Oliver Sartor, MD

Jason, you and I have talked about this off and on through the years. Being chief medical officer of a fairly large group, how are you trying to push forward for these progressive patients? Is there a battery of tests, if you will, as Dan and Oliver have talked about? What are you trying to push forward to make sure that your providers are appropriately testing and understanding what therapies are out there?

Working in a large urology group practice, we have the benefit of using analytics, third-party software, to identify these patients, to make sure that these patients are being properly evaluated. It’s hard for our partners to keep up with the pace of advancement in prostate cancer. What we focus on is developing processes and pathways to make sure that these patients are being treated according to guidelines. When they fail a line of therapy, they’re getting the appropriate somatic testing. We send the panels out with third parties and make sure that these people are getting evaluated. And if they’re not, through our software the physicians will be prompted or reminded that, “Your patient Mr. Jones needs to get tested.” We don’t have the luxury of a Dr Sartor or a Dr Petrylak in our community, in our practice. Most of our community oncologists treat everything. What we’ve found is that we have to be the leaders for GU [genitourinary] oncology for prostate cancer. We have to do the testing ourselves. We don’t have access to highly specialized GU oncologists like Dr Sartor or Dr Petrylak.

Great comments, Jason. Lenny, I’m going to ask you 2 questions. Probably the first one is more of an interest. I want to get your stance on where do we stand now, because everybody was so consumed with it, with AR-V7 testing? And then No. 2, from your personal perspective, because you obviously have an institution that’s the forefront leader in genomic testing and counseling for prostate cancers, how do you guys work these patients into your very robust genetic testing program? Speak about AR-V7 first.

 We work with Kevin Kelly, DO, here. Like Jason’s out there, we happen to have somebody right next door to us, and Dr Kelly and myself, and Adam Dicker, MD, PhD, care for these patients jointly. Everything is a group discussion when we start treatment, and then we send them off to the different providers. AR-V7 was great. It’s a great tool, but at the end of the day, we know that the AR-V7 has a very variable cycle that sometimes you can clear a lot of the cells. Sometimes they return. I have to say that it’s great research tool, but in our world here at the Sidney Kimmel Cancer Center, we don’t use it. Again, it’s a very strong research tool, but the variability in AR-V7 over time makes it less useful. Is that the first cleanup?

Yes, that was the first one. And now talk about your relationship with your very robust testing with your genetics clinic.

 We’re blessed here to work with Veda Giri, MD. She’s been incorporated into our GU health clinic since 2014. Everybody when they walk in the door gets a brief introduction to genetic testing. We don’t necessarily do genetic testing right away, but we let them go through their treatment. A lot of quick questions about family members get answered. One thing that I’ve become fascinated by is that about 5% to 10% of men with newly diagnosed prostate cancer have the bad DNA repair pathway genes, localized cancer. This is an untapped area. These are the gentlemen who need our attention because we know more likely than not, if you don’t treat them right up front they’re the ones who are going to develop metastatic castrate-resistant disease and ultimately die. We spent a lot of our time today on advanced prostate cancer and somatic and genetic testing. But the next wave is going to be getting back and identifying the men with localized prostate cancer who have the genetic fingerprint that they’re in trouble into the future and they need to be treated aggressively, let’s say without active surveillance or without a conservative management approach. I think that’s going to be our next wave of identification.

Very well said. We have 1 question, which is, I’ve been told that when a man has a recurrence of prostate cancer, he should immediately see an oncologist. Isn’t that a bit premature with all the new treatments the urologists are gaining? Jason, thoughts?

In our practice, it’s not an automatic referral to the oncologist. We’re in the community. We’re not in a university setting. I’ve been in advanced prostate cancer for almost 10 years now, and we treat it ourselves, from diagnosis to death. I don’t think you need to refer to an oncologist. That being said, it depends on your relationship with the university, your position in the community, and honestly, this is a fast-paced field right now. You must be involved and up to date on the trials and the guidelines because this is a deadly prostate cancer. This isn’t a Gleason 6 score, active surveillance. These are the guys who can get very sick if improperly treated.

