Transcript: NCCN Guidelines for Treating Metastatic Castration-Resistant Prostate Cancer: Genetically Unselected Patients

Dr Atish Choudhury: Welcome to the Journal of Clinical Pathways. My name is Dr Atish Choudhury, Senior Physician at Dana-Farber Cancer Institute and Co-Director of the Prostate Cancer Center at the Dana-Farber/Brigham and Women's Cancer Center. I'm also Assistant Professor of Medicine at Harvard Medical School.

I'll be moderating today's session. I'm joined today by Dr Alicia Morgans.

Dr Morgans, can you please introduce yourself and tell us a bit about your background?

Dr Alicia Morgans: Sure. Thank you so much, Dr Choudhury. As you heard, my name is Alicia Morgans. I am a GU Medical Oncologist at the Dana-Farber Cancer Institute, where I'm also the Medical Director of the Survivorship Program.

Dr Choudhury: Welcome. Thank you for joining us today. In this 2-part series, Dr Morgans and I will be discussing the NCCN guidelines for treating patients with metastatic castration-resistant prostate cancer. In part 1, we'll dive into treatment modalities that have demonstrated survival benefit in mCRPC for genetically unselected patients.

Dr Morgans, just to list for our viewers, the modalities that have been approved in mCRPC and have demonstrated as survival benefit. We're talking about sipuleucel-T, radium-223, abiraterone, enzalutamide, docetaxel, cabazitaxel, and probably soon to come lutetium PSMA.

With all of these different modalities that are approved and demonstrated a survival benefit, how do you decide on a first-line treatment for mCRPC? What factors do you keep in mind when you make those kinds of decisions?

Dr Morgans: It's a great question. Lest we not forget the olaparib, rucaparib, and pembrolizumab as well. I usually try to focus on what a patient has had in the past to help direct me in a good path forward for where that patient can go in the future.

I typically try to focus on changing mechanism of action, particularly if it is exposure to an AR-targeted agent that I want to try to switch away from following with another AR-targeted agent. The reason that I mentioned the PARP inhibitors and pembrolizumab is that I also think about using targeted agents in the situations where they may be available to patients.

Those can be both highly tolerable for a majority of patients and relatively easy for patients to get in terms of clinic visits, lab, follow up and those kinds of things. Those are the main things.

Of course, I always ask patients what they want, what their preferences may lean towards, because if want to try to avoid losing their hair, for example, perhaps they'd want to use something that is radium-223, which is not associated with alopecia.

If they, for whatever reason, want to use a cytotoxic agent, or they like the consistency of having that infusion every three weeks then docetaxel or cabazitaxel may be the best options for them. It's such a multifactorial process that I know you know very well, and there are many things to consider, but those are the main points.

Dr Choudhury: It would be reasonably fair to say that our most common management for mCRPC for patients who have progressed on ADT alone would be one of the hormonal agents, either abiraterone or enzalutamide.

Are there situations in which you might consider doing any of the other treatments, either a taxane chemotherapy or a PARP inhibitor or pembrolizumab or sipuleucel-T or radium, before one of those agents?

Dr Morgans: Another great question. If a patient has a visceral crisis, for example, if they have cord compression, if they have something where I want to make sure we have a rapid activity, sometimes I might lean towards docetaxel chemotherapy if this is truly a first-line mCRPC with no prior intensification in the hormone-sensitive metastatic setting, for example.

I would say that we do know that things like abiraterone and enzalutamide do work in those instances. That may be a remnant of oncologists of yesteryear where we think about needing to have that chemotherapeutic approach for that rapidly progressive disease. It's still a strong pull. It's something that I certainly think about.

For patients who are progressing very asymptomatically with minimal disease, you could consider sipuleucel-T. When you don't have any visceral metastases, when patients are pretty asymptomatic and things are progressing slowly, that can be an option. Usually, I will use an AR-directed therapy before I integrate that. You're correct in saying that for the most part, that's the direction that we take.

Dr Choudhury: As you know, now in first-line hormone-sensitive prostate cancer, the standard is to use these more potent agents earlier in the disease course. It is very common for patients to be on abiraterone or enzalutamide or apalutamide at the time they might transition to mCRPC.

They might have received docetaxel previously. If they have, and they are on one of these more potent hormonal agents at this point, how do then decide what the next treatment might be?

Dr Morgans: That's where I focus on understanding whether there might be targeted options for patients, things like a PARP inhibitor or perhaps pembrolizumab, or also thinking about ensuring that we change mechanism of action, as I mentioned before.

I am a firm believer that the majority of patients will not have a sustained and clinically meaningful response to a second AR-targeted agent after exposure and progression on a prior agent. I do try to switch that mechanism of action.

Then, it's thinking about how rapidly the disease is progressing, where are the locations of metastatic disease that help us understand which other options, and whether there are targeted adoption available, which other option is going to be right for the patient.

Dr Choudhury: Do you ever use molecular biomarkers, for example, ARV-7, to make a decision between a second hormonal drug and taxane?

Dr Morgans: That is a great question. I have not used that because as I said, I am in the camp where I believe that if patients have evolved resistance to one, in most cases, they will have evolved at least a resistance that does not allow them a meaningful response in that second-line stage. I don't typically use something like ARV-7 to help me make that decision.

I also think that we can get our answer relatively quickly. It's not to say that I never use one of those AR-targeted agents in the second-line setting. There are always instances even on clinical trials where we have that as one of the components of the trial. We do find out relatively quickly if a patient seems to have disease that is progressing.

Again, that test doesn't necessarily add to my decision-making, but I'd like to throw that one back at you. Do you use ARV-7 or other markers to make that decision?

Dr Choudhury:  I don't use ARV-7 because, in my perspective, it's a marker of more aggressive disease. Many of the markers of very aggressive disease are things that we know instinctually. Things that you mentioned before, symptomatic progression, high-volume progression, visceral disease, these are all features where it certainly would not make sense to use the second hormonal agent.

We would use most commonly a taxane-based chemotherapy. However, getting backwards, are there patients in whom you might consider a second hormonal drug?

I'm not sure that we know that for sure because we should discuss the CARD study where patients who received prior docetaxel and a prior AR-targeted agent were randomized to receive the second AR-targeted agent versus cabazitaxel. That study demonstrated in that population that there were benefits to cabazitaxel.

Those benefits were progression-free survival, overall survival, which is surprising because patients were allowed to crossover, and benefits to a variety of secondary outcomes, including pain and quality of life.

Now, the issue with that study, so one all of the patients had prior docetaxel. Second, it lumps patients with those prior treatments altogether, but there's a subset of patients with low volume disease where maybe they are just not quite candidates for cabazitaxel at the point that we're seeing them.

Is this a place where we could consider the second oral drug, understanding that the likelihood of a deep and profound benefit is probably limited but might buy some extra time? Is that a time that we might consider clinical trials?

This brings me to the next question is where does sipuleucel-T, for example, set up for you? Do you consider it in those kinds of cases, even in patients who have received prior docetaxel or abiraterone, and now they are progressing in a pretty asymptomatic way?

Dr Morgans: That's exactly the population where I think about it. It's those patients with no high-volume visceral metastases. In that trial, they even excluded patients who had liver metastases, for example, and so would want to avoid liver metastases for the most part in patients who I was thinking about sipuleucel-T for. These patients were asymptomatic.

The patients where I find that they might benefit are going to be patients with a relatively low PSA who have relatively slowly progressing disease radiographically. I typically make my decisions regarding when to start the next therapy based on radiographic progression rather than PSA progression.

Minimal radiographic progression, no visceral disease, relatively asymptomatic, and relatively low PSA, and that's the population I aim for.

I do think it's interesting that in some of the analyses that have been done, particularly, it was the PROCEED registry where there was a potential signal where Black American men could have had a better response to the sipuleucel-T treatment than the White Americans who were included in that trial. That's very thought-provoking and interesting.

When talking about this with my patients, always encourage them that, "You as a Black American may have even better response to this treatment. I don't know that for sure, but there is a potential signal."

That's a useful talking point when trying to talk to patients about something that can be a little more intensive in terms of the trips that they need to make back and forth, the potential line that they need to get to receive sipuleucel-T, which can be a little bit daunting for some patients. These are all aspects of what I think about, but that is the population.

I also think about telling patients on the front end that if we are going to try this, it's very possible that within a few months, or even one month after completing this treatment, we may find that we need to move on to the next therapy.

That we usually are trying to put this therapy into our treatment algorithm, but don't necessarily think that use of sipuleucel-T is going to delay time to next therapy by a long amount. That's something else to consider when counseling patients in this setting.

Dr Choudhury: One thing that you might be aware of, and this came up in some of my insurance reviews, is that the most recent NCCN guidelines list appropriate treatments for patients who have received prior docetaxel, received a prior novel hormonal agent, or the combination of both.

Sipuleucel-T was excluded from the list of preferred treatments for patients who received both. Now that we have data from the PEACE-1 Trial that suggests that docetaxel and abiraterone together might have benefit in the hormone-sensitive setting.

What do you think of this idea that sipuleucel-T is not favored in that particular population, or do you think that that was an error or a misrepresentation, or how would you interpret the exclusion in that population?

Dr Morgans: I don't necessarily think it's an error because that PEACE-1 data was just recently reported. I could be wrong, but I don't think I've seen that in manuscript forms. I haven't seen the publication yet.

It's completely reasonable for the team that puts together the NCCN guidelines, if those are the ones that are being used to help direct some of these insurance decisions, that they have the opportunity to review the manuscript and review that data before anything is incorporated into the guidelines. That's completely reasonable.

I don't think that many patients are going to be severely harmed if they are unable to get sipuleucel-T after a PEACE-1-type regimen, especially since I would imagine that most of the patients that I'm going to be treating with a PEACE-1-type regimen are going to be high-volume patients and probably will have more aggressive disease than I typically would see in my sipuleucel-T patient population.

I understand why the guidelines are made that way. It is possible that as that PEACE-1 data becomes available in manuscript form, the guidelines and the insurance restrictions may be revised. Not a mistake, but just I would say a treatment paradigm that is in rapid flex, and they just need some time to catch up.

Dr Choudhury: My perspective on it is that the NCCN guidelines is for docetaxel and abiraterone in the mCRPC space because there is very limited data of sipuleucel-T after both agents.

If you're using them both in the hormone-sensitive space and a patient has slowly rising PSA afterwards, that is a therapeutic window and opportunity to give sipuleucel-T if you think patients are going to receive a survival advantage from it.

As you had mentioned before, retrospective studies of impact have suggested that it's the patients with the lowest PSA quartile that seem to benefit. It is important to get it in before real symptomatic progression because that's not a population that benefits from sipuleucel-T. There probably still is a role, but just in a very specific spot in a patient's treatment course.

Speaking of agents that have modest cytoreductive properties, how about radium- 223? How do you sequence that in thinking about your CRPC patients?

Dr Morgans: Radium-223 is interesting in the algorithm that I use because I find that, especially patients who are receiving ADT and one of the AR-targeted agents in the hormone-sensitive space, if they are progressing symptomatically and in bone only, I find them trying to make that decision between radium-223 and docetaxel pretty early on in the mCRPC setting, if not the first step in mCRPC.

The ALSYMPCA trial did include a portion of patients who had not been exposed to docetaxel. It wasn't necessarily because they weren't fit for docetaxel. There was a about a 30% of the population that just opted out of docetaxel from what I can tell from reading that.

It is reasonable to consider radium-223 in that first line mCRPC setting, where I'm also considering docetaxel. That puts it in the patient's hands. We do talk about things I mentioned before, alopecia. We talk about cytopenias. We talk about how frequently the treatments are given. I do have some patients who choose just taxane. I have some patients who choose radium-223. That's the space where I typically am thinking about it.

For patients who have already had docetaxel and who have already had an AR-targeted agent, then usually, radium would be the next option in that setting as well, if they have bone-only metastatic disease. I tend to think about the symptomatic part of that label as being a lot broader than just having bone pain.

It's important, just as you mentioned the sipuleucel-T, to make sure that we give patients access to this treatment for its survival benefits. Even things like fatigue, mild pain, those are things that I think of as symptoms related to the prostate cancer and would, in my mind, justify the use of radium in the patient population who has bone-only metastatic disease.

Dr Choudhury: This is a case where pace of progression plays into my considerations of using radium-223 as well. Retrospective studies have suggested that the patients who receive 5 or 6 doses from radium-223 have a much-prolonged survival compared to patients who can only get one to four before they have to go on some other treatment.

It does seem that the benefit to radium-223 is in patient populations where they can receive 5 or 6 treatments without needing to come off early for symptomatic progression. If patient has very rapidly rising PSA, I do tend to favor docetaxel over radium.

If the PSA is rising relatively slowly and the symptom complex that you're describing is fairly modest, I do think they can probably get the 5 or 6 doses and get benefit from it. With the goal of making sure that the PSA isn't rising too quickly while patients are getting radium-223, do you ever give it in combination with abiraterone or enzalutamide that they were previously on or may be switching to?

Dr Morgans: I generally do not. I find that the opportunities for that are relatively rare in my practice, although I definitely have colleagues who do this layering type practice, especially if there's a low volume of lymph node disease. It does seem reasonable to me, but I don't typically do that.

If I do that, and I have. On rare occasions, I have done that. When I do, I am very attuned to the fact that I may be putting their bone health at risk and maybe putting them at higher risk than for those skeletal-related events. Anytime I'm using radium or any of these agents in mCRPC, I do try to focus on bone health as well.

That's a particular situation, where I try to make sure my patients have access to whether it's denosumab or zoledronic acid that we're getting them on that schedule and usually monthly dosing when we're in the setting of radium, especially if it would be in combination with an AR-targeted agent. What do you think?

Dr Choudhury: I absolutely agree. This is based on the ERA-223 study where patients with mCRPC were randomized to get abiraterone with radium-223 versus abiraterone alone. The rate of skeletal-related events was much higher in the combination arm than in the control arm.

The addition of a bone-protective agent seemed to protect patients from those early skeletal-related events, but it wasn't the same as in the control arm.

In the PEACE-3 study, which was a similar design, but using enzalutamide, when they did add a bone-protective agent, then the rate of skeletal-related events did seem similar in the two arms. That particular analysis is not yet published to this point.

I do make it a point to pretty much never combine radium-223 with abiraterone. However, if a patient has been treated with enzalutamide, is tolerating well, and I feel like their PSA is on enzalutamide at a slower pace, then I might expect off treatment.

Sometimes I will do that layering on strategy of radium-223, but if I'm going to do that, I will mandate bone-protective agent at that every 4-week schedule with every radium-223 dose for exactly that reason.

Now that lutetium PSMA is coming, as you're aware, the entry criteria for the VISION Trial, where lutetium PSMA was tested, required at least 6 months since patients have received prior radium-223.

What does that mean in terms of the role of radium-223 after the lutetium PSMA is going to be approved? Do you think we should still use it? Should we not use it? Should we be more cautious? What's your perspective on that?

Dr Morgans: The time difference or the stipulation about time from radium for the VISION Trial was probably around safety. It was to ensure that there weren't ongoing cytopenias or some later effects that might make a patient have poor bone marrow reserve so that when they did get lutetium, they could have complications associated with that.

I do think that as lutetium is approved, we're going to have some instruction on the label that will help us understand where radium fits. Maybe we won't because it wasn't necessarily written into the inclusion criteria that certainly one didn't have to be exposed to radium to get onto the VISION Trial. Maybe it won't be in there at all.

This is going to be a consideration for each individual clinician and each individual patient encounter. If the patient has bone-only metastatic disease, it's possible that some may choose to go for radium first knowing that if that patient has progressive disease in the future, there may certainly, be the opportunity for lutetium for patients who have PSMA-positive disease, but they may not then have the opportunity for radium.

I'm always a little cautious about losing access to a therapy over time and want to try to have every treatment exposure that I can for a patient to ensure that that patient has, hopefully, the longest time to benefit from every single therapy available.

That being said, lutetium appears to be very well tolerated. Certainly, attacks micrometastatic disease potentially even when we can't see it in lymph nodes, for example, and a patient may look like a patient has only bone metastatic disease but may have more disease than we can see. In that sense, lutetium may be a good option even earlier on.

We do know that the earlier we use any of our treatments, at least those that we've studied so far, the more benefit we seem to get out of that particular treatment. That things seem to give you a longer survival benefit, a longer PFS, and maybe even better quality of life outcomes the earlier we use it.

I don't know where lutetium is going to fall out. There will be some push and pull with radium, but these are different agents. Importantly, if we can use both in a patient, that would be my preference.

Dr Choudhury: It's very difficult because we don't have safety data of doing radium and lutetium back-to-back. It would be very difficult for me use radium in a situation where I feel like the lutetium PSMA is going to be the very next treatment option that I might consider. If I do think that they can get a break, and often that break is taxane chemotherapy, which is also in itself myeloma suppressive.

If I feel like there can be other treatments that can be sequenced in between, then I feel more comfortable with radium-223, but if that the very next treatment strategy might be lutetium PSMA, it's very difficult because we just don't have safety data on the back-to-back radiopharmaceutical, and whether that's going to be better or worse than using chemotherapy in between.

It actually might be better than chemotherapy. I just don't think we know.

Dr Morgans: We don't know.

Dr Choudhury: We don't know what the label for lutetium PSMA is going to be, but most likely, we are going to need a PSMA PET as part of the eligibility criteria as a companion diagnostic. Do you think that that's necessary?

Then, there's also data around use of FDG PET to exclude patients who have FDG-positive disease that's not PSMA positive. What do you feel about PET imaging as far as eligibility for lutetium PSMA?

Dr Morgans: If the FDA stipulates that it's necessary, it's going to be necessary for us to get a PSMA scan. I would love for us to be able to do PSMA staining on a biopsy sample, for example, and say that because we can find this bi IHC or whatever method we're using in our laboratories to identify PSMA-positive pathology that we and use things like lutetium PSMA.

I don't think that that's going to ultimately be an option. At least not early on because that's not how the study was performed. If it is linked as essentially a requirement for therapy, then it is going to be a requirement for therapy.

That will set up its own challenges in terms of access for patients having access to both the scan and then access to the treatment may require patients to travel a fair distance and may pose quite a bit of toxicity in terms of time lost at work. Ultimately, this combination that could make some treatment with lutetium pretty financially difficult for some patients.

My hope is that we find a way to get this treatment out to as many people as possible and don't find ourselves setting up a major disparity because of things like requiring the PSMA scan in at first, and then the difficulty that patients may have getting lutetium itself in terms of that treatment.

This is an area in flux and an area that we need to pay a lot of attention to and need to ensure equity around. That's a concern, but not a concern that's born out in data yet because it's not yet approved. We will see. We will prepare as much as we can, and then hopefully repair on the back end if we have to.

In terms of FDG PET, at least the VISION trial did not require that, so it doesn't seem like that will be required in the label. Now, TheraP and some of the other studies that of end up in Australia did require both of these. It's beautiful the way that these scans can identify the patients who have the highest chance of responding.

When we look at the patient population included in VISION, it seems like if we don't need necessarily to have a PSMA-positive scan because 87% or so of the patients seem to meet criteria without even having that scan or with the scan but met criteria, it doesn't seem necessarily like an FDG PET will necessarily add very much.

The work still needs to be done. We could do a study similar to VISION where we have both of these scans. We treat everyone under the criteria used in the VISION trial and then see if the FDG PET identifies patients who wouldn't respond. Not everyone responded in VISION and maybe adding an FDG PET could help us identify non-responders, for example.

Work needs to be done. Certainly, we can all speculate that the Australians have a cleaner way to identify patients who may benefit and that the VISION trial tried to treat as many and give as many patients benefit as possible. The truth is probably somewhere in between.

The bottom line is that it's going to be hard enough to get one PET, a PSMA PET, if that's what we need to deliver treatment, having the requirement to potentially have both will be an even bigger hurdle for us to overcome.

Probably not going to be required in the label, but I would be very interested to see further research to help us understand the utility of an FDG PET in addition, and perhaps in different disease states to help us best identify patients.

Dr Choudhury: Those are wonderful points and access is going to be so critical so we don't propagate disparities when we have access to these novel treatments. That's a wonderful summary of this particular space in the biomarker unselected patients.

Just as a closing thought, I would say that we're very much in alignment, philosophically, that we do think that the way to maximize quality of life and maximize clinical benefit from the treatments that we have available is to be strategic around what treatments we use, when, and in what population of patients, and certainly, exposure to more life-prolonging therapies probably relates with more life prolongation.

Did you have any closing thoughts that you wanted to include, Dr Morgans?

Dr Morgans: I would echo that, and I would just say that including patients in the discussion is always going to be something that helps them feel like they are doing their part to help buy into whatever treatment decision is made. That will be important as well. It may affect what ultimately is chosen, and sometimes patients say things that we wouldn't expect, and it does help guide at the end.

The only other thing is to ensure that we are all, as clinicians, checking biomarkers, doing that germline and somatic testing that we know is so important to give access to patients to things like PARP inhibitors and potentially pembrolizumab if they fall into those categories. If we don't test, we won't be able to find those options.

Dr Choudhury: Absolutely. That's a great segue. Thank you and thank you for joining us. Thank you to the Journal of Clinical Pathways for the opportunity to have this discussion. Please, check back for part 2, where we'll discuss treatment modalities that have demonstrated clinical benefit in mCRPC for biomarker-selected patients.