Evan Y. Yu, MD

 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?

 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.

 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.

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.

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.

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.

 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?

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.

 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.

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.

 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]?

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?

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

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?

 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?

 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?

 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.

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?

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

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.

: 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.

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?

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.

 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.

 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.

 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?

 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.

 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.

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.

 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.

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

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

: One thing I discuss is that there are 6 regulatory approved agents in the United States that lead to a survival benefit for patients with metastatic castration-resistant prostate cancer. If you consider that patients who have microsatellite instability can receive pembrolizumab—that does happen in maybe around 5% of men with metastatic castration-resistant prostate cancer—that could add a potential seventh option for select patient populations. Pembrolizumab, as we know, is a PD-1 antibody that leads to many improved outcomes across many disease states. For an unenriched population with prostate cancer, there are ongoing trials in combination and in select populations. So, we still have to see, but certainly for microsatellite instability that drug can be used as well.

I think another exciting area in metastatic castration-resistant prostate cancer is the concept behind finding DNA repair mutations. This includes 

. This patient did undergo germline testing, but you could develop somatic alterations as well. That can happen in around 23% of patients with metastatic castration-resistant prostate cancer. About half of those patients in the studies had germline alterations. But biallelic alterations that are somatically occurring happen as well.

Now, when one has a DNA repair alteration, that might make them exquisitely sensitive to agents like PARP inhibitors. The PROfound trial recently showed an important progression-free survival benefit with the addition of a PARP inhibitor, olaparib, for men who have metastatic castration-resistant prostate cancer and DNA repair deficiency. We’re waiting to see what the FDA says, but that could come out as soon as this is posted. We’ll see. It could be very soon. But I anticipate that’s another treatment option to come.

And obviously there are many other exciting treatments. I think another thing that’s around the corner is novel radiopharmaceuticals—radioligand therapies, theranostics, as one might say—that are targeted towards highly-expressed proteins on prostate cancer like PSMA [prostate-specific membrane antigen].

For instance, lutetium is another radiopharmaceutical tagged to a small molecule that can find PSMA on prostate cancer cells. The randomized phase 3 VISION trial has completed accrual, and we’re waiting for results. Obviously, there are many other exciting areas that are being explored in prostate cancer, and I could go on and on forever, but those are some of the things that I think are right around the corner.

Case: A 66-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

A 66-year-old man presented with increasing difficulty walking and sleeping on his back due to lower back and hip discomfort

PMH: hypertension, medically controlled; no known family history of cancer

PE: DRE revealed a nodular prostate; otherwise unremarkable



Biopsy with TRUS showed adenocarcinoma of prostate

Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement

EBRT for 8 weeks + neoadjuvant concurrent, and adjuvant ADT for 2 years

At 6 months post-ADT follow-up; PSA 5.9 ng/mL

Patient reported continued back discomfort, difficulty walking and loss of appetite

Bone scan showed multiple lesions in the right femur and pelvis

Abiraterone + ADT was initiated for 1 year

Patient complained of increased bone pain in right femur

Treatment with radium-223 dichloride was initiated; 6 infusions completed and well-tolerated at post-infusion follow-up

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Rapidly Expanding Options in mCRPC

 Another thing that I didn’t previously discuss is goals of therapy with this patient. For every patient who I see with cancer, and especially those who have a life-threatening cancer—those with an incurable cancer like this patient—I certainly discuss goals of care.

I’m very forthright in counseling the patients on what the goals of our treatment are. If they’re somebody who can potentially be cured of the cancer, that’s always the goal if we can accomplish it safely and with good quality of life. However, if that’s just not possible, I let the patient know that. I talk to the patient about that. I always ask the patient if they want to know about prognosis. I don’t want to surprise anybody with numbers. Most patients do want to know their prognosis, but if they don’t, I respect that as well.

I generally do lay out what our goals are in advance, whether this is a curative therapy or whether this is a palliative therapy. But in prostate cancer, in particular, I emphasize that even palliative therapy can be used for many years.

I think it’s very important to give patients a prognosis, or some sort of a time frame they can think about and work with if they’re interested in that. The reason is so they can do good life planning, family planning as well. They can also feel reassured. We have many good treatments available. Generally, the course of the disease and the natural history of some other cancers are that they are more aggressive.

Our patients with prostate cancer can live for many years. It’s helpful for them to know that, and it’s helpful for them to know that there are many other treatment options that can be used down the road to help them accomplish their goals.

Setting Realistic Goals With Palliative Therapy in mCRPC

 Unfortunately, we’re facing challenging times right now. Obviously at the forefront of everyone’s mind is COVID-19 [coronavirus disease 2019]. That has significantly affected oncologic practices across the country, and the world. Being a part of a large comprehensive cancer center, many clinical trials have been put on accrual pause to limit extra visits for the patients and also to limit touch points for our clinical and research staff. I think that has been a challenge, and hopefully will be a short-term issue. We’re starting to come out of our darkest time with COVID-19, and things are starting to ramp up again. I know our center is slowly starting to open up some clinical trials.

There are many other considerations. This includes hospital beds, and ICU [intensive care unit] beds, and ventilators, in particular. Our center has made a real effort to try to limit hospital admissions of patients who don’t absolutely need to be admitted. That includes considerations of inpatient regimens, clinical trials with inpatient regimens, and even the thought of administration of drugs that have high potential for toxicity that might lead to the patients requiring inpatient admissions to the hospital.

This really affects how we think about cytotoxic chemotherapy agents. In some diseases, the myelosuppression can be very pronounced and very long-lasting. And febrile neutropenia risk is very high. We’re fortunate in prostate cancer, where that risk is not as high with single-agent docetaxel or cabazitaxel chemotherapy. However, it still happens, and it needs to be a consideration.

In my practice, it is certainly a discussion that we have. We are concerned that myelosuppression might increase a patient’s risk of COVID-19. And in that situation, when we have good alternative treatment options, we’re discussing this with the patient. And oftentimes, we’re choosing other treatment options.

So if we were to insert the COVID-19 discussion into this patient’s case that I just presented, I already find enough reasons to use radium-223 and to save docetaxel for later. But another consideration would be that I think the myelosuppression that radium-223 causes is at a much lower level and is a much lower risk than with a chemotherapy like docetaxel. And with that consideration, I think that emphasizes that this patient probably gained the best treatment at that time with radium-223.

There is one issue that wasn’t discussed in this case, and that’s the use of bone protective agents. We all know there are very strong data that support both denosumab and bisphosphonates for use to prevent skeletal-related events and the symptomatic skeletal events in those who have bone metastatic cancers. Certainly, that includes castration-resistant prostate cancer. There are also data for use of these agents in patients who might be at high risk for osteoporotic fractures.

Certainly, men treated with androgen deprivation therapy for prostate cancer are at higher risk of osteopenia and osteoporosis, and there are data to show that use of these agents can prevent osteoporotic fractures.

There are also some data from some database and retrospective analyses that show that these agents don’t cause antagonism with radium-223 and may be beneficial in combination. So that is a discussion I would have with this patient. I would personally add either a bisphosphonate or denosumab in that setting. I would probably use denosumab in this situation.

Significant Impact of COVID-19 on the Treatment of mCRPC

 In my mind, if I was taking care of this patient, the 2 drugs that I really would have considered would be docetaxel or radium-223. I think that the decision there comes down to many pragmatic factors. I can give docetaxel to somebody who is either asymptomatic or symptomatic. I prefer to give it to someone who is symptomatic and has metastatic castration-resistant prostate cancer. This patient was symptomatic, so it would have been reasonable to offer this therapy.

Radium-223 must be given to a patient who is symptomatic. When I think about the timing of these agents, it’s very clear that if you give radium-223 earlier—it’s 6 doses once every 4 weeks—you’re more apt to get all 6 doses into the patient. There are some data that shows that is associated with better survival outcomes. It’s hard to know whether that’s driven by those 6 doses, getting them all in, or whether that’s driven by the patient having a better prognosis. But it’s very clear that those who get 5 or 6 doses in seem to do better than those who get fewer doses in.

Now, that being said, there are a lot of practical considerations. If you give radium-223, you have to get insurance preauthorization. There are rules in regard to what the absolute neutrophil count, hemoglobin count, and platelet count should be. You can’t have visceral metastases. And for those practical reasons, patients’ counts are usually better earlier in the disease course. That’s because they haven’t yet received cytotoxic agents that might cause chronic myelosuppression. It’s also because prostate cancer can infiltrate the bone marrow. If it takes up space in the bone marrow, some patients can be suppressed due to disease involvement in the bone marrow.

That’s one of the challenges. For an agent that requires insurance preauthorization and has clear requirements and limits, you can’t have visceral disease, you have to have certain counts, it makes sense, pragmatic sense, to give it earlier rather than later. If I give it later after docetaxel, they’ve already had chemotherapy and that could be associated with myelosuppression. Well, the visceral disease tends to develop later in the disease course and that might prohibit use of radium-223. You know they might have marrow involvement that would lead to counts being inhibited.