The best answer I ever heard, and I’m going to steal your thunder Dan. Somebody asked this question to Dr Dan Petrylak, and I thought Dan gave the best answer. The most appropriate specialist to treat advanced prostate cancer is the person who’s most comfortable and knowledgeable. It’s not specialty specific. It’s the person who’s most comfortable and the most knowledgeable. It could be a urologist; it could be a medical oncologist. But all of us are moving toward understanding the multiple therapies. And Lenny, as you’ve said repeatedly, all of us believe it is a multidisciplinary approach. With that being said, I’m going to give each one of you 30 seconds for final thoughts, if any.

 I’ll give you a final thought. We didn’t talk at all about PSMA [prostate-specific membrane antigen]-based therapy, which is going to be coming. And if you read your 

 in September of this year, you would’ve seen that PSMA Lutetium-177 is prolonging survival. Stay tuned.

 We’re about to enter a phenomenal era. Molecule medicine and therapeutic events are beginning to intersect. The improved survival that you’re seeing with the PEACE1 trial will continue to be shifted toward longer survivals with the development of new agents and new treatments.

I agree with Oliver. I’m excited about the lutetium PSMA and applying this in the clinic. This is groundbreaking, disruptive technology that I’m excited to apply to my patients once it becomes widely available. I’m excited for that.

: Dr Gomella, once again in the cleanup spot.

 Thank you for that. What we’re going to be seeing here, again lutetium is great, but I also think the pendulum is going to be going back to dealing with the primary, the local disease in the setting of metastatic disease. We’re seeing more and more data suggesting you’ve got to get rid of the beehive to prevent the bees from spreading, and we’re going to be operating on or radiating a lot more localized disease in the coming years.

I want to thank all the panelists. A wonderful discussion. I want to thank the people who logged in, the reviewers, and I want to thank the folks from 

Videos

Jason M. Hafron, MD, CMO, and Oliver Sartor, MD, share their approach for the optimal management of mCRPC through genetic testing.

Optimization of Genetic Testing for mCRPC

If you had a patient who had received docetaxel and then progressed, where do you tend to go for your next line of therapy?

 If they’ve received docetaxel then progressed in hormone-sensitive disease, I’ll go with a next-generation antiandrogen therapy as the first treatment. Then I would consider going on to cabazitaxel afterward. A lot of it will also depend upon rapidity of the disease progression, what their molecular profiling is. Clearly, if it’s appropriate for them to receive a PARP inhibitor at some point, I would do so. The other thing we always must look out for is microsatellite instability [MSI]. I’ve seen some very dramatic responses to pembrolizumab in patients who have microsatellite instability. In fact, I’ve got a CR [complete response] right now in a patient who had been on both doce [docetaxel] and cabazitaxel. That’s another molecular marker we’ve got to be sensitive to.

 Dan nailed it. We must remember these rare groups of patients that have, either MSI-high, mismatch repair, or high tumor mutational burden [TMB]. Some of these PD-1 inhibitors, pembrolizumab in particular, I mention it by name because it’s FDA approved in that setting, high MSI, TMB, or mismatch repair deficient. Some of the responses will knock your socks off. I’ve got one guy who is in complete remission, off hormonal therapy, still in complete remission. And he’d already failed abiraterone and docetaxel. You can’t miss it because it can make a huge difference in the lives of patients. The genetic testing is not going to benefit most patients, but for rare patients, it can make a huge difference in their lives.

You and Dan both bring up a great point, that for a while there we just fixated on individual biomolecular markers, looking at precision medicine and trying to determine the next line of therapy. And again, what you’re both saying is that as these patients progress through first, second, third lines of therapies, we have to be cognizant of what molecular testing can be done, whether it’s homologous recombination, mismatch repair, like you said Oliver, MSI, CDK12, because these are actionable mutations. And again, we have multiple drugs. We have drugs in different categories, whether it’s PARP inhibitors, whether it’s immunotherapies, checkpoint inhibitors, and there are going to probably be more and more over the next few years.

