Oliver Sartor, MD

For this patient, we presented it as low-volume disease. In polling question 4, if the patient had high-volume disease—Jason, as you and Oliver outlined, high-volume disease is defined as visceral metastases or greater than 4 bony metastases, 1 outside the axial skeleton. Would this affect your treatment choice? In other words, would you use abiraterone–ADT [androgen deprivation therapy], enzalutamide-ADT, docetaxel-ADT, apalutamide-ADT? Then would you add on an antigen receptor–targeting agent, enzalutamide-abiraterone plus docetaxel-ADT or other? Dan, when you see these de novo metastatic castration-naïve patients, does the volume of disease play a factor for you relative to your therapeutic options?

 Yes, the volume of disease, the age of the patient, and comorbidities all play an important role. Recently we had the PEACE1 trial, where patients received standard-of-care docetaxel and then were randomized to receive observation or abiraterone. There was a significant improvement in rPFS [radiographic progression-free survival] in patients who received the 2 different treatments, docetaxel and abiraterone. Although we don’t have an abiraterone-alone arm, which would have been wonderful for that study, this is something I’m obligated to discuss with my patients. This is an intricate plan of action because the results were so striking. That needs to be administered. 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 Lenny’s institution [Thomas Jefferson University at Sidney Kimmel Medical College], where there’s an increased rate of cardiovascular morbidity in patients 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.

 Dan, that’s very well said. I want to make a brief comment that goes back to Lenny. We have data in the castration-resistant setting over 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 trial, each of which is 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 castration-sensitive [disease], but for people whose financial toxicity is substantial, you can cut the price of the drug by 75% and see if you feel like abiraterone may be appropriate.

Dan raised some good points. I don’t want to disagree with Dan, but if you think abiraterone is appropriate and financial toxicity comes to the 4, you could drop down to 1 or 2 abiraterone with food as a poor-man substitute. It’s not FDA approved, not really proven, but something I’ve done in practice when faced with the problem.

We’ve gone to basically standard dosing regardless of body weight and everything with all these oral agents. Oliver, you’re bringing up an interesting point. Has anybody looked at potentially checking PK [pharmacokinetics], abiraterone, or enzalutamide levels to see metabolism and bioavailability and those types of things with PSA [prostate-specific antigen] response?

 That’s been done…. It was published in 

] a couple of years ago in castration-resistant disease. I always bring up a really interesting point because we know the PK of docetaxel is different if there’s testosterone on board. If you want to avoid that, perhaps you wait. In most of these trials, if you have all these trials administer abiraterone within 3 months of starting the initial androgen deprivation therapy, if the testosterone is down to castration levels within a month, I don’t think the PK will make much of a difference. It’s going to be about the same. You probably can get away with it. If you want to formally evaluate that, you’d have to do that at the time that you’re castrating the patient, but it’s probably not going to be any different. It’s a very interesting and an important point.

 Do medical oncologists have any experience with the generic forms? Not necessarily for this patient, but in general, the generic forms of abiraterone vs the Janssen product. Do you have any experience with that, either from using it or how expensive or inexpensive it might be?

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

 There’s the new Kirkland abiraterone. That’s a very interesting point. I haven’t seen much of a difference in price with the generic in my experience. Maybe it’s regional and dependent upon insurance, but I haven’t seen much of a difference.

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

: Jason, we know there’s another branded drug, microparticle abiraterone? Do you have any experience with that?

It’s limited. We’re trialing a granule that you can put in a liquid. But for the 1 you’re referring, the data are limited; not a great experience. I want to go back to PEACE1, though. Dan brought up PEACE1. I’m just a community urologist treating patients, and I’d love to hear the panel’s response. When I saw those data, I was blown away with the rPFS [radiographic progression-free survival] and OS [overall survival] from ESMO [European Society for Medical Oncology], and it was really impressive because this is the first major trial since 2015. Prior to that median survival was 3 years. When you look at the data, the median survival is going past 5 years. In my book, this was is a game changer in how to manage this high-volume patient with mCSPC [castration-resistant prostate cancer]. I’m curious if you guys see it that way, or you still have some questions about it?

A couple of issues. No. 1, the appropriate control should have been ADT-abiraterone because we don’t know if docetaxel adds value. No. 2, and 1 of the reasons I didn’t discuss PEACE1, is that the high-volume subset was the only subset that benefited. If you look at Grain’s presentation, the low-volume subset had no survival benefit. Now the rPFS was better, but we don’t treat people for our PFS [progression-free survival] in general. We want that OS benefit, and that was high-volume disease-restricted funding.

