- Raoul Concepcion, MD, FACS, Vanderbilt University School of Medicine, Nashville, Tennessee
- Jahan Aghalar, MD, Board-certified Hematologist and Oncologist, New York, New York
- Gordon Brown, MD, Rowan University School of Osteopathic Medicine, Glassboro, New Jersey
- Jorge Garcia, MD, Cleveland Clinic, Cleveland, Ohio; Jonathan Henderson, MD, Regional Urologist, Shreveport, Louisiana
- Paul Sieber, MD, Penn Medicine Lancaster General Hospital, WellSpan Ephrata Community Hospital, Lancaster, Pennsylvania
Raoul S. Concepcion, MD, FACS: 2020 begins another exciting year in the field of genitourinary oncology, especially in prostate cancer, where we’ve made significant progress with several recent FDA approvals. I am joined by a panel of my colleagues, all experts in the management of advanced prostate cancer.
Today we are going to highlight recent clinical data and discuss practical implications for patient care.
I am Raoul Concepcion and the director of The Comprehensive Prostate Center, as well as a clinical associate professor of urology at Vanderbilt University School of Medicine in Nashville, Tennessee.
I am joined by Dr Jahan Aghalar, a genitourinary medical oncologist at New York Cancer and Blood Specialists in New York City;
Dr Gordon Brown, the director of the New Jersey Urology Center for Advanced Therapeutics, and the medical director of robotic surgery at Thomas Jefferson Hospitals in New Jersey;
Dr Jorge Garcia, the Kerscher Family Chair for Clinical Prostate Cancer Research and a staff physician in the Department of Hematology and Oncology and Urology at the Cleveland Clinic in Cleveland, Ohio;
And Dr Paul Sieber, urologist in private practice in Lancaster, Pennsylvania. He also serves as president and medical director of research at Lancaster Urology.
Gentlemen, thank you so much and let’s begin.
I think as we move forward, we’ve always thought of prostate cancer, especially for the urologists here on the panel…we’ve either looked at it as local or metastatic. And there have been certain cut points, if you will, where the urologists have historically taken care of the diagnosis management for localized disease, and then certainly once patients have progressed beyond androgen deprivation therapy [ADT], historically pre-2010, the medical oncologists with very limited resources obviously were involved in metastatic disease. And as we all know, prostate cancer, especially the generic term, advanced prostate cancer, has really come a long way. In my opinion, we need to start looking at our prostate cancer patients mostly in terms of buckets, if you will. I’m a believer that when we talk about advanced prostate cancer, there’s probably 4 buckets that I want to discuss as part of this segment today.
First, is the nonmetastatic castration-sensitive prostate cancer patient. I think, by definition, those are the patients who have been definitively treated, whether that be with radiation therapy or surgery, who have gone on to have a biochemical recurrence. Then this ever-larger population is the metastatic castration-sensitive prostate cancer patient, which again now there are new changes in how those patients are being managed. Then the nonmetastatic castration-resistant prostate cancer, and then finally this bigger bucket where we’ve spent a lot of time over the past decade discussing is the metastatic castration-resistant prostate cancer.
I think to start this discussion, let’s first, again addressing these individual patients as separate entities. And I think it’s important to do that primarily because the trials and the treatment regimens are all very different. Let’s first talk about this patient who has historically been called biochemically recurrent or again nonmetastatic castration-sensitive prostate cancer. So basically, Gordon, this is where the urologists have always been in play very early on. Give us a little bit of your insight, how you tend to manage these patients once you identify a biochemical recurrence, what do those values look like, that type of thing.
Gordon Brown, MD: Sure. Historically, we’ve probably, as urologists, been over treating patients with the use of ADT therapy for a variety of reasons. Historically, we’ve done this because of the lack of good alternatives, patient anxiety, and concern around progression of disease. However, we’ve taken a little bit of a closer look in terms of our approach to ADT therapy, certainly within the last 5 to 10 years. And really in the absence of good data suggesting a clinical benefit to the use of ADT in the nonmetastatic patient population, we’ve really tried to risk stratify who gets ADT versus who doesn’t in our biochemically recurrent patient population. So Raoul, what we’ve tried to do is look at those patients we deem to be at highest risk of progression over time to development of metastases, specifically those patients who have failure within 3 years of primary therapy, those patients who have Gleason score group 4 or higher type disease, or those patients who have PSA [prostate-specific antigen] doubling times inside 10 months. Those patients, upon identification of biochemical recurrence, are started on an ADT regimen within our practice.
Raoul S. Concepcion, MD, FACS: You’re talking basically, in your big practice in New Jersey, are you primarily using LHRH [luteinizing hormone-releasing hormone] analogues? Do you go to complete androgen blockade?
Gordon Brown, MD: Our initial approach usually is the GnRH [gonadotropin-releasing hormone] antagonists as an initial starting therapy for these patients with biochemical recurrence. And then after 2 doses transition on to LHRH agonist therapy for their maintenance doses. We monitor these patients with a baseline testosterone prior to initiation of therapy and usually also check their testosterone within 4 months of initiation of therapy to ensure castrate levels of serum testosterone.