Daniel P. Petrylak, MD, leads the discussion on sequencing treatment for a patient with mCRPC, such as in case 2, who progresses on docetaxel therapy.

Sequencing Therapy for mCRPC

: Lenny, a little bit different question for you. We had alluded to PET [positron emission tomography] molecular imaging, PET/CT scanning. We believe that the indication for PSMA [prostate-specific membrane antigen] is anyone for whom we’re worried about metastatic disease. Obviously, Axumin, or fluciclovine F18, scanning has been available, and that indication was for patients who have failed therapy. What are your thoughts, particularly in this patient because he’s obviously failed therapy? Comment if you will, on pluses and minuses of Axumin versus PSMA.

 We have become virtually an exclusive PSMA shop. We’ve got it here at Thomas Jefferson University since early April. I will say it’s shocking me how it is changing our treatment of patients. I’ll give you one example. A person had a radical prostatectomy by me about 25 years ago, has had slowly rising PSA [prostate-specific antigen], going up and up, got up to about 2, 2.5 ng/mL. We put him on intermittent hormone therapy, then continuous hormone therapy. Then he started to manifest metastatic castration-resistant disease [mCRPC]. PSA went to 1.5 ng/mL. Standard imaging is negative. And PSMA shows he’s riddled with metastases. He’s absolutely riddled, completely asymptomatic. Oliver mentioned this, and I think my medical oncology colleagues, in ASCO [American Society of Clinical Oncology] there’s been a white paper that has come out saying be very careful how you use PSMA today, particularly in the context of a clinical trial. But it’s completely changing what we do.

Our only problem with PSMA however is, if it’s a straight Medicare patient here in Philadelphia, we have no problem. The minute we get involved in a supplement or anybody under the age of 65, the amount of time that we have to spend begging and peer-to-peer reviews and things like that make it very difficult. But there’s no question to your point that I think PSMA is basically going to knock Axumin and all of the others out of the water until we get the next generation of PSMA that comes down the line. It’s going to be revolutionary in how we understand prostate cancer.

Are you getting it Lenny, are you routinely using it for staging, especially in high grade, high risk?

 Yes. Any man who has a high risk. Again, our problem is that patient population that we’re considering for radical prostatectomy. High-volume disease like this gentleman was, under the age of 65, it’s very difficult for us to get it. And every once in a while, I’ll have a patient who wants to pay the $6500 out of pocket. They really feel that they want to have it. But yes, we’re using it for staging. We have a clinical trial that’s associated with some of the VISION study work where you have the PSMA and then a radical prostatectomy. We are big believers in a very short period of time of the power of PSMA redefining prostate cancer.

Jason, do you have any issues in the Detroit area? Is PSMA available to you?

It’s not widely available. We have similar experience as Leonard, but our hospitals are just getting it online. But I think Leonard said it best. It’s going to redefine prostate cancer. We’re going to be in places that we never imagined. It’s disruptive technology. I don’t see the future role for Axumin. As we get PSMA online, Medicare’s going to cover it in 2022. That’s going to be our go-to test for staging and for recurrence.

For the viewers, it’s important to understand that there are different agents and different labels. There’s obviously Pylarify [piflufolastat]. Then you have Gallium PSMA, which is limited to UCLA [University of California, Los Angeles] and UCSF [University of California, San Francisco]. There are going to be a couple of other agents coming to the market. Some of these are renally cleared; some of these are hepatically cleared. There’s going to be a whole menu of PSMAs, and I would encourage the viewing audience to bone up on this if you will because as Lenny said, this is going to change the face, especially for the patients we consider high grade, high risk localized. These patients are going to be restratified.

In the last 10 minutes, because I want to give some time for comments; in the polling question, if the patient in case 2 had received prior docetaxel and progressed, what would your treatment of choice be? Would you switch over to an antigen receptor targeting agent, whether it’s ABI [abiraterone], enza [enzalutamide], or obviously because cabazitaxel is approved in patients who have failed or have not tolerated docetaxel, would you go to cabazitaxel, or other?

Dan, if you had a patient who had received docetaxel and then progressed, where do you tend to go for your next line of therapy?