 That was my point before, and it helps us answer the question when a patient comes into the clinic and says, “Doc, I want the kitchen sink thrown at me. I want everything possible done. I want everything up front.” For low-volume patients, there’s no major justification for it. For high volume, there is.

Lenny, I’m going to give you the last word. Dan made some comments when he was talking about what patient comorbidities he was looking at. He mentioned the cardiovascular dysfunction that may be associated with abiraterone. We haven’t talked about it—it’s not really part of this—but when you see a patient’s cardiovascular history, how strongly are you trying to determine whether to use an LHRH [luteinizing hormone-releasing hormone] agonist or oral antagonist?

 That’s certainly an ongoing debate. Our mantra at the multidisciplinary Kimmel Cancer Center is that even if you have a urologist or a GU [genitourinary] medical oncologist caring for you, you need a primary care doctor to organize your overall health. We rely on that primary care doctor to make sure we have good cardiovascular status. Dan mentioned the hypertension and the other problems with abiraterone. So we make sure patients have a good head-to-toe doctor, and we make sure we comanage the patients because I can’t evaluate how significant or insignificant somebody’s cardiovascular disease might be. We’re getting to this phase right now, where men are living longer and longer. These issues are going to become more prominent as men move into many years of being on these agents. We don’t know what the long-term impact is. We don’t use a lot of the oral agent. At Jefferson, we have limited experience with it because we often get into insurance problems in the Philadelphia market with an oral agent. The injectables we never have an issue with, but these are all things we have to look at: quality of life and quantity of life. With all these options, we’re going to be under more burden to customize the treatment for a patient based on all aspects of their life: financial toxicity, comorbidities, their expectations. We’re throwing the kitchen sink at people. Some people want that. Other people say, “I’m good. I’ve got my 18 great-grandchildren. I don’t need all that.” It’s got to be very customized.

Very nicely said, Lenny. A great take-home point to conclude this is toxicity. We’ve always thought about toxicity as 1 big physiologic, but Dave Penson gave a nice talk a couple of years ago about how we need to consider financial toxicity in this age of multiple drugs and the cost associated with targeted agents.

Videos

Daniel P. Petrylak, MD, leads the discussion on approaching treatment of high-volume metastatic castration-naïve prostate cancer.

Treatment options for high-volume mCNPC

 I have a castration-resistant case where all the lesions regressed except a new lesion, and we can’t find anything on conventional imaging in bone. The question is, for a patient who has all the metastatic—4 lesions, for example—and you find 20 on a PSMA [prostate-specific membrane antigen] PET [positron emission tomography], do you change their management? We use the conventional imaging as our way of determining whether they have extensive disease. A PSMA PET is nice. It’s a great thing, but at this stage, we need to understand how we’re going to use that in our management.

 Dan, you’re making a great point because all our level 1 data are built around conventional imaging. As we introduce a PSMA PET—and it’s here—it raises a new series of questions to which our level 1 evidence does not apply. I mentioned the tests as directed therapy, but I may get a PSMA PET scan. This guy may not have 1 lesion to the bone, and he may have 14. Then it becomes a whole different scenario. As we gain new imaging insights, we also have to ask new imaging questions and address it with clinical trials to have the best answers.

That’s great. Let’s go around the table. Oliver, you said you’d consider PSMA. Obviously, 69, ECOG 1 is in retention, which is fairly active. Jason, given that he’s got conventional imaging and low-volume disease, would you push for molecular imaging?

Yes, I would. It’s coming, and we’re getting into a space that we don’t have data on. Based on the STAMPEDE data, which showed a significant improvement in overall survival, over 30%, I’d give localized therapy to this patient and then probably transition to novel hormone therapy. The issue with PSMA and finding more bone lesions is that, as Oliver said, it’s up for grabs. It’s hard to apply the old literature to this new imaging. But of what we presented, and the case that’s there, I’d offer them localized therapy based on STAMPEDE.

Also, I’d like to bring up for the audience SWOG S1802. You talk about historically treating advanced prostate cancer. There’s a major US trial looking at radiation therapy or even surgery. It’s crazy to think that we could potentially be operating on advanced disease and removing the prostate. The key is that we’re moving away from single modality therapy and clearly moving into multimodality therapy. How do we apply it with this new imaging? I guess we’ll have to wait for Oliver and Dan to create some great trials to make that connection to the past.

