Around the Practice: Improving Outcomes in Advanced Prostate Cancer - Episode 9

Recap: Recent Advances in the Treatment of Metastatic Prostate Cancer

Experts in prostate cancer discuss recent advances in the treatment of patients with metastatic castration-naive and metastatic castration-resistant prostate cancer and strategies for optimizing therapy.

At an Around the Practice presentation hosted by Urology Times® in partnership with Large Urology Group Practice Association (LUGPA), a panel of experts discussed how to optimize therapy for patients with metastatic castration-naïve (CNPC) and castration-resistant prostate cancer (CRPC). The discussion was moderated by Raoul S. Concepcion, MD, FACS, chief science officer of US Urology Partners in
Nolensville, Tennessee.

Castration-Naïve Prostate Cancer

To begin, the panel directed their conversation to a case of a patient with (CNPC).

HAFRON: Metastatic disease represents a wide spectrum of disease. Historically, we would look at the patient’s metastatic disease and put them on androgen deprivation therapy [ADT], but there are a lot of nuances with metastatic disease, especially castration-naïve disease. Specifically, what’s the timing of the metastatic disease? Is it de novo? Is it metachronous? Is it a failure of a primary therapy? Most importantly, what’s the number of metastatic lesions? When you look at these patients, you [must] understand that all metastatic disease is not the same and that there are these small nuances, whether they’re high volume—4 bone lesions outside the spinal column, pelvis, or visceral [metastases]—or low volume, if there are less than 4 lesions. On top of that, where is the metastatic disease? Is it bone, lymph node, or visceral? Once you understand the nuances, you’ll better understand the literature and published clinical trials, so you can apply the newer therapies and the combination therapies that are available.

SARTOR: This will be low-volume metastatic disease by the CHAARTED criteria. It’s interesting, if you look at the de novo patients, there may be some additional benefit from docetaxel, but it’s probably more problematic than 1 of the hormonal therapies. I’ll simply say that the data with abiraterone acetate [Zytiga], enzalutamide [Xtandi], and apalutamide [Erleada] may be a little better here.

A couple other points I’d like to add: We should get germline genetics on this patient, [as] that’s part of the [National Comprehensive Cancer Network] guideline, [and] with a single focus of bone metastatic disease, I may want to know [whether] there [is] more to this story. I may get a prostate-specific membrane antigen [PSMA] PET scan on this patient to determine whether he really is oligometastatic. If we look at the STAMPEDE [NCT00268476] data on a low-volume patient like this, it should radiate the prostate and have level 1 evidence to demonstrate that radiation to the prostate can prolong survival. I would consider metastasis-directed therapy, even though that’s a little more controversial. In my practice, I would try germline genetics. I do not necessarily need any somatic genetics right now. I’d get a PSMA PET scan and I would plan on radiation to the prostate. I would be using ADT plus a novel hormone, and I would consider the possibility of metastasis-directed radiation.

GOMELLA: The problem here is that you have a whole host of level 1 evidence options to treat this patient. You have everything from basic ADT through docetaxel plus ADT, or many of the novel oral androgen receptor pathway blockers. Then you complicate the treatment decision further, making Dr Sartor’s point about treating the primary, then considering treating the oligometastatic lesion.

One of the issues is, [although] this is a low-volume metastatic patient and docetaxel may not be his best option, very often there’s what we sometimes call “financial toxicity” associated with many of the novel oral agents. The pharma companies can sometimes help certain patients with the cost. [Although] the data would suggest docetaxel plus ADT is not a top-line treatment, this may be [the] best option [for] a man who has limited resources for $8000 to $10,000 a month for these oral agents. [Although] there are data for low-volume metastatic disease that ADT plus docetaxel may not be necessary, there may be individual considerations to guide the quickest, easiest, and least financially toxic way to treat this man [which] might be a chemotherapy regimen.

PETRYLAK: I have a case just like this right now, a castrate-resistant case, where we found all the lesions regressed, except a new lesion, and we can’t find anything on conventional imaging in bone. The question is: Would you deny a patient who is oligometastatic—4 lesions, for example, and you find 20 on a PSMA PET—do you then change their management, because we use the conventional imaging as our way of determining whether they have extensive disease? A PSMA PET is a great thing to do, but at this stage, we need to understand how we are going to use that in our management.

SARTOR: You’re making a great point because all our level 1 data are built around conventional imaging. As we introduce PSMA PET, it begs a whole new series of questions to which our level 1 evidence does not apply. I mentioned metastasis-directed therapy, but I may get a PSMA PET scan. This patient may not have 1 lesion to the bone. He may have 14, then it becomes a whole different scenario. As we gain new imaging insights, we also [must] ask new imaging questions and address it with clinical trials to have the best answers.

CONCEPCION: Given the fact that he has low-volume disease on conventional imaging, would you push for molecular imaging?

HAFRON: Yes, I would. We’re getting into a space that we don’t really have data on. But just looking at this case, I would give localized therapy to this patient, then probably transition to novel hormone therapy.

The issue with PSMA and finding more bone lesions, like Dr Sartor said, it’s up for grabs right now. It’s hard to apply the old literature to this new imaging. But with this case, I would offer localized therapy based on STAMPEDE. I’d also like to bring up SW0G 1802. This is a major [ongoing] US trial [that is] looking at radiation therapy, or even surgery for advanced disease. The key is that we’re moving away from single-modality
therapy and clearly moving into multimodality therapy. How we apply it with this new imaging—I guess we’ll have to wait for Dr Sartor and Dr Petrylak to create some great trials to make that connection to the past.

CONCEPCION: Your point is well taken [about] the SWOG trial because we are finally moving for these patients with high-risk, high-grade localized prostate cancer, or in this particular case, which seems to be an oligometastatic disease. To me, that is the way it’s moving, given the fact that now we have better systemic therapies beyond ADT. Dr. Sartor’s point [about] how we incorporate hereditary germline and somatic testing is also going to be key as we launch into this era of precision medicine.

When you see these patients with de novo metastatic castration-naïve disease, does the volume of disease play a factor for you relative to your therapeutic options?

PETRYLAK: Yes, the volume of disease, age of the patient, and comorbidities all play important roles. Recently, the PEACE1 trial [NCT01957436] came out, where patients received standard-of-care docetaxel, then were randomized to receive observation or abiraterone. There was a significant improvement in [radiographic progressive-free survival] in those patients who received docetaxel and abiraterone. Although there wasn’t an abiraterone-only arm, which would have been wonderful for that study, this is something I’m obligated to discuss with my patients. I’m going to look at the age, the aggressiveness, the comorbidities. Abiraterone may not be an appropriate drug for patients with preexisting cardiovascular disease because it can cause hypertension. There have been some reports out of Dr Gomella’s institution of an increased rate of cardiovascular morbidity in patients who are treated with abiraterone who have preexisting cardiac conditions. I’m going to look at my patient in terms of what the long-term goal is, how long they’re going to be treated, what their overall performance status is, and their volume of disease.

SARTOR: We have data in the castrate-resistant setting for taking 1 abiraterone with food as compared [with] 4 without food. There’s also a Canadian trial that had 2 with food as opposed to 4 without. In each of those trials, both of which were relatively small, there did not appear to be a difference between the 1 with food or the 4 without food. There are no data in castrate-sensitive, but for people whose financial toxicity is substantial, you can basically cut the price of the drug by 75%. If you think abiraterone is appropriate and financial toxicity comes to the fore, you could drop down to 1 or 2 abiraterone with food. It’s not FDA approved and not proven, but it’s something I’ve done in practice when faced with that problem.

CONCEPCION: Has anybody looked at pharmacokinetic [PK] levels, abiraterone levels, or enzalutamide levels to see metabolism, bioavailability, and those types of things with PSA response?