There are no data that definitively shows that radium-223 should be given before docetaxel and that leads to a better survival benefit. But if you live by the theory that my goal is to help my patients live as long as possible with the best quality of life as possible, and to use as many of the treatment options as I can that prolong survival, then I have to think about just pragmatically taking all of these considerations into account. That’s why I like to use the radium-223 rather than docetaxel in this patient in that situation.

Additionally, the toxicities are low for radium-223. It could cause some myelosuppression. Since it’s degraded and excreted from the body rather than metabolized by the liver or kidney, it can go into the small bowel and can cause some diarrhea. But generally speaking, the toxicities are less than what is seen with docetaxel. In real-life practice, I haven’t seen more toxicities than what one would see when reviewing the randomized phase 3 ALSYMPCA trial that was published back in 2013. There have been some subsequent publications that show long-term safety to not be a concern as well either. Some people worry about giving radiopharmaceuticals and the long-term risk of developing a leukemia or a myelodysplastic syndrome, but we really haven’t seen significant challenges with that.

One thing I’d like to emphasize, that I mentioned earlier, is that it makes a lot of sense when a patient progresses on 1 line of therapy to not keep pressing down on that same pressure point.

For instance, if a patient progresses on abiraterone and you give enzalutamide, the results are not ideal. And, vice versa—abiraterone after enzalutamide. That’s because they’re all working via that androgen axis.

I mentioned that changing mechanism of action makes a lot of sense. This is a unique mechanism of action, as radium-223 sits on the same column of the periodic table as calcium. Therefore, if you think about it, calcium incorporates into bone. Prostate cancer, being a bone-predominant disease, causes osteoblast metastases, where there’s a lot of bone turnover. Calcium can sit in those areas. Likewise, radium can incorporate into those areas. It basically is an alpha-emitting radiopharmaceutical and has very potent kill. It can induce double-strand DNA breaks in the cancer without a lot of spread. So it doesn’t have as much myelosuppression as some of the older radiopharmaceuticals, like samarium-153 or strontium-89. So again, it brings a unique mechanism of action that fits with the biology of prostate cancer.

Pragmatic Considerations for Early Radium-223 in mCRPC

 This patient and physician provider chose to use radium-223. There are certainly many treatment options for metastatic castration-resistant prostate cancer. At this time, for an unenriched all-comers population, there are 6 options that are regulatory approved, FDA approved in the United States, that show a survival benefit. And so, whenever I see a patient, I like to run through what all of those options are.

Now, he’s already received 1 of those options. In the hormone-sensitive setting, he was started on abiraterone and prednisone. There are obviously novel hormonal agents that work via androgen signaling pathways. Abiraterone is a CYP17 lyase inhibitor, and it decreases production of androgens by 1 to 2 logs lower than what LHRH [luteinizing hormone-releasing hormone] therapy can do alone. But he had already received that.

Another androgen signaling inhibitor that he could have received that is approved in this setting is enzalutamide. However, we have good data that show that sequencing 1 novel hormonal agent after the next usually doesn’t lead to outstanding response rates or outstanding outcomes. I think it is very reasonable to consider going to an agent that switches mechanism of action.

Another approved agent in this setting is sipuleucel-T, and that’s an immunotherapy. The idea is you’re basically producing an androgen presenting cell that targets prostatic acid phosphatase, and that leads to a survival benefit. It’s ideal for patients who are asymptomatic or minimally symptomatic. It’s ideal for patients who have lower volume of disease and lower PSA [prostate-specific antigen] levels. In this situation, given that he was starting to become symptomatic—he was minimally symptomatic but was starting to become symptomatic—and because of the treatment course that he had, I think the choice of sipuleucel-T might not have been ideal.

Another option that I think would have been very reasonable to consider in this situation is moving on to cytotoxic chemotherapy. Docetaxel is regulatory approved for metastatic castration-resistant prostate cancer and can also be used to treat metastatic hormone-sensitive prostate cancer. In this setting, they used abiraterone in that situation. So for somebody who’s becoming symptomatic, certainly I think the risk-benefit ratio starts to fall in favor of giving docetaxel. Docetaxel, when efficacious, can improve pain symptoms, and that might be worth the adverse effects of chemotherapy. Cabazitaxel is another microtubule disrupting agent that is regulatory approved after docetaxel. I wouldn’t consider it in this patient since he had not received docetaxel.