Roundtable Discussion: Yu Explores the Role of Hereditary Germline Testing in Nonmetastatic CRPC

Evan Y. Yu, MD

During a Targeted Oncology Case-Based Roundtable event, Evan Y. Yu, MD leads a discussion on hereditary germline mutations impact on prostate-cancer risk.

YU: If a patient had family history of breast cancer and pancreatic cancer, is there a role for hereditary germline testing in that patient?

KOSIEROWSKI: I don’t see why [you would]. You have to treat them with standard therapy anyhow, so I would hold off until they failed standard therapy.

ZHANG: I would check it right now if the patient is starting off with high-risk disease. I think right now National Comprehensive Cancer Network [NCCN] guidelines recommend patients with localized high-risk disease or metastatic disease should all undergo germline testing.

YU: I think for high-risk localized disease it’s not exactly clear because the risk of harboring...an actionable alteration or a DNA repair gene alteration is probably somewhere between the 3% to 7% range depending upon which study you look at. For metastatic disease it’s much clearer at 12%. If you ask a geneticist, they’d say any incidence greater than 10% they would definitely test.

ZHAO: Based on NCCN guidelines for high-risk disease, or very high-risk group, they do recommend considering germline mutation testing.

Knowing a patient has family history of breast cancer at a young age...makes the case stronger. I agree that the percentage of germline testing positive is probably not that high if we screen everybody with high-risk or very high-risk disease, but I would follow the guidelines to go over those kinds of options with every patient with high-risk disease.

ZHANG: There are [multiple] purposes of germline testing for patients [with hereditary disease]. One is to inform [them about] treatment options, another is prognostic, and also to inform other family members. So if a patient has a son or siblings, then it’s good to know.

YU: I completely agree. Although I agree with what Dr Kosierowski said—that even if you were to find....a BRCA2 mutation, I wouldn’t reach for a PARP inhibitor right away. I would use it in the later disease state, where it has clear indications. But I think the real reason to strongly consider it is strong family history and also the fact that doing germline testing is not just about finding a therapy; it is also about identifying risk for siblings, for offspring, and first-degree relatives. Many of these alterations predispose not just the prostate, but to breast, ovarian cancer, etc. You might save a lot of lives down the road if you do that.

YU: When do you restage or image a patient? Do you have prostate-specific antigen [PSA] doubling time, a certain PSA cutoff, or do you do it before you think about starting therapy?

XIE: That’s a good question. I don’t have a set rule. I think if the PSA is rising, it makes you concerned. That’s the time to scan the patient.

MITIN: I try nowadays to image all patients before the initial treatment, so especially patients with high-risk disease. I realize many of those patients harbor metastatic disease that’s only going to be seen on PET/CT scans with either fluciclovine [Axumin] scans or prostate-specific membrane antigen [PSMA] scans. I try as much as I can to get patients those scans, even though often they have to pay out of pocket.

In case of biochemical recurrence after any initial treat-ment, be it surgery or radiation therapy, we are able to order Axumin PET/CT scan for all those patients. The problem is that when the PSA is low, when they are referred to us for salvage radiation therapy, usually Axumin PET/CT scan is not very sensitive. PSMA PET/CT scan is much more sensitive, 40% sensitivity with PSA between 0.2 and 0.5 ng/mL, so I try to go for PSMA PET/CT scan and send my patients to University of California, Los Angeles.

YU: The vast majority of people said add a novel hormonal therapy. Whoever selected “add a first-generation antiandrogen,” I’m curious if that somebody would like to give their rationale why.

ZHAO: I chose that one. There’s no great reason; they are just cheap. It’s easy, and sometimes you get a very durable response. The quality of life is great.

YU: If a novel hormonal agent was [used, would you select] abiraterone [Zytiga], apalutamide [Erleada], darolutamide [Nubeqa], or enzalutamide [Xtandi]?