PETRYLAK: We know the PK of docetaxel is different if there’s testosterone on board. Now if you want to avoid that, perhaps you would wait. In most of these trials, you administer abiraterone within 3 months of starting the initial ADT. If the testosterone is down to castrate levels within a month, I don’t think the PK will make much of a difference. It’s probably going to be about the same, so you probably can get away with it. If you want to formally evaluate that, you’d have to do that right at the time you’re castrating the patient, but it’s probably not going to be any different. [However], Dr Sartor raises a very interesting and important point.

GOMELLA: Do any of you have experience with the generic forms of abiraterone vs the original Janssen product?

SARTOR: The price is better. It’s hard to evaluate. I know you can go to Costco and get some good deals. It’s hard for me to endorse anything beyond that because I can only speak to price. I can’t speak to efficacy.

PETRYLAK: That’s a very interesting point. I have not seen much of a difference in price with the generic. It may be regional and dependent upon insurance, but thus far, I haven’t seen much of a difference.

HAFRON: To expand on that, the problem with the generics is you can’t get foundation support. So, it sometimes works against you if you can’t get that foundation support for a generic. It seems counterintuitive, but sometimes it’s more challenging to write for the generic medication.

Choosing an Optimal Therapy for Patients With Metastatic CRPC

Continuing the discussion, the panelists turned their conversation to a case of a patient with CRPC.

CONCEPCION: What are your thoughts relative to this patient?

HAFRON: I like to get somatic testing up front. It’s probably not going to make a difference at this point, but I would like to understand the pathology of his disease, and [it] helps me guide the patient's expectations and disease. I would get him on bone-resorptive agents, because there’s more and more literature saying it’s important to get that started right away. We evaluate the patient’s fitness for androgen receptor inhibitors for abiraterone [Zytiga]. We also talk to them about whether they can tolerate chemotherapy. The key is having that discussion with the patient using the shared decision-making model, understanding what their goals are, looking them over from head to toe, and seeing what the best treatment regimen [would be], but it would probably be sipuleucel-T [sip-T] plus an oral [agent] in our institution.

CONCEPCION: What are your thoughts about somatic testing early on in somebody like this, who’s never seen a line of therapy?

PETRYLAK: The yield would be pretty low. Usually, I like doing somatic testing when there is a change in condition. This patient is accelerating fairly rapidly, so it’s possible you’re going to see something, but at the beginning [of] castration-resistance is the time I would check for.

Treatment-wise, this is a dilemma because he is out of the category where I would use sip-T. What I mean by that is the absolute PSA value. I like to use sip-T early, generally if the PSA is less than 22 ng/mL, which is an indirect measure of the volume of disease. The patient does have 2 lesions on bone scan, so you’ve got a really low-volume disease, but [it is] rapidly progressive. If you’re going to give sip-T, I would consider giving it in this particular situation prior to chemotherapy or second-generation hormones.

SARTOR: I’m very similar to Dr Petrylak on this one. The patient is borderline for sip-T because of the aggressive nature of the progression. The people who tend to do a little better on the sip-T are those with a little more indolent disease.

In terms of the testing, it’s reasonable to consider somatic testing, and you can either do it now or do it later. I sometimes find that if the biopsies are done elsewhere, you can shuffle around for a month or so before you even get tissue to do the somatic testing. If I know I’m going to need it—and I know I’m going to need it in this patient—I might go ahead and try to get the somatic testing relatively early, even though I don’t know what to do with it at the time I get the results back because I’m probably going to use the secondary hormone.

Now, the one point I’m going to raise—and this gets into a future category that is very undefined—is that the PROpel study [NCT03732820], which is a combination of abiraterone and olaparib [Lynparza], has been reported by a press release that it is positive. I don’t know what that means. It’s positive in the eyes of the manufacturer, which may not be the positive I want to see, but it raises this new question about PARP inhibitors coming up front. There’s another study, called TALAPRO-2 [NCT03395197], looking at enzalutamide in combination with talazoparib [Talzenna]. We don’t know anything about that, but I would simply say that if PROpel is positive, maybe TALAPRO-2 is going to be positive, too. So even though we’re locked into considering these novel hormones [today], it could be that combination therapies will play a role in the near future. We’ll hear about it at [the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium], but we just have to learn more.

