Roundtable Discussion: Petrylak Examines Challenges From Updated Treatments in Metastatic Prostate Cancer

Daniel P. Petrylak, MD (Moderator)

Professor, Medicine (Medical Oncology)

Professor, Urology

Yale School of Medicine

Co-leader, Cancer Signaling Networks

Yale Cancer Center

New Haven, CT

PETRYLAK: We have 4 modalities [to consider]: 3 antiandrogen treatments [abiraterone (Zytiga), enzalutamide (Xtandi), and apalutamide (Erleada)] and docetaxel chemotherapy. [We can] probably include darolutamide [Nubeqa] also; given the positive data, it will [probably] get approved as well.¹ I think that would be interesting in terms of how we’re going to select from among the antiandrogen [options for different patients].

In terms of treatment-related effects, what do you think about the efficacy data? Do you think there’s any difference among these treatments in terms of efficacy?

BYEFF: I think that in the appropriate patient, docetaxel combined with hormonal therapy is probably the most effective.

PETRYLAK: Yes, I think that the PEACE-1 [NCT01957436] data look interesting, but again, we don’t have absolute proof.²

DRUCKER: Among the different hormonal or androgen-targeting agents, I’m not sure if there are clear differences between them. I think many people suspect that abiraterone is a little bit better. Maybe you’re aware of more data. I [generally choose] whatever I think will be better tolerated. I think that the combination of antiandrogen therapy with chemotherapy, a double-hit approach, perhaps will be better.

PETRYLAK: Yes, in terms of the antiandrogens, my feeling is they’re all similar. The hazard ratios from all 3 trials are very similar. I look at this in terms of convenience and toxicity, and there are different patterns in terms of toxicity. For example, abiraterone requires more monitoring than the other agents. You have to watch the LFT results. We’ve unearthed about 3 cases since I’ve been at Yale, patients who’ve developed autoimmune-type hepatitis related to abiraterone. We’ve also seen, certainly, LFT abnormalities and hypertension, which is an issue with all of these antiandrogens.

The issue of steroids is interesting from the standpoint that abiraterone does require steroids to prevent hypertension. But there are some patients who want to go with chemotherapy. It’s 6 cycles and you’re done; you don’t need to give steroids with docetaxel in the [context of] hormone-sensitive disease, so I think that there are choices.

Has anybody here experienced any cardiac toxicity with abiraterone?

MITTAL: I’ve had a couple of patients who had coronary artery events while on abiraterone for metastatic castration-sensitive disease shortly after [that drug] got approved,³ before enzalutamide and apalutamide were approved.^4,5 I did end up taking them off androgen-directed therapy at the time and continued androgen deprivation therapy [ADT] alone, with the understanding that when they progressed, we would put them on an alternative agent. I don’t think there was any special diagnostic test that would [have helped] me pinpoint the etiology [of the coronary artery events], but the timing seemed to match up, [with the events occurring] within 3 to 4 months of starting abiraterone.

PETRYLAK: Did they have preexisting cardiac disease?

MITTAL: They did, but at the time, they didn’t want chemotherapy, and I didn’t have an alternative. This was [soon] after the LATITUDE trial [NCT01715285].⁶

PETRYLAK: Looking back on the studies that got abiraterone approved for both hormone-sensitive as well as castration-resistant prostate cancer, these patients were selected. They had to have a baseline ejection fraction [and] no cardiovascular events within a certain period of time. When these drugs move on to the general population, the patients don’t necessarily fit the exact criteria that were [applied] in the clinical trials.

The group at Thomas Jefferson University has reported that there was an increased risk of cardiovascular mortality in patients who had preexisting events if they were treated with abiraterone. I haven’t seen similar analyses done for the other antiandrogens. Hypertension’s a big problem with abiraterone as well; that may be related to people trying [to reduce] the steroid dose. The issues with selection also include cost—abiraterone is generic, [in contrast] to the other agents. I think, also, it’s just simply easier to put patients on the other antiandrogens because you don’t have to monitor as closely. And of course, there are drug-drug interactions as well as comedication [to consider].

Does anybody consider the primary Gleason score [when selecting a] treatment? I generally don’t; I base [my selection] on what’s there at that moment. One interesting thing is the issue about molecular testing. When do you obtain next-generation sequencing?

DESHPANDE: I used to do it only when [a patient] had exhausted all treatment, but now, with so many new agents I try to get it at the very start. This way I know what to expect if I have to go to second line.