Raoul S. Concepcion, MD, FACS: Segueing from that, let’s talk a little bit about, because we know the goal is for testosterone suppression, get it to that “castration level.” So, Jorge, give us the background on castration levels. What’s the current definition? Where should we be going, those types of things?
Jorge Garcia, MD: I think that’s a great question, and it actually reflects on what you, Gordon, stated earlier. I think there are not great data to suggest that a testosterone level of 50, 40, 30, or 20 ng/dL is better than the next level. The standard guideline for us really is castration levels, and castration levels traditionally have been defined by a testosterone level under 50 ng/dL, period. Now, the Europeans and certainly some of the new guidelines in the United States would suggest that the lower your testosterone, the better for you with regard to outcome. But there are no prospective data comparing a level of less than 50 or less than 20 ng/dL. I would argue that there are pockets of practitioners within the United States who would say the lower the better, maybe you want to have under 12 or under 20 ng/dL. We use a supersensitive assay at the Cleveland Clinic, so we can detect levels of testosterone less than 12.
Contrary to you, to some extent, in my practice, I do not repeat and/or check testosterone levels in my patients because the likelihood of you having a primary resistant patient, if you will, to ADT whether you use LHRH agonist or antagonist therapies, is low. For younger men, maybe that would be intriguing to do, especially when you see patients who may not be able to achieve undetectability of their PSA values, but I traditionally do not follow testosterone for those patients.
Now, I think it’s important also to remind ourselves that when you look at testosterone baseline, I think that’s relevant for us. Because if you take a bracket of patients in their 70s or 80s developing rising PSA or above chemical recurrence after local definitive therapy, a significant proportion of those men may in fact be hypogonadal, raising the question as to well, could they really be castration resistant from the get-go or not? I don’t think we know that yet.
And importantly as well is when you have received local definitive therapy with radiotherapy specifically, especially if you have done ADT and radiation for high-risk patients, it is imperative that you follow testosterone because you want to know when testosterone recovers, so you know if the patients are having a rising PSA, you want to ensure then that testosterone has recovered because if not, those patients are castration resistant from the get-go. And also, important to follow testosterone levels in patients who are doing intermittent therapy, that is periods on suppression and periods off therapy. Because you always want to pay attention to when testosterone recovers for those patients and what happens with the PSA over time once testosterone recovers.
Raoul S. Concepcion, MD, FACS: So, you do check a testosterone level pre-institution of ADT.
Jorge Garcia, MD: Yes.
Raoul S. Concepcion, MD, FACS: Paul, do you do that?
Paul Sieber, MD: Yes, routinely.
Raoul S. Concepcion, MD, FACS: Jahan?
Jahan Aghalar, MD: Yes, I would routinely do that as well, again to the points that Jorge very finely pointed out, to have a better idea as to whether a patient up front may already have some signal that they may be portending castration-resistant disease.
Raoul Concepcion, MD, FACS: Jorge, you brought up the concept of intermittent versus continuous dosing. Jahan, in your practice—again let’s be very clear that the patient we’re talking about here is nonmetastatic. Again, I think the terminology is interchangeable. I personally like to call these patients nonmetastatic castration sensitive, but they can be labeled as biochemically recurrent, they can be labeled as nonmetastatic hormone-naïve or nonmetastatic hormone sensitive. It’s that patient population that’s been definitively treated. Working off Dr Gordon Brown’s really nice comments about optimizing the patient, how do you differentiate? What are the current data looking at intermittent versus continuous, specifically in these nonmetastatic castration-sensitive patients?
Jahan Aghalar, MD: That’s a great question. It’s a consideration we always have to keep in mind. Although we understand that we want to ensure we have good cancer control, at the same time [we want to minimize adverse] effects and toxicity that hormone therapy definitely does have. We have good randomized data to indicate that patients with nonmetastatic castration-sensitive disease—using the intermittent approach as opposed to the continuous approach, at least we can say in a randomized trial they had noninferiority to it. This was published in the New England Journal of Medicine in 2012. But it does also improve quality of life and minimized amount of bone absorption that we may see, and it perhaps may have cardiovascular benefits in the future. Certainly, in the patient who is in the rising PSA [prostate-specific antigen] stage, to take an intermittent approach, we can safely say that it’s not necessarily doing any harm to the patient by taking that approach.
Raoul Concepcion, MD, FACS: I think your points are really well taken. In this patient, nonmetastatic castration sensitive, that intermittent versus continuous, we’ve been able to show that it’s noninferior.
Jahan Aghalar, MD: Correct.
Raoul Concepcion, MD, FACS: It may not be superior, but it is clearly noninferior.
Jahan Aghalar, MD: Correct.
Raoul Concepcion, MD, FACS: I think you bring up a good point, and I think we’ve known that prostate cancer is basically an endocrine disease. We’ve induced castration levels of testosterone, and now we’re becoming more and more aware of the adverse-effect profile of these drugs long term. Paul, you have been a leader studying bone-mineral-density loss and have been on the forefront of establishing bone clinics in your practice. Give us your slant, if you will—for somebody who has done the clinical trials, [who] stays on top of this data—on how you look at patients with institution of ADT [androgen deprivation therapy] in bone health.
Paul Sieber, MD: What’s changed over the years—I mean, our bone health was the first thing we did when we looked ADT. And as we’ve learned more and more the adverse effