice. So it’s exciting to see and to hear this debate and to hear this conversation about something that really was almost absent a year or 2 years ago from our conversation.

What are your thoughts on things like fluciclovine [Axumin] or Axumin scans or PyL-PSMA scans? Are you ordering those? Are you using those in this biochemical recurrent setting if you have negative imaging? Are you not? What are your thoughts? Because I think this is also a complex thing to integrate into our practice algorithm.

NUTHAKKI: I think they’re not available everywhere. They’re only available in 2 or 3 centers. Nobody has any experience. At MD Anderson, a couple of weeks ago, at a prostate tumor board, the president was saying that he had seen the scans from India; they were so beautiful. But he didn’t see anything at MD Anderson, even. So I don’t know where they’re available.

MORGANS: What’s interesting and important for all of us to recognize is that Pyl-PSMA was just approved by the FDA.¹ So even though it’s not something we can order today, we should expect we’re going to be ordering it soon. As long as our centers and programs and nuclear medicine doctors put together the algorithm to get the marker or the tracer into our practice. Because Medicare is going to start covering it, presumably, and other insurers, as well, because it was just approved. At least, that’s my expectation…Does anyone have a conversation with their team about how we integrate these into practice?

SABAGH: I haven’t and I’m not sure when those are available, [and if those] will be done after a negative bone scan and a CT scan. Then you do that PSMA or would it come first? What are the indications?

MORGANS: I think that’s the part that’s still a little bit nebulous. I believe it is in restaging and it’s in the biochemical-recurrent state. So I think this might be an area where we could use this PyL-PSMA agent, Axumin or fluciclovine, that is approved in this setting. It’s already out there. Are you guys using Axumin scans at all?

BEED: I’m in a rural hospital; we’re in a kind of a desert but there’s big places all around. If I needed something, I could send people there, but again, these are old guys, most of the patients I see. They wouldn’t want to go [to a bigger center farther away], so we don’t have those right now. If there’s something we need, I can ask our guys and I’m sure they’d be only too happy to put them in, especially if it gets paid for.

MORGANS: That’s true. That helps everybody, I think. But I’d love to hear, is anybody routinely using an Axumin scan in this biochemical-recurrent setting? I’m not saying you should, or you shouldn’t. This particular patient refused radiation. Sometimes I’ve used it to make sure that the patient’s not metastatic if we’re going to do pelvic radiation to make sure there’s not more widespread disease.

KUMAR: Recently I did order Axumin in 1 patient. But it was denied because that patient never received any previous therapy. Some retroperitoneal adenopathy and patient was planning to go for surgery but [they said no to non-surgical treatment]. I was trying to rule out any occult metastatic disease, but it was denied.

MORGANS: I have a feeling that’s not uncommon. Certainly, ours are denied sometimes, too. Sometimes we keep pursuing and sometimes we let them go. Anybody else with experience, either with getting it done or with a denial that they want to mention?

KNAPP: I had a patient recently denied on that same scan. How is the PSMA significantly better than an Axumin scan or is it just slightly better?

CHOWDHARY: We have ordered a fair number of Axumin scans in Cleveland. I think many of them have been done. There are a number of times you have to do peer-to-peers on them. One of the areas where we use it is if you have more of a rapid PSA doubling time, your PSA velocity is a bit more rapid and you’re still concerned this may just be locally advanced disease and you’re trying to decide between whether it’s metastatic or you need to treat a locally advanced tumor. That’s where we use it quite a bit with our radiation oncology colleagues. That’s where we use it most that I’ve seen, trying to figure out if it’s more metastatic vs not. We’ve had quite a few of them approved, though, but on occasion, they can be denied.

MORGANS: If I’m going to do pelvic radiation, I just want to make sure that there’s not distant metastatic disease somewhere else before we start radiating the pelvis, because we won’t be able to affect disease that’s more distant with that radiation. But sometimes they’re denied, so I have a very similar experience. In terms of whether the PyL-PSMA is going to be better than fluciclovine, my understanding is there hasn’t been definitive head-to-head comparative trials that I am aware of. Though there are some series that do try to compare some of these different modalities like PyL-PSMA, which is one of the PSMA tracers, is more sensitive to identifying metastatic disease or for identifying metastatic disease than Axumin at a lower PSA. So even PSAs 0.2 to 0.5, and certainly in 0.5, it seems to be able to identify a reasonable percentage of patients who have positive metastatic disease. Whereas Axumin, I think, is described over 2 PSA or at least that was some of the initial reporting on its best sensitivity.

All of that being said, in this particular situation for this particular patient, I think the answer that you’re all giving is that there’s not necessarily a role for this particular type of imaging. That’s actually the right answer. Because right now, you have a patient with a rising PSA, and conventional imaging is negative. This is in the setting of castrate levels of testosterone. So, this patient meets the definition of nonmetastatic castration resistant prostate cancer [nmCRPC].

The reason that I wanted to make sure that we talked about this imaging is, it’s becoming more available. But the question at the end of the day is whether or not this imaging is going to change your treatment recommendation. Because we wouldn’t want to order a test without having a purpose behind that test.

CHOWDHARY: The question I have was that, a lot of times, if we’re worried that a lot of times when you have a patient who has lesions that are questionable that you’re going to biopsy or there are lesions that are questionable and you’re ordering an Axumin scan for it, would you start them on leuprorelin [Lupron] before doing the biopsy? Or do you wait until after the Axumin scan or the biopsy is done? I’m not even sure I fully know the answer, but wanted to get your thoughts on that. Again, these questionable lesions, small lung lesions, you’re going to biopsy them, there could be stage IV prostate cancer. Do you wait on leuprorelin until you’ve done the scan or the biopsy? What are your thoughts on that? Because I’m always worried if it’s going to give you a false negative testing then.

MORGANS: I certainly have colleagues who have biopsied and then seen it’s not prostate cancer. More of the negatives and false positives are in lung lesions and sometimes there’s been a rib lesion or 2 that we have, just odd spaces for prostate cancer and then it turns out to not be prostate cancer. I think if the patient is asymptomatic and you can get the biopsy within a relatively short period of time, I don’t think you need to start necessarily. I think you have to think about the whole clinical context. If the patient is symptomatic, if the patient has disease elsewhere or if this looks like it’s a much more intensive metastatic disease state and the patient really needs palliation now, then you’re in a different situation if it’s 1 small questionable lesion and you really don’t know, is this prostate cancer or if this related to a new primary or some sort of inflammatory process?

In that case, I think I would probably hold back on my treatment, not because I think the biopsy is going to be negative or that the Axumin would necessarily be so effective, but because I wouldn’t want to overtreat the patient if I don’t know what’s going on in the lungs. That’s the purpose for my biopsy. I probably would even just biopsy instead of getting an Axumin. I really think an Axumin, these nuclear medicine tests, PSMA, are going to be potentially helpful for radiation to the pelvis in a biochemical-recurrent patient to ensure that we don’t have metastatic disease, or potentially for the use of stereotactic body radiation therapy. But in patients who are already on ADT, like this patient, there’s not a clear role for this type of imaging.

That’s not to say that people don’t use it. In Australia and Germany, they’re replacing all their scans with these PSMA tests, but in this case, this is another 1 of those red herrings.

We’re having a whole conversation about something just because it is coming down the pipeline and you’re going to see these in your practice. This may not be the point at which you might find it optimally useful.

LANG: I’m sure that PSMA can be used or will be used very useful in the right setting. A lot of times, we have referrals from the urologists and [the patient’s] disease is very late stage. I suspect that we may not have many opportunities to use it. Probably it will be used more by urologists. We get a routine CT scan, bone scan and so I just want to point it out. We may not use that very often because, again, many times we have a referral to some at a very late stage.

MORGANS: We are all in different patterns with our referring doctors. We don’t get patients with prostate cancer until someone sends them to us, in most cases. Unless their diagnosis is wildly metastatic in the hospital, and we can see them there.

LANG: I have been using apalutamide [Erleada] and I feel very comfortable in using it. And, if I remember correctly, it’s just 2 to 3 years of survival benefit by adding apalutamide.

MORGANS: I think that the years of benefit was not defined. The metastasis-free survival was about 2 years longer for apalutamide, enzalutamide [Xtandi], and darolutamide [Nubeqa]...I don’t know that we’ve reached the overall survival [OS] final end points. But we’ll look at that data, too, but all 3 of these agents are also associated with a similar survival benefit, exactly as you’ve said.

BASTOLA: I think a lot of it is familiarity. Although, it sounds like in the cross-trial you can talk about tolerance, maybe some agents are more tolerable than the others. I haven’t really been paying a whole lot of attention to that. I have been using a lot of enzalutamide, just because I have a lot of experience with it in other settings. But it does seem like I may have to start thinking of others, because there are some data suggesting better tolerance. Efficacy-wise, it seems similar.

We wish we had a head-to-head trial, which we’re probably never going to have. We’ll have to be stuck with figuring out what works best when we have these agents, especially when working in the community, and we are treating multiple cancers.

We do like to have 1 go-to agent that we can get more experience and stick with it. That’s where it becomes hard sometimes.

MORGANS: I think those are incredibly valid points. It’s not just in the community that we like to have a go-to agent. I like a go-to agent, too.

NEMUNAITIS: I’ve used apalutamide and enzalutamide multiple times. I’ve never used darolutamide. Is there a certain situation where you would use that 1 in particular or not particularly?

MORGANS: That 1 is the only trial that included patients who had a seizure history in the randomized trial. It’s the only 1 that doesn’t seem to cross the blood-brain barrier, so patients who had a seizure history or a low seizure threshold because of other drugs that they might be on, they were in the trial. There was no real risk of seizures, so to me, that’s compelling for that population. The other thing that is interesting is that the drug is shaped differently than the other 2. Apalutamide and enzalutamide are very close relatives of each other and darolutamide is a little bit shaped differently, so it doesn’t cross the blood-brain barrier in the same way and doesn’t seem to have the same drug-drug interactions that we can see, particularly with enzalutamide.

I use all of these agents. Enzalutamide can have some interactions with certain cardiovascular medicines and anticoagulants that can be frustrating, because then I have to call the cardiologist and say, “Can you change this medication, please?” Darolutamide has fewer drug-drug interactions, so I find that easy to use. None of these have been compared head to head to the points that have been made. It’s hard to really say that this one’s better than that one. But [with] some of the patient-reported outcomes there seemed to be a little less fatigue, perhaps, with darolutamide, so maybe a little bit better tolerability. But again, they’re not compared head to head, so it’s really hard to say.

SABAGH: I used the apalutamide for a patient and for some reason he didn’t tolerate it. He was complaining of abdominal distension, upset stomach. I don’t know why. This was 1 experience, which somehow discouraged me and made me go back to the enzalutamide, which I’m more familiar with from before in the metastatic setting.

KUMAR: I think you can use any of the 3, but it depends on the co-pay and the cost, I think.

MORGANS: A lot of times we try to make our decisions, but there are situations where insurance says, yes, I appreciate that, but unless you have a compelling reason, this is the 1 I’m going to pay for. We sometimes find ourselves in that situation. In this case, this patient started darolutamide.

MORGANS: The patients included in the nmCRPC trials had to have a PSA that was at least 2. But the other PSA-related factor that they had to have was a PSA doubling time of 10 months or less, because those were the patients in other trials, particularly 1 of denosumab, that demonstrated a higher propensity or a higher risk to develop metastatic disease in their bones or elsewhere and die—or die of prostate cancer.

So this doubling time of 10 months was used to identify those patients at highest risk for all 3 of the clinical trials. If this patient had a doubling time of 15 months, so a much longer doubling time, despite being on ADT, what would you guys think about that? Would you want to add another drug if they were non-metastatic with a very long PSA doubling time? Would you wait until they had a shorter one?

SABAGH: I go by the PSA in this situation. If it’s 2 or higher, I would consider treatment.

NUTHAKKI: I think we should go with what the studies have done. I think the NCCN also, if I’m not mistaken, mentions that 10 months is the cutoff where you decide to go on treatment or not. If it is more than 10 months, you observe. Less than 10 months, you treat.

SABAGH: Does it require both PSA of 2 and doubling in 10 months or less?

MORGANS: The labels do not have a 10-month requirement for the PSA doubling time. Nor do they have a PSA of 2 on the label that restricts the use of the drug. You can use, if you have nmCRPC, per the FDA, you kind of have an open label.2 But just like the NCCN, I tend to focus on patients who have a PSA doubling time of 10 months or less. Because these are the patients who might have the most chance of benefitting from an additional drug. At least per the trials that were done. I tend to start somewhere between a PSA of 1 and 2, usually, sometimes 2 to 5. Sometimes the PSA jumps, and you don’t have that window but I don’t say that patients have to get to 2 before I start. I do want to be able to be somewhat confident in their PSA doubling time, though. That is hard when the PSA is less than 1. It’s just not as reliable.