PETRYLAK: I think that’s important. I think, [first of all], that patients want a road map. They want to know what’s ahead of them and what the possibilities are. But also, very importantly, the rest of the family is involved. So, if you identify a germline BRCA mutation in a man with prostate cancer, then the sons, the daughters, the sisters, the brothers, they all have to be counseled because that could be a gene that was passed on.

The 2 [tests] that I think are absolutely required at this point are [those for] mutations of DNA repair and microsatellite instability. I’ve seen some spectacular responses to pembrolizumab [Keytruda] in microsatellite-unstable patients.

[Patient-related factors worth considering are] age, frailty, [and] comorbidities such as liver impairment. Compliance is important too; some patients who may not take pills [might be better suited for] a chemotherapeutic agent. So there are many factors that go into treatment choice.

What [do you consider to be] the typical patient [who would receive] chemotherapy?

NEWSOME: It’s always, obviously, a conversation. This gentleman said he wasn’t interested in chemotherapy, but the benefit [of chemotherapy], like you suggested, [is that] it’s only 6 cycles of chemotherapy and then you can stop and continue with ADT. I think a lot of it depends upon patient preference—whether they want to continue to take a pill indefinitely, as long as they tolerate it and as long as [the disease is] responding, or if they prefer a fixed amount of chemotherapy treatments. Obviously, comorbidities, such as neuropathy, always come into consideration.

PETRYLAK: And of course, now, with the PEACE-1 data, a patient who says, “Doctor, I want to do everything to maximize my chances.² Give me chemotherapy and give me abiraterone after that,” tends to be a younger patient.

As far as monotherapy with antiandrogens, what are your thoughts? What’s your typical patient [who would receive] either enzalutamide or apalutamide?

SONPAVDE: I think that, generally, I would [use] enzalutamide. I have not [used] apalutamide in patients with low–tumor burden, metastatic, hormone-sensitive disease. I’ve just not [used apalutamide] that much. There have been patients who have had problems with skin rash [while receiving apalutamide], something not seen with enzalutamide or abiraterone, so that’s been my preference.

PETRYLAK: I think that there is less central nervous system [CNS] penetration with apalutamide than with enzalutamide. There are some patients who can’t tolerate that. I generally don’t like to give enzalutamide in somebody who’s particularly frail because the CNS issues and seizure issues become important.

[What I find] sobering [is that] half of the people in this country are not using next-generation antiandrogens or chemotherapy. There may be reasons why patients don’t get this, either cost or comorbidities. But this should be discussed with every patient in this clinical scenario.

SHPARBER: What [do you think] about the [suggestion of] taking 250 mg of abiraterone with a fatty meal?⁹ You would save a lot of money [by doing that].

PETRYLAK: Yes, I have patients who do that. You save 75% of the cost in that situation, and that [idea] was based upon pharmacokinetics. The question is, how reliable is it to take the drug with food vs on an empty stomach? I think it’s a reasonable alternative for somebody who can’t afford the full dose.

SHPARBER: What about in cases where there was progression on the full dose of abiraterone? [In a situation like that], I made the patient take his full dose of abiraterone at 1000 mg with meals, [and] we still got a response for another year and a half.

PETRYLAK: Well, there could be dose-response effect. [Another] trick I like to use in castrate-resistant disease is to switch steroids. About 10% to 20% of patients who switch from prednisone to dexamethasone will respond. There are different ways that you can get the [longest] response period [possible]. The trouble is that switching antiandrogens generally doesn’t work for most patients. It’s something we all do in somebody who is frail and who doesn’t want chemotherapy, but it generally does not result in a good outcome.

BYEFF: I agree with your statement about mismatch repair [and] microsatellite instability. We had a family member who was treated at Fox Chase [Cancer Center]. He was 57 years old and looked like he was dying of castrate-resistant prostate cancer. He had huge nodal masses that were close to impinging on his spinal cord. They tried everything, including sipuleucel-T [Provenge]. I sent him to Johns Hopkins, and they tested him, which Fox Chase had not done, and he had a mismatch repair mutation. He was treated with pembrolizumab, and now, 3 and a half years later, you wouldn’t know there was anything wrong with him.

PETRYLAK: I’ve got a case just like this, and I’m saying to myself, “He’s been on pembrolizumab for about a year and a half. Do I continue hormone therapy?” Because his nodal disease is completely gone. For the 3% of patients with microsatellite instability, you’ve got to look for it because, when it’s identified, it can be lifesaving.

