Roundtable Discussions: Choudhury Leads Debate on How to Treat Nonmetastatic Prostate Cancer

During a virtual Targeted Oncology Case-Based Roundtable event, Atish D. Choudhury, MD, PhD, codirector of the Prostate Cancer Center and senior physician at Dana-Farber Cancer Institute and an instructor in Medicine at Harvard Medical School, discussed methods for treating patients with nonmetastatic prostate cancer with a group of peers.

CHOUDHURY: Most of the people say add a novel hormonal therapy. A couple say add a first-generation antiandrogen and others say other.

If a decision to use a novel hormonal agent was made, which of the following would you recommend: abiraterone [Zytiga], apalutamide [Erleada], darolutamide [Nubeqa], or enzalutamide [Xtandi]?

CIRRONE: [I would choose] apalutamide. I’m a radiation oncologist, so the medical oncologist usually choose this and it’s one of the [available] medications.

CHEUNG: I would pick apalutamide. I also use enzalutamide, too. It depends on the insurance.

CHOUDHURY: If the patient had a history of seizures and was on an antiepileptic, would that change your consideration of using enzalutamide compared with any of the other agents?

CHEUNG: I’m more inclined to use apalutamide.

STRAUSS: I don’t think enzalutamide is a great idea in a patient with a seizure history. I think it has the most activity in the central nervous system [CNS] of all these agents.

I would choose enzalutamide [if] there wasn’t a seizure issue. I think apalutamide has less activity in the CNS, and maybe darolutamide has a bit less than that even. But I think those would be reasonable options too.

CHOUDHURY: As you’re all aware, there are 3 pivotal trials in the space of nmCRPC. The SPARTAN trial [NCT01946204] demonstrated that in patients who were randomized to apalutamide compared with placebo, where the prostate-specific antigen [PSA] doubling time was less than 10 months, there was a benefit to metastasis-free survival [MFS] with the use of apalutamide versus placebo.1 Similar studies were subsequently reported. PROSPER [NCT02003924] was the name of the trial for enzalutamide.2 ARAMIS [NCT02200614] was the name of the trial for darolutamide.3

All 3 of those agents demonstrated a MFS benefit. Abiraterone has been tested in the nmCRPC space, but in a single-arm trial called IMAAGEN [NCT01314118], and it was not placebo controlled so it’s not approved in this setting. Basically, the options are of 3 agents: apalutamide, enzalutamide, and darolutamide.

CHOUDHURY: Have you used all of those 3 agents in your practice, and what’s your impression on the differences?

STRAUSS: I haven’t used the darolutamide, but I’ve used the apalutamide and enzalutamide.

They are pretty similar to me. Maybe apalutamide was a bit better tolerated in general amongst the patients that I’ve used it in, but enzalutamide has been around for longer and it’s been approved in other indications. So, I think physicians, myself included, have a better familiarity with it and a little more confident experience with it.

CHOUDHURY: Has anyone prescribed darolutamide? What’s your impression of darolutamide compared with the other agents?

DESHPANDE: I’ve prescribed it. I don’t have a vast experience of comparing [these agents]. The reason I would choose darolutamide, and the reason I have chosen apalutamide [in the past] was because of someone who I’m worried about either intense fatigue or [inability to perform] leisure activity affecting their quality of life. But I can’t say that I’ve noticed a huge difference between the 2.

CHOUDHURY: What are your thoughts if darolutamide was chosen? There was a risk of seizures seen in the early trials of enzalutamide. In fact, patients who had risk of seizures or history of seizures were excluded from the PROSPER trial and the SPARTAN trial. So, as far as the degree of difference between the agents, even with excluding seizures from those trials, there were a couple grade 3 seizure events seen in the patients who received enzalutamide in PROSPER, and a couple grade 1 and 2 seizure events in SPARTAN, whereas darolutamide does have significantly less CNS penetration than the other 2 agents and seizures were not seen with darolutamide in the ARAMIS trial.

CHOUDHURY: What [would you use] if a patient had PSA doubling time of 15 months? That’s now out of the range of the doubling time that was allowed in enrollment on the ARAMIS trial.

MALIK: I have used enzalutamide and abiraterone [before]. The more we learn about these agents, the more I think we understand that they have a survival benefit. But on the other hand, if there is a patient whose PSA doubling time is not really fitting [with the criteria used on the trial], then I think we can hold back on this agent and save on the toxicity for the patient. [I can also] explore some of the newer therapeutic options I have. [Maybe] there are a couple of [sites of] metastatic disease we could easily target with the radiation….I think this is an evolving field and I would rather keep my options open.

CHOUDHURY: So, your thought is that if patients doubling time is slow, then adding one of these agents early in the process adds adverse effects [AEs] and costs early in the process. You can use imaging to identify sites of disease early and at the time of progression and you could even consider radiation therapy alone rather than one of these systemic agents.