Your point is well taken relative to this SWOG trial because we’re finally moving forward in these patients with high-risk, high-grade localized prostate cancer, or in this case, which seems to be an oligometastatic disease. To me, that is the way it’s moving, given that we do have better systemic therapies beyond ADT [androgen deprivation therapy]. Oliver’s point relative to how we incorporate hereditary germline and somatic testing isalso going to be key as we launch into this era of precision medicine.

A panel of experts in prostate cancer examine the use of conventional imaging and PSMA PET/CT and the impact on their approach to the management of mCNPC.

Role of conventional imaging vs PSMA-PET in mCNPC

Let’s go to the first case. This is module 1, and we’re going to talk about recent advances in the treatment of metastatic castration-naïve prostate cancer. We’ve generally gone to this type of nomenclature. We should have some standardization. Everybody is very comfortable with castration-resistant prostate cancer. Many of us have used castration sensitive and hormone sensitive. I changed this because I was looking at the 2022 NCCN [National Comprehensive Cancer Network] Guidelines, and they changed their nomenclature to castration naïve.

In this case, we have a 69-year-old, white man who presents to the emergency department with progressive fatigue, low back pain, decreased appetite, weight loss, and an abnormal DRE [digital rectal exam] showing a bilateral induration and urinary retention. Fully captured and replaced. He was referred to urology for evaluation. In the urology office his prostate-specific antigen level was 144 ng/mL. He underwent biopsy and showed a Gleason grade group 3, which is 3+4 in 8 of 12 cores. Conventional imaging reveals both nodal and a single bony metastatic lesion into the pelvis. His ECOG performance status is 1. 

For the audience, before we get into the discussion, what would your treatment of choice be for this patient? This is a de novo, newly diagnosed metastatic castration-naïve prostate cancer. What would you recommend: A) docetaxel plus ADT [androgen deprivation therapy], B) abiraterone plus ADT, C) enzalutamide plus ADT, D) apalutamide plus ADT, or—just for grins—E) ADT only. I’d like to see how this is answered.

Jason, as we’re talking about this—and this is a fairly common presentation that you see— what’s your thought process?

For neurologists, it’s critical that we use it differently from how we have before. Metastatic disease is a wide spectrum. Historically we would look at a patient’s metastatic disease and put them on androgen deprivation therapy. But there are a lot of nuances with metastatic disease, especially in castration sensitive. 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 important, what’s the number of metastatic lesions in the bone? When you look at these patients, you have to understand that all metastatic disease is not the same. There are small nuances, whether they’re high volume for bone lesions outside the spinal column or the pelvis, or visceral metastases, or low volume if there are fewer than 4 lesions. On top of that, where is the metastatic disease? Is it bone, lymph, or visceral? Once you understand the nuances, you’ll better understand the literature. Then once you understand that and relate to the literature, you can apply a lot of the newer therapies and combination therapies that are available.

 Oliver, anything to add to Jason’s commentary?

 Yes. A couple of things. This will be a low-volume metastatic disease by the CHAARTED criteria. It’s interesting: if you look at de novo patients, there may be some additional benefit from docetaxel, but it’s probably more problematic than 1 of the hormonal therapies. The data with abiraterone, enzalutamide, and apalutamide may be better here.

A couple of other things that I’ll add. No. 1, we want to get germline genetics on this guy because that’s part of the NCCN Guidelines. No. 2, with a single focus of bone metastatic disease, I may want to know if there’s more to this story. I may get a PSMA [prostate-specific membrane antigen] PET [positron emission tomography] scan on this guy, if I can get it, to define whether he’s oligometastatic. He’s got a PSA [prostate-specific antigen] of 144 ng/mL, but it’s high, so I might want a PSMA PET. If we look at the STAMPEDE 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. To be honest, I’d consider metastasis-directed therapy, even though that’s more controversial. In my practice, I try to do germline genetics. I don’t necessarily need any somatic genetics right now. I’ve got a PSMA PET scan. I’d plan on radiation to the prostate. I’d be using ADT plus a novel hormone, and I’d consider the possibility of metastasis-directed radiation. That’s what I would do. I may be a little out there. Let me hear from others because sometimes I get a little exuberant about new data.