KUMAR: Obviously, if some other drug has OS data, that is important.

LANG: Yes, I agree. We like to put emphasis on OS, but I’m also very impressed with MFS for an average couple of years.

MORGANS: Between apalutamide and enzalutamide, does anyone have experience with both and could comment on whether there’s a big difference between these agents or do they seem relatively similar? Has anybody used both?

SABAGH: I used both with 1 patient, but at the end of the day, he quit treatment just because he didn’t see, to his own mind, a benefit. I’m not sure if that lack of tolerance to the apalutamide was real or not.

BEED: I have not used them. I guess I don’t even think of them as novel, because I answered the other question and just said that I’d use a second agent. The other ones, I don’t think anybody really treats with the older ones. I don’t think of these as novel, and I usually use the enzalutamide. I don’t use the other 2 a lot. I think that’s just because maybe it’s more familiar to the people in practice or something. I don’t really know. But the seizures are a thing that I know you have to look at.

MORGANS: I think of them as the AR antagonists of today, because you’re right, the other ones don’t have good data. But some people, particularly I think in the urology community, still cling to those for reasons that I’m still trying to understand myself. But you seem equally baffled.

Early intervention for patients who are nonmetastatic by bone scan and CT but have a rising PSA on ADT, castrate levels of testosterone—these are patients with nmCRPC. Early intervention can improve MFS, as we saw, by about 2 years and OS as well. Even when we’re hitting these patients over time even though we’re giving these patients additional therapies, we can never make up for that earlier intensification that appeared to be present as far as in our treatment arm. The placebo patients never made it up. They never made up that time. Three drugs are now approved: apalutamide, darolutamide, and enzalutamide.

Maybe we shouldn’t think of these as novel anti-androgens, these are the anti-androgens of today. We should use them. They’re distinct from each other a little bit in terms of their safety, their tolerability, seizure issues, drug-drug interaction issues, and their tolerability maybe by those adverse event profiles. But I think it’ll be important for us, as we continue to practice, to see which ones we feel comfortable with. Because as you said, familiarity is very important. We become more familiar by trying the drugs as you see patients, see what you think and continue to find the drug that works best for you and your patient.

BEED: If it’s earlier when we treat it, they do better, even if they don’t have a doubling time of 10 months. Even though we can’t see the things, this is the head of the parade, the tip of the iceberg. We know with these PSAs, there’s disease there. It’s just having to prove it. As soon as I see doubling times, I try to treat them as soon as I can talk them into it. Now these are expensive, though as we have to look at the fact, they are expensive and what people have to go through. But depending on their whole situation, I think the earlier, the better. Just because we can’t prove it on scans doesn’t mean it’s not there. The PSA is proof, in my mind.

MORGANS: I’ve been in multiple ad boards where people said the same thing, why are we calling this nonmetastatic, we know it’s there. It’s there, you’re right. It’s just not visible on our imaging. But we know it’s there. That’s why we’re able to make such a big difference, I think.

SABAGH: I’m asking the group: How do you measure the doubling time? How do you calculate the doubling time?

NUTHAKKI: Time interval, 10 months vs how long. I mean, if we take 1 to 2 to get 18 months, then that is more than 10 months doubling time. You repeat it in 3 months, and it is already double, then you know you have to treat the patient. Ten months, then it doesn’t need treatment.

SABAGH: I used to think of that in the 3-month or 6-month interval with the PSA. But then I realized there was a formula where you can go to online and calculate doubling time. So that’s why I wasn’t sure. That’s why my question to the group if just the old-fashioned way or if there is a formula which should be used.

MORGANS: A lot of people end up using the eyeball method, which is what they were just describing. There’s a Memorial Sloan Kettering PSA doubling time calculator [that I use] and then I write PSA doubling time calculator. Then I type, you can put in the date of your PSAs and you can do it back for a year or year and a half, whatever duration you want to put in there, then you put in the PSA value and it does calculate it for you. I find it most useful when I’m looking at low numbers that seem to be creeping. Sometimes they’re creeping more quickly than I realized.

_REFERENCES

_{1. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. News release. May 27, 2021. Accessed August 4, 2021. https://bit. ly/2TU7vhY}

_{2. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342}