NEWSOME: Can I ask a question about BRCA? If you test someone with next-generation sequencing, and they don’t have a BRCA mutation, do you do germline testing?

PETRYLAK: I generally don’t. The opposite question is, if you don’t identify [a mutation] initially, do you look for a somatic mutation later? [It happens] very rarely [that a somatic mutation develops later], but I do [test for this] routinely in people who have changes in their clinical parameters. For example, if bone-only disease becomes visceral, I’ll look again [for mutations], usually with a liquid biopsy.

PETRYLAK: I generally regard the patient’s preferences and goals as important. If the patient is not [involved in] selecting the treatment, they’re less likely to be compliant. I think it’s important that the patient does have some voice in [the decision]; of course, there should be data to support [that decision].

KHANANI: For me, patient preference comes first. I practice in a rather underserved area where most of the people are [older], do not have much family support, and cannot come every 3 weeks for chemotherapy; [moreover], many of them would not want to be treated with chemotherapy but would rather [have] oral therapy. The goal of therapy is important as well.

Do they want to suffer from the [adverse] effects of treatment when [the disease is terminal]? Does 6 months or 1 year mean a lot to them? Do they have any goal, such as [seeing] a grandchild graduate next year? I think these things are important [considerations] in tailoring the treatment to the patient’s goals and preferences, and while they’re on chemotherapy, the reported outcome data [become] important.

I’ve had several [patient situations] where the [older] gentleman is experiencing [adverse] effects, but he doesn’t want to give up treatment because of his spouse. Even though they see that the patient is [declining] and experiencing adverse events [AEs], they focus on the fact that, “Hey, the PSA’s coming down.”

PETRYLAK: That, I think, is one way of trying to balance therapeutic intensity and quality [of life]. Because clearly, some patients get dramatic responses to chemotherapy, and their quality of life goes up. But then there are others, as you’re pointing out, whose PSA goes down but they feel miserable. What cost is that? This is a very, very big dilemma. I counsel patients, “If you are afraid of chemotherapy, just try a cycle or 2. If you feel that you’re benefiting from it, then [you can] keep on going. If not, then [you can] stop, and we’ll think of other things to help you.”

DESHPANDE: Patient preferences and goals of therapy are quite easy to obtain, but patient-reported outcome data are not that easy [to obtain]. I would like to see more [data and for those data to be] more available because I think [they are important] for us to know.

PETRYLAK: Yes, exactly. I think the more recent studies are now using [those data]. We didn’t see a lot of [those data] in trials from the early 2000s.

DONNELLY: With a lot of experience in breast cancer [and based on the] National Comprehensive Cancer Network guidelines, we absolutely preach [for the use of more] endocrine therapy and then chemotherapy. When the docetaxel data came out, we didn’t have these other drugs that we now have [for use] in prostate cancer. You would think as an oncologist that I would like chemotherapy, but I don’t. I would rather do something else if I could if the outcome is relatively the same and the quality of life is very different.

I think it should be looked at again, since we have enzalutamide, darolutamide, apalutamide, [and] abiraterone. Those were not established treatments when the docetaxel data came out.

PETRYLAK: Certainly, the [current, popular] sequence is to go with those agents first and then to go to docetaxel afterward. The real question is, is that the right way to do things? We don’t have a marker to tell us. It may be androgen receptor splice variant 7, [a biomarker for resistance to androgen axis–targeted therapies], but even that is not a great marker in this situation. [You make an] excellent point, and the real issue with chemotherapy, I think, is that you don’t want to miss that sweet spot where the patient could benefit.

MITTAL: I have used apalutamide for quite a few patients recently—patients who had progressed on abiraterone— who did not want chemotherapy [and who had] castration-resistant disease, and I didn’t think they would do well with enzalutamide. My perspective of apalutamide has been that it’s a reasonably tolerated drug, although I would like to point out that the incidence of hypertension with apalutamide is next in line to [that of] abiraterone. So if I have a patient who has uncontrolled hypertension and I cross abiraterone off my list, apalutamide is next in line to be crossed off the list because most patients tend to do better with enzalutamide.

I do think that, in terms of efficacy, both for castration-sensitive and castration-resistant [disease], these agents are comparable. I tend to focus on hypertension, CNS toxicities, and LFT-related derangements when I try to choose [among] these 3 different therapies.

PETRYLAK: Yes, I’ve seen hypertension with both. The hypertension mechanism’s probably a little bit different with abiraterone because of the excessive mineralocorticoids and the use of steroids in the situation. In general, the hazard ratios seem to be pretty much the same for all of these in the hormone-sensitive state. I think that these seem to be very, very similar across the board.

What’s the most challenging toxicity to manage? [In our experience] with abiraterone, it’s been the liver function abnormalities.

DESHPANDE: We just had an admission for someone who had a seizure. He was being treated with enzalutamide. I would say for me, I don’t mind neutropenic fevers and stuff like that, but neurological toxicities scare me the most.

PETRYLAK: I have never seen an enzalutamide- or apalutamide-related seizure, but I think that they’re there. In fact, Bristol Myers [Squibb] was developing a drug [that was] very, very similar to both agents, well before these were approved, and they pulled the drug because of seizure issues. I do think that [seizures are] a concern.

DRUCKER: [There is], I think, a more insidious toxicity. Obviously, seizures and neutropenic fevers are dramatic and severe, but [in the end what happens is that] the patient’s more tired, they have less muscle mass, they’re getting fat, and that’s what they start complaining about the most, [even though] they’re not highly symptomatic from [the] disease. And I don’t have any way to make their energy any better.

PETRYLAK: That’s bringing up an important point in managing all toxicities with our patients. When I discuss hormone therapy with our patients, the first thing I ask the patients is, “Do you have an exercise regimen?” That helps with the fatigue, it helps with the weight gain, it helps with the muscle mass issues; weightlifting is especially helpful.

There’s a great book that I’ve often referred my patients to. It’s by an 86-year-old lawyer named Fred Bartlett, [and he] looks [like he’s] 60 years old. This man pumps iron like crazy, and he believes that’s one of the keys to aging well.

We all [see our patients] lose muscle mass, and we all see falls in patients. With some of these drugs, there’s a higher rate of falls in some of the clinical trials.

There are some things you can’t do chronically with these patients when they’re on hormone therapy, they all do feel tired. [It is often said] that men feel as if the wind’s been knocked out of their sails [due to this therapy], so that’s something we have to keep in mind. Of course, with the bone [issues], all patients must be on calcium and vitamin D to prevent bone mineral loss. I think that in the early stages, these [things] can help patients maintain a good quality of life.

DRUCKER: To take another lesson from the breast cancer community, I know for our [patients with breast cancer], though usually for [patients with] early-stage [disease], there’s an institution-supported physical therapy rehab program. I think it [is worth considering] something like that [so we could tell patients], “Here is your antiandrogen therapy, and here is your referral to our survivorship clinic.”

PETRYLAK: Yes, I think you can’t emphasize that enough with our patients. Preventive medicine’s a good thing.

BOYD: One of the problems is that the [patients] may be slightly frail, but we make them much frailer. And the second consequence of endocrine therapy is insulin resistance, [which] increases the risk of diabetes and cardiovascular disease. That is another adverse outcome that sometimes [leads] to higher mortality with our treatments. So we need to address all of those secondary consequences earlier rather than later.

PETRYLAK: The number 1 cause of death in men with prostate cancer is cardiovascular disease.⁹ That’s got to be kept in mind.

PETRYLAK: Dr Mittal, you treat a lot of patients with apalutamide. Is there something different that you do?

MITTAL: I do have some frailer patients from the central Massachusetts area, similar in description to Dr Khanani’s patients. I bring them back in [at] about 3 or 4 weeks for a toxicity check visit. [This is] to make sure that they’re doing OK and to evaluate them for dose reductions if needed, just to ensure that I’m titrating the dose to the quality of life, since they’re going to be on these medications long term. Then I see them at a 6-week visit before I switch to 3-[month] follow-ups.

PETRYLAK: The other thing I look for with these patients is hypothyroidism. We check their thyroid function tests very regularly. It is different than [when using] docetaxel and prednisone, as you’re usually looking at neutropenia. You basically give the docetaxel and prednisone, and then you simply watch the patient’s PSA levels or do imaging. The controversy is how often do you image castration-responding patients? And do you find the “neuroendocrine undifferentiated tumors” that way? I generally will image somebody based upon symptoms or PSA level.

SONPAVDE: In general, I agree with you. That’s what I have been doing. One of the things that is done here [at Dana-Farber Cancer Institute is] to get a scan somewhere near the nadir of the PSA, just to get a new baseline with which you could compare when patients have PSA progression later. I’ve felt that could be useful in select patients, so I’m adding that to my practice.

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