Lenny, let’s pump this to you because you and I grew up in the era when if it was metastatic, we didn’t do anything with the primary. We just chopped it up to metastatic disease, and we didn’t aggressively manage the primary. We all lived through the disasters of people once they blow through hormonal therapy, and we wish that we would have at least taken out the prostate to control local disease. Dovetailing on what Oliver said, relative to your first thoughts, I want you to tell them, from a urological perspective, your thoughts in managing the primary.

 As Oliver and Jason laid out, you have a whole host of level 1 evidence to treat this patient. You have everything from straight ADT through docetaxel plus ADT, plus ADT plus all the novel androgen receptor pathway blockers. Then you compound that with Oliver’s point about treating the primary and then consider treating the oligometastatic lesion. One of the things we must remember, because this is a low-volume patient and docetaxel may not be his best option, is that docetaxel is limited in a course of infusion. Very often there’s financial toxicity with a lot of the oral agents. The data would say docetaxel plus ADT is not a top-line therapy, but the subtleties that Jason mentioned for individual patients are that this may be a man who has no resources for $8000 to $10,000 a month for those other agents. The data say for low-volume metastatic disease ADT plus docetaxel may not be necessary, but there may be personal and individual considerations. That may be the quickest, easiest, most efficient, and least financially toxic way to treat this man. But apalutamide, enzalutamide, and all the oral agents are open to this gentleman with basic ADT.

The point that you’re stressing is that the standard of care is ADT plus some agent for intensification of therapy. The days of ADT alone, especially in a de novo metastatic castration-naïve patient, are—dare I say—passé.

Dr Raoul S. Concepcion presents the case of a 69-year-old man with metastatic castration-naïve prostate cancer (mCNPC), and the panel shares their personal approaches to treatment.

Patient Case #1: Treatment Selection in mCNPC

. I’m Raoul Concepcion. I’m the chief science officer for US Urology Partners in Nashville, Tennessee. Tonight, we’re going to present a couple of cases on improving outcomes in advanced prostate cancer. I’m fortunate to be joined by 4 friends and colleagues who will introduce themselves, and then we’ll proceed right into the program.

Good evening, everyone. I’m Dr Jason Hafron. I’m the chief medical officer at the Michigan Institute of Urology in West Bloomfield, Michigan. I also oversee our advanced prostate cancer clinic.

 I’m Dr Dan Petrylak. I’m a professor of medicine and urology at Yale School of Medicine in New Haven, Connecticut, and I’m head of the GU [genitourinary] DART, or disease-related research team.

 I’m Dr Leonard Gomella from the Department of Urology at Thomas Jefferson University in the Sidney Kimmel Cancer Center in Philadelphia, Pennsylvania. I’m also the senior director for clinical affairs for the cancer center, and I oversee the Jefferson Health Urology Enterprise.

The fourth panelist is Dr Oliver Sartor. He’s a professor of medical oncology at Tulane University School of Medicine in New Orleans, Louisiana, and a recognized expert in advanced prostate cancer. It’s always great to have all of you involved, and I’m looking forward to a great discussion.

This is for the audience. We’re trying to get a feel of the demographics of who’s tuning in tonight. Polling question No. 1: what is your specialty? A) general medical oncology, B) urologic oncology, C) urology, D) other. We have mostly urology coming in tonight, which is great. Hopefully we’ll have others voting shortly. Let’s go to polling question No. 2: approximately what percentage of your patients who you personally manage have a diagnosis of prostate cancer? Is that A) less than 10%, B) 11% to 20%, C) 21% to 30%, D) 31% to 40%, E) greater than 50%? Go ahead and enter that response, obviously depending upon what the actual mix is going to be. Clearly, we know that oftentimes community medical oncologists don’t have the higher percentage of patients with advanced prostate cancer relative to some of the urology practices and academic centers. We have 1 respondent who has greater than 50%, but for the people who are entering in, it’s less than 30% of the practice. We’ll keep tabulating that and make those available.

Raoul S. Concepcion, MD, FACS, poses polling questions for the audience’s medical specialty and the percent of patients they receive with prostate cancer.

Oliver Sartor, MD

Articles

Treatment options for high-volume mCNPC

Role of conventional imaging vs PSMA-PET in mCNPC

Patient Case #1: Treatment Selection in mCNPC

Polling Questions: Advanced Prostate Cancer