CONCEPCION: Dr Gomella, we believe the indication for prostate-specific membrane antigen [PSMA] is anyone for whom you’re worried about metastatic disease. Axumin [fluciclovine F 18] has been available, and that indication was for patients who have failed therapy. What are your thoughts in this patient because he has obviously failed therapy? Comment, if you will, on the pluses and minuses of Axumin vs PSMA.

GOMELLA: Since the May FDA approval of the second PSMA-targeted imaging drug, piflufolastat F 18 [Pylarify], our team at the Sidney Kimmel Cancer Center has basically become an exclusive PSMA PET shop for our high-risk patients. It’s been shocking how it is changing our management of patients. I’ll give you 1 example: A person had a radical prostatectomy about 25 years ago and has a slowly rising PSA over many years, getting up to 2.5 ng/mL. We put him on intermittent ADT, and ultimately continuous hormone therapy, with an excellent long-term PSA response. He then began to manifest castrate-resistant disease when his PSA went to 1.5 ng/mL. Standard imaging was negative, but PSMA PET showed he’s riddled with extensive metastases. There have been concerns expressed on how to use PSMA today, particularly in the context of current clinical trials, but PSMA PET is completely changing how we manage our patients who are not on a trial.

Obtaining authorization here in Philadelphia for PSMA PET with a Medicare patient, we have no problem. We do have challenges with Medicare supplemental or with men under the age of 65. Even though it has been incorporated into National Comprehensive Cancer Network guidelines, the amount of time we spend going through peer-to-peer reviews and other approval burdens make it very difficult. But there’s no question that the current piflufolastat F 18 PSMA we have been using as a standard-of-care imaging study is going to significantly reduce the use of the other prostate cancer PET imaging agents, such as Axumin, that we have been using. There will be another generation of PSMA-based PET imaging and other targeting agents in development that will continue to revolutionize our understanding and management of prostate cancer.

CONCEPCION: Are you routinely using it for staging, especially in high-grade [or] high-risk?

GOMELLA: Yes, we use it in any man who has a high-risk feature. Our challenge is that the patient population we’re considering for radical prostatectomy—high-volume disease, like this gentleman, under the age of 65—it’s very difficult for us to get the scan. I had a recent patient who had insurance denial and who was able to pay the $6500 out of pocket. But yes, we’re using it more and more for staging. We have clinical trials using the PSMA-based 18F-DCFPyL PET/CT followed by radical prostatectomy in collaboration with the National Cancer Institute. Our Sidney Kimmel Cancer Center was also involved with the therapeutic VISION 177Lu–PSMA-617 trial [NCT03511664] led by Dr Sartor. We are big believers of the power of PSMA PET redefining prostate cancer.

CONCEPCION: Dr Hafron, is PSMA available to you in the Detroit area?

HAFRON: It’s not widely available yet. Our hospitals are just getting it online. Dr Gomella said it best. It’s going to redefine prostate cancer. We’re going to be in places we never imagined. It’s disruptive technology. I am so excited to use this technology, and Medicare is going to cover it [in] 2022. I think that’s just going to be our go-to test for staging and a great option for recurrence.

CONCEPCION: For our audience, it’s important to understand there are different agents and different labels. There is Pylarify, then you have [Gallium 68 PSMA-11], which is limited to [the University of California, Los Angeles] and [the University of California, San Francisco]. There are going to be a couple other agents that are going to be coming to the market. Some of these are renally cleared. Some of these are hepatically cleared. So, there’s going to be a whole menu of PSMAs, and I would really encourage the audience to bone up on these because, as Dr Gomella said, this is going to change the face [of prostate cancer], especially in the patients [who] we consider high-grade, high-risk localized. These patients are going to be restratified. My next question is: If this patient had received prior docetaxel and progressed, what would your treatment of choice be?

PETRYLAK: If they’ve received docetaxel, then progressed in hormone sensitive, I’ll go with a next-generation antiandrogen as the first treatment. Then I will consider going on to cabazitaxel [Jevtana] afterward. A lot of it will also depend on rapidity of the disease progression, what their molecular profiling is. Clearly, if it’s appropriate for them to receive a PARP inhibitor, they would do so [at some point].

The other thing we always [must] look out for is microsatellite instability [MSI]. I’ve seen some very dramatic responses to pembrolizumab [Keytruda] in patients who have MSI. In fact, I’ve got a [complete response] right now in a patient who had been on both docetaxel and cabazitaxel. That’s another molecular marker we [must] be sensitive to.

SARTOR: Dr Petrylak nailed it. We [must] remember that in this rare group of patients, [who] have either MSI-high, mismatched repair, or high tumor mutation burden, the responses [from some of the PD-1 inhibitors] will knock your socks off. I’ve got 1 patient who is in complete remission, off hormonal therapy. He’d already failed abiraterone and docetaxel. You can’t miss it, because it can make a huge difference in the lives of patients. Genetic testing is not going to benefit most patients, but in the rare patients, it can make a huge difference in their lives.

CONCEPCION: You and Dr Petrylak both bring up a great point, which is that for a while, we just fixated on individual biomolecular markers, trying to determine the next line of therapy. You’re both saying that as these patients progress through first, second, and third lines of therapies, we [must] be cognizant of what molecular testing can be done, whether it’s homologous recombination, mismatch repair, MSI, or CDK12, because these are actionable mutations. We have drugs in different categories, whether it’s PARP inhibitors, immunotherapies, [or] checkpoint inhibitors, then there’s going to probably be more and more over the next few years.

Dr Hafron, you and I have talked about this off and on through the years. In your role as chief medical officer of a fairly large group, how are you trying to push forward for these progressive patients to make sure your providers are appropriately testing and understanding what therapies are out there?

HAFRON: We have the benefit of using analytics and third-party software to identify these patients [and] make sure [they] are being properly evaluated and treated. It’s hard for anyone to keep up with the pace of advancement in prostate cancer. What we focus on is developing processes and pathways to make sure these patients are being treated according to guidelines, and when they fail a line of therapy, they’re getting the appropriate somatic testing. We don’t have the luxury of a Dr Sartor or a Dr Petrylak in our practice. Most of our community oncologists treat everything, so we [must] be the leaders for genitourinary [GU] oncology for prostate cancer and do the testing ourselves.

CONCEPCION: Dr Gomella, I have 2 questions for you: What is your opinion of the androgen receptor variant 7 [AR-V7] test, and how do you work your patients into your robust genetic testing program at your institution?

GOMELLA: AR-V7 is a great research tool in the study of responsiveness to antiandrogen-based therapies in advanced disease. Not all patients with androgen resistance express the truncated androgen receptor, and there can be very variable cycles where you may clear a lot of the ARV7-positive cells, but sometimes they return based on specific therapies. AR-V7 remains a useful research tool, but in our Sidney Kimmel Cancer Center, we don’t use it for clinical management.

Regarding our genetics clinic, we’re blessed here to work with Veda Giri [MD], and her team of certified genetic counselors. Every new prostate cancer patient seen in our GU multidisciplinary clinic gets a brief introduction to genetic testing. We don’t necessarily do genetic testing right away, [we] typically let them go through their treatment. A lot of initial questions about family members get answered. I’ve become fascinated by the findings that [approximately] 5% of men with newly diagnosed prostate cancer have the mutated DNA repair pathway genes and still have early localized cancer. I believe this is an understudied area. These are the gentlemen that need our attention because we know, more likely than not, if they’re not treated correctly initially, they’re the ones that are at risk of developing metastatic castrate-resistant disease and may ultimately [die] of their disease.

Much of our time today has been dedicated to advanced prostate cancer and the role of somatic and genetic testing, but I think the next wave is going to be going back and identifying the men with localized prostate cancer who have the genetic alterations that suggest they should be treated very aggressively, perhaps without conservative management with active surveillance. This will be an important next step in prostate cancer genetic testing.