TIRUMALI: There is probably the largest amount of experience with abiraterone/prednisone right now. We know what the long-term adverse events [AEs] are, and we know what the efficacy data are. There are also some data suggesting that initial administration of abiraterone, and then later administration of enzalutamide, might be OK in some patients, rather than the reverse sequence. The data from MD Anderson Cancer Center about sequencing also supports the use of abiraterone up front. Similar data for apalutamide and darolutamide are not available yet. So that’s the reason for choosing abiraterone/prednisone.

YU: Anybody have a rationale for picking darolutamide?

KOSIEROWSKI: I think it’s the best tolerated of the medi-cations, [with] the least toxic AEs.

ZHAO: Darolutamide [has] level 1 data and probably much better progression-free survival compared with bicalutamide [Casodex], so there’s no question about it. There are also very few drug interactions between darolutamide and other medications.

YU: It still has some, but it has the fewest drug interactions of these agents. If a patient had seizure disorder and was on antiepileptics, how much does that matter?

ZHANG: I think darolutamide has no central nervous system penetration.

YU: It has the least [drug interaction] because it’s biochemically, structurally different. That’s a good point you’re bringing up; it’s a subtle point. But there are contraindications—some of these agents like enzalutamide and apalutamide cross the blood-brain barrier. It’s thought that enzalutamide crosses quite readily and has interactions with γ-aminobutyric acid receptors that interact with androgen receptors in the brain. Apalutamide is thought to have less, and darolutamide is totally biochemically, structurally different, and is felt to have the least [central nervous system penetration].

Interestingly, patients with seizure, or at higher risk of having seizures based on their medication profile or on other history of strokes, were mostly excluded from the enzalutamide and apalutamide clinical trials. But because darolutamide is felt to have the least crossover through the blood-brain barrier, those patients weren’t excluded from the darolutamide clinical trials. So I would probably select darolutamide [in that situation] because of my concern with seizures. Because I know that there were patients with seizures and higher risk of developing seizures on the randomized phase 3 trial [of darolutamide], I think that’s probably the safest choice.

YU: What other factors influence your ultimate selection?

ZHANG: Financial.

YU: That’s always a key factor. That’s variable, but in your experience, what situations have you run into regarding cost and especially patient co-pay issues with all these agents?

ZHANG: My general experience is the cheapest of the 4 is still abiraterone. Most patients’ co-pay, regardless of insurance, varies between $0 and $500. Enzalutamide and apalutamide can be up to maybe $2000 per month co-pay. It’s crazy. Although we were able to get patients some funds, how we are going to get funds for so many years? I don’t know exactly the co-pay for darolutamide.

KOSIEROWSKI: All my patients get their medicine for nothing. We’re talking about overall cost. Basically, they’re all $10,000 a month. They have insurance, you get a discount, you have a co-pay, but the total cost to society is about $10,000 a month for each of them.

YU: Yes, I think that’s approximately right. What if the PSA doubling time was 15 months? Would that affect your treatment decision-making?

XIE: Then I would either wait or sipuleucel-T [Provenge] is something to think about, but I would probably wait.

YU: You’ll observe the patient longer. I think that’s reasonable because [for 1 trial], the eligibility criteria was 10 months or less PSA doubling time [NCT02200614], and about 70% of the patient population [had a PSA doubling time of] 6 months or less in just about all the trials [in this setting]. With that being said, it’s not wrong to treat somebody [with a PSA doubling time of 15 months with darolutamide], but I would say that it doesn’t necessarily fit in the label.

As a matter of fact, I don’t think the [darolutamide] label designates the PSA doubling time; it’s just the eligibility criteria that do. But then, the label’s looser, and it lets you make your choice. You could certainly treat, but you could also argue that we know PSA doubling time in this situation is a good prognostic marker, and if it’s really long, we might observe. Even though the AEs aren’t awful, there are still AEs to everything, so it’s very reasonable to observe the patients.