KOBRINSKY: I want to point out that if a patient was on antiepileptic agent, it may negate the enzalutamide or other agents’ possibility of seizures. As far as I remember, even in those trials with [events of] de novo seizures, the incidence of seizures was very small. In an ideal world, I would use enzalutamide in [a patient with seizures]…but in the real world it’s a different story, because of the danger of lawsuits I would probably go to another agent. But that’s not because I think it’s the right medical decision.

CHOUDHURY: Enzalutamide and apalutamide also have significant drug-drug interactions. At your institution, do you have pharmacists that you can run through the drug-drug interactions with these agents, for example, antiepileptic and make sure that it would not affect the patients’ levels one way or the other?

KOBRINSKY: It needs to be checked, but in my career as a doctor, I haven’t seen any case so far with drug-drug interactions that had clinical significance. Considering how much money and effort and information is spent on [evaluating these] drug-drug interactions, I really haven’t seen a single case of drug-drug interaction that had some clinical significance; maybe I was just lucky.

CHOUDHURY: The main drug-drug interaction for enzalutamide is induction of enzymes that break down other drugs. So really, what you would see as the interaction is that it would lower the levels of some clinically meaningful drugs. But a lot of the drugs that we use, if you see dramatic reduction of levels, you’re not going to see that have much of an impact on the patient except in very specific circumstances like the cardiac medications and the seizure medicine, which have a fairly narrow window.

My experience is similar to Dr Strauss’s, where the agents are similar in their tolerability. Apalutamide may have a bit less fatigue than enzalutamide but it does have a risk of rash in about 20% of people. Then you have to make a decision of what you’re more comfortable with and what you think that the patient can tolerate.

The key point with darolutamide is that there is less CNS penetration. When there was a discussion about how much less, there were some nuclear medicine scans that were done in [either] rats or mice where the CNS penetration of apalutamide was 2 times less than for enzalutamide, but for darolutamide it’s 46 times lower.4 So there is significantly less penetration of the CNS with darolutamide. I think most of us would say that a seizure history is a contraindication to using enzalutamide and apalutamide. Given that there’s another agent in its class that does not seem to lead to increased risk of seizures, that would be the favored agent for patients with a seizure history.

CHOUDHURY: Because there’s OS benefit in patients with a PSA doubling time of less than 10 months, the arguments for not using these agents dissipates. You’re paying more and getting more AEs early in the treatment paradigm, but if it prolongs OS—I think many people have said once the OS data were mature, and we saw a statistically significant improvement, that there’s a role and rationale for these agents.

If you did a PSMA PET scan or an Axumin patch and saw metastases, they’re still non metastatic by the definition of the trials, because on the trials patients had to have metastases by conventional imaging.

CHOUDHURY: If you have PSA-only metastases, how does that change your paradigm? Let’s say you did novel imaging and you saw a lesion; does that change your utilization of these agents?

DESHPANDE: I agree with you. I think all the trials were based on bone scans and CAT scans, so I think it shouldn’t change my opinion. But if I did see something on a PSMA scan and the doubling time was slightly greater than 10 months, it might push me towards starting one of these agents because I’m a bit more worried. You mentioned that you didn’t have trouble getting the agents [covered] if the doubling time was greater than 10 months. Was that in patients whose doubling time was 10.1 months or was it 15 months?

CHOUDHURY: They don’t ask as long as you document nmCRPC. Because it’s not in the FDA label, the doubling time, the insurance companies have never asked even though it’s in the National Comprehensive Cancer Network [NCCN] guidelines. That’s my experience.

However, they will not approve darolutamide outside of nmCRPC. So, if you have a patient with metastatic prostate cancer who has a seizure history, you need to fill out a letter of medical necessity to get darolutamide approved in that particular indication. Insurance will not approve it outside of its indication.

CHOUDHURY: Would you do radiation treatment to the metastasis alone for a patient with a single site of disease? Or would you combine it with the systemic treatment? Does the PSA doubling time matter in that decision for you?

DESHPANDE: I don’t think it would matter. I probably would bring it to a tumor board and ask the radiation [oncologists] to see if they could radiate that spot. I know it’s not based on any data, but my feeling from the STAMPEDE data [NCT00268476] would be that adding radiation to low volume, metastatic disease burden seems to be a good thing to do. I know that wasn’t based on PSMA imaging, but I guess we sometimes do things that are not completely based on phase 3 trials.

HASAN: I think it’s tough. I agree with the idea of presenting this to a multidisciplinary tumor board and discussing the pros and cons. Typically, when we treat oligometastatic disease, we’re doing it concurrently. We’re doing it with some type of systemic therapy. Usually, we’re seeing patients earlier when they’re still hormone sensitive, but if they’re not and we know they have metastatic disease, it’s still going to be beneficial for them to have a systemic agent, even though we think we can provide a longer durable response with radiation or whatever we’re targeting.