: If they’ve received docetaxel then progressed in hormone sensitive, I’ll go with a next-generation antiandrogen therapy as the first treatment. Then I will consider going on to cabazitaxel afterward. A lot of it will also depend upon the rapidity of the disease progression, what their molecular profiling is. Clearly, if it’s appropriate for them to receive a PARP inhibitor at some point, I would do so. The other thing we always have to look out for is microsatellite instability [MSI]. I’ve seen some very dramatic responses to pembrolizumab in patients with microsatellite instability. In fact, I’ve got a CR [complete response] right now in a patient who had been on both doce [docetaxel] and cabazitaxel. That’s another molecular marker we’ve got to be sensitive to.

: Dan nailed it. We must remember these rare groups of patients who have either MSI-high, mismatch repair, or high tumor mutational burden [TMB]. Some of these PD-1 inhibitors, and pembrolizumab in particular; I mention it by name because it’s FDA approved in that setting, high MSI, TMB, or mismatch repair deficient. Some of the responses will knock your socks off. I’ve got one guy who is in complete remission, off hormonal therapy, still in complete remission. And he’d already failed abiraterone and docetaxel. You can’t miss it because it can make a huge difference in the lives of patients. The genetic testing is not going to benefit the majority of patients, but for the rare patients, it can make a huge difference in their lives.

You and Dan both bring up a great point, that for a while there we just fixated on individual biomolecular markers, looking at precision medicine and trying to determine the next line of therapy. And again, what you’re both saying is that as these patients progress through first, second, third lines of therapies, we must be cognizant of what molecular testing can be done, whether it’s homologous recombination, mismatch repair, like you said Oliver, MSI, CDK12, because these are actionable mutations. And again, we have multiple drugs. We have drugs in different categories, whether it’s PARP inhibitors, whether it’s immunotherapies, checkpoint inhibitors, and there are going to probably be more and more over the next few years.

Prostate cancer experts review the use of PSMA PET/CT imaging and Axumin imaging for patients with metastatic castration-resistant prostate cancer.

Role of PSMA PET Imaging in mCRPC

Let’s switch gears. Now we’re going to move into module 2, which is choosing an optimal therapy for patients with metastatic castration-resistant prostate cancer [mCRPC]. In this case, we have a 64-year-old man who was being treated for metastatic prostate cancer with lower abdominal pain, constipation, lower urinary tract symptoms. His PSA [prostate-specific antigen] was 30.2 ng/mL. His initial biopsy showed Gleason group 5 (5+5), all cores positive. He had 2 metastatic bone lesions in the pelvis, but no nodal involvement. His ECOG performance status was 1. For comorbidities, he was a diabetic. Let’s just summarize this. This is a patient who presented with high-grade disease, underwent radical prostatectomy, got started on ADT [androgen deprivation therapy]. Initial work-up was negative. He had ADT plus bicalutamide because he never hit nadir and then rapidly progressed to having recurrent disease with 2 metastatic bone lesions in the pelvis. By definition, he has metastatic castration-resistant prostate cancer and presents for initial therapy.

In this case, he’s treatment-naive, but he is metastatic and he’s castration-resistant. The choices are docetaxel plus ADT, ABI [abiraterone] plus ADT, Enza [enzalutamide] plus ADT, or other? Let’s let the audience vote. Jason, I’ll start with you again. This is the patient we used to see 10 years ago. I don’t think we’re seeing them much now because we’re treating so many patients early and in the nonmetastatic space, but this was a guy who would have presented. What are your thoughts relative to this guy? High-grade disease, really blew through ADT quickly and became metastatic.

First of all, if germline hasn’t been tested, I would get my germline testing. I like to get somatic testing up front; it is probably not going to make a difference at this point, but I like to understand the pathology of his disease. Vitamin D, calcium, get him on these bone resorptive agents because there’s more and more literature saying that’s important to get that started right away. Then in our center, we mostly start with sipuleucel-T [Sip-T]. For early mCRPC, we like to start with Sip-T and then typically transition to one of the oral treatments. Then the choice of the orals is what we’ve already discussed. Fitness for an ARI [alpha-reductase inhibitor], fitness for [abiraterone], and talk to them about chemotherapy, their fitness, can they tolerate chemotherapy? The key is having that discussion with the patient, the shared decision-making model, understanding what their goals are, looking them over from head to toe and seeing what the best treatment regimen is, but it would probably be Sip-T plus an oral in our institution.