YU: What are your personal experiences with darolutamide [or the other agents]? What do you think is the biggest difference if you were to use darolutamide versus any other of these drugs? If you don’t think there’s any difference in your experience using these drugs, please tell me that you haven’t noticed any difference in terms of comorbidities or AE issues.

KOSIEROWSKI: I don’t think I’ve seen any real difference. I probably have seen more patients with abiraterone. May 2021 | Case-Based Roundtable Meetings Spotlight 35I think darolutamide looks better on paper, but in terms of real patient experience, I can’t confirm what’s in the studies.

ZHAO: I think darolutamide is better tolerated....compared with apalutamide and enzalutamide.

YU: In your personal experience, what are the toxicities that you think are better?

ZHAO: Fatigue, light-headedness can sometimes be seen with enzalutamide, and sometimes quite serious dizziness, but I have not seen this in darolutamide. Muscle and joint pain is pretty pronounced with enzalutamide, but not so often in darolutamide.

TIRUMALI: In my experience with these medications, I cannot see a significant difference between darolutamide and apalutamide. Enzalutamide is probably a little bit [harder], in terms of AEs, especially fatigue.

YU: I think that’s fair. Sometimes it’s hard to tell, and if the differences are subtle you must really treat tons of patients with each one before you really can tell a difference. Sometimes you just get unlucky, too. For instance, with apalutamide, there’s [chance of] a rash, but for the longest time I never saw it. I used a lot of apalutamide, and I’d see what was cited in the literature, and I’m [thinking], “Well, it’s not that high for me.” Then, all of a sudden, I did see it, and I’ve only had probably 1 patient with a really bad rash, but everybody talks about the rash. But I don’t think I’ve seen it as much. So sometimes you get lucky or unlucky.

YU: Dr Mitin, the radiation oncologist, you were saying that you’d consider getting PSMA PET imaging, and even doing oligometastatic-directed therapy for this patient population. So what do you do with this? Let’s say you get a PSMA PET for a patient and you find metastases. But the trials in real-world patients were without PSMA PET; they just used standard bone scans and CAT scans. How are you going to use that information in this situation, and how will this affect what you do?

MITIN: I think that the jury is still out in terms of whether the ablative radiation therapy on oligometastases leads to improvement in overall survival. We know it delays the subsequent systemic therapies or it buys more time for these patients. The Johns Hopkins study has shown that ablating all PSMA PET/CT visible lesions is much more potent than ablating lesions only visible on the conventional imaging. So I think that this is just to help patients stay on the current systemic therapy and control the disease that is visible.

YU: What you’re saying is that you would consider oligometastatic-directed therapy in select patients, but you would probably do it in combination with systemic therapy. You would start them on one of these agents, like apalutamide, darolutamide, or enzalutamide and then if it just was maybe 1 or 2 metastases, you’d consider ablating it in that situation.

ZHANG: I probably wouldn’t do it at this time. I think the main concern here is cost, and it’s probably not going to change how we manage the patient right now. In the future, if we widely use PSMA PET, maybe the M0 castration-resistant prostate cancer space is going to be closed.

YU: We’re starting our PSMA PET imaging program. We already started using PyL, but we’re doingGallium 68 PSMA-11 of a protocol in investigational new drug application; that’s going to kick off in about a month. But we’re going to be pretty limited in our approach right off the bat, doing very select patients, not for everyone. In this disease setting, because we have good agents like apalutamide, enzalutamide, and darolutamide, I don’t feel as compelled to do it.

I’m more doing PSMA PET for the patients with biochemical recurrence, still on the castration-sensitive disease setting, where the patients may have had radical prostatectomy, salvage radiation, and their PSA’s going up, and they want to give local therapy a last good shot before they move on to systemic therapy, [for example]. That’s where I’ve been doing more of it. But there’s no clear right or wrong answer yet; we’re going to have to learn as time goes on. The National Clinical Trials Network has multiple trials that are starting. So we’re going to learn more in maybe a decade from now, because it will take that long for these studies to read out.