I think the goal here is to prolong the disease-free interval or metastasis-free interval as long as you can. So, is it better to see what the radiation does, then look at the PSA response, and then come back to it to [use one of these agents]? I think that makes sense. But do you think that there’s a synergistic effect? I don’t think we really have the answer. There are pros and cons that you go into. I know I’m comfortable in a setting where we’re doing radiation concurrently with the systemic therapy. I think that anecdotally, the results are better that way, but I don’t know.

SHAO: I agree with Dr Hasan. I would do the [radiation] to the site of metastatic disease and systemic therapy, we typically also include that.

CIRRONE: If the PSA doubling time is more than 10 months, I would give a patient the benefit of doubt and just treat the oligometastasis, and then hold off. If the PSA time was shorter, I would consider doing the medication.

KOBRINSKY: Not just prostate cancer, but for many other cancers, generally speaking, the more aggressive you are with oligometastatic disease, the more results you get in terms of duration of response, and even maybe OS. It’s hard to prove, but you can see in many other cancers that we are changing paradigm to go aggressively after oligometastatic disease. Even if you don’t cure the patient, they live longer and have better quality of life.

So, in this disease, I would be aggressive in using multimodality treatment. I would use radiation to the oligometastatic site and definitely would use maintenance with ADT plus one of the newer agents to maximize the potential of these agents and to make the burden of disease as minimal as possible. The lower the burden of cancer, the more chance any treatment can work. In real clinical practice, you see it over and over again, these people live longer; they have better quality of life. Of course, things happen and you need to be careful, but I would go aggressively with both treatments.

STRAUSS: I agree that it makes sense to go after oligometastatic disease, but I wouldn’t do it at the expense of using something that’s been proven to have OS and MFS data. If you’re going to use [both of] them, I would use them concurrently. I wouldn’t do it at the expense of the one that there’s more data for.

CHOUDHURY: I tend to agree. I think the hazy part of this, and this is where data conflict with the idea—your conceptual notions as what to do with PSA doubling time greater than 10 months and microscopic disease, because my inclination is similar to Dr Kobrinsky, which is that multimodality therapy using systemic agents and radiation treatments to try to cytoreduce to the degree possible seems to fit a therapeutic paradigm of decreasing the likelihood of developing resistant disease. However, you can see in NCCN guidelines that these agents are not recommended for PSA doubling time greater than 10 months. So, what should you do in your own practice? I think it has to do with your own inclinations and experiences, sometimes even beyond what’s in guidelines.

CHOUDHURY: It’s just so variable, because I think people who have prescribed a lot of enzalutamide know that there’s some patients who tolerate it very well and don’t experience AEs much more than what they experience with ADT alone. Then there are some people who have trouble with this—increased fatigue and mental fog. I would comment simply that I think most people would say that seizure history is a contraindication to using enzalutamide.

The rest is dependent on your experience and the patient in front of you. I have used darolutamide quite a bit and I find in my own practice that these cognitive symptoms and symptoms of gait instability that

leads to falls, it’s not something that I really see [with darolutamide]. I do see that grade 1/2 fatigue that’s slightly more than placebo that was reported in ARAMIS but not very much beyond that. It’s not associated with rashes, either.

I would say none of these agents have impact on pain to any significant degree. They all cause arthralgias to some degree and I would say that the results from the SPARTAN, ARAMIS, and PROSPER trials don’t show any real significant differences on arthralgias between the 3 agents.

MO: Patients on darolutamide [can] develop hypertension sometimes. How you manage those patients with hypertension?

CHOUDHURY: If somebody has grade 3 hypertension on enzalutamide, I think the management is to add antihypertensives and if [they are] refractory, you would reduce the dose of the enzalutamide. Now, if that’s a reason to switch to another agent that might cause less hypertension, that’s a conversation to have with the patient.

CIRRONE: Do you biopsy those PSMA or Axium PET positive lesions? A single initial presentation is not unreasonable to biopsy these lesions.

CHOUDHURY: In general, they’re small, that’s the definition of PET positive [lesions] that are not seen on conventional imaging. So the biopsy yield is pretty low. Our interventional radiologists are not going to go after these tiny sub-centimeter things. But if there’s something of reasonable size and in a reasonable location, you could biopsy to confirm. But I think the PET imaging is specific enough in most cases that you feel comfortable treating without a biopsy. I don’t know if our radiation oncologist would say anything otherwise.

_References:

_{1. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546}

_{2. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892}

_{3. 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}

_{4. Crawford ED, Stanton W, Mandair D. Darolutamide: an evidenced-based review of its efficacy and safety in the treatment of prostate cancer. Cancer Manag Res. 2020;12:5667-5676. doi:10.2147/CMAR.S227583}