: Dan, if you will, he was germline negative. What are your thoughts about somatic testing early in somebody like this who’s never seen a line of therapy? I guess the question is how early are we now moving up genomic testing for these patients?

: Certainly, I think the yield is going to be pretty low. Usually, I like doing somatic testing when I have a change in condition. If they’ve gotten visceral disease, or this patient is accelerating fairly rapidly, so it’s possible you’re going to see something. But I would probably at the beginning, at castration-resistance is the time I would check for it. May I make comments about treatment?

: This is a dilemma because he is sort of out of the category where we would use Sip-T. What I mean by that is the absolute PSA value. I like to use Sip-T early 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 he’s got a really low volume disease, but rapidly progressive. If you’re going to give Sip-T, I would consider giving it in this situation prior to chemotherapy or second-generation hormones.

: I’m similar to Dan on this one. It’s a little borderline for Sip-T because of the aggressive nature of the progression. He really didn’t get a lot of the hormones. The people who have a tendency to do a little better on the Sip-T are those who have a little more indolent disease. At the time of the Sip-T studies going all the way back, this was published in 2010. It’s 11 years ago, it didn’t have access to the novel hormones, so there’s a question about how much do we add on the Sip T front when you have the novel hormones? That’s an unanswerable question. I just raise it, but I don’t mean to give an answer because I don’t know. In terms of the testing, it’s reasonable to consider the somatic, and you can either do it now or do it later. I sometimes find that if the biopsies are done elsewhere that you can shuffle around for a month or so before you even get some 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 a secondary hormone.

Now, the one thing I’m going to raise, and this gets into a future category that is very undefined, the PROpel study, which is a combination of abiraterone and olaparib, has reported by a press release that it is “positive.” I don’t know what that means. I don’t know if positive means slam dunk positive. It’s positive in the eyes of the manufacturer, which may not be the positive that I want to see, but it raises this new question about PARP inhibitors coming up front. There’s another study called the TALAPRO-2 looking at enzalutamide in combination with talazoparib. We don’t know anything about that, but I would simply say that if PROpel is positive, then maybe the TALAPRO-2 is going to be positive too. Even though today, we’re kind of walked into probably considering these novel hormones, it could be that combination therapies may play in the near future. I think we’ll hear about it at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], but we just have to learn more. Anyway, I just wanted to raise the PROpel study and mention it.

: With the PROpel study, the devil is in the details. I’m excited that it showed a positive result. However, we’ll draw on our experience at Yale School of Medicine; Joe Kim, MD, who works in our group, did a randomized trial of olaparib plus or minus cediranib, used potentially to increase 

-ness by causing hypoxia, randomized phase 2. Our primary end point in selected patients was rPFS [radiographic progression-free survival], very similar to the other trial. What we found when we analyzed the molecular data was rPFS was being driven by

patients. It may be that the combination prolongs PFS [progression-free survival] or OS [overall survival] in that subgroup. The subgroups would be crucial in this trial to understanding how to use this combination.

Ultimately, I would have loved to have seen another arm, which would have been PARP only. They had [abiraterone], they had [abiraterone] plus the PARP, but they didn’t have the PARP only. And to your point, Dan, at the end of the day, is all this going to be driven by 

Raoul S. Concepcion, MD, presents the case of a 64-year-old-man with mCRPC, and Jason M. Hafron, MD, CMO, leads the discussion on the optimal treatment approach for the given case.

Oliver Sartor, MD

Articles

Optimization of Genetic Testing for mCRPC

Sequencing Therapy for mCRPC

Role of PSMA PET Imaging in mCRPC

Patient Case #2: Choosing Optimal Therapy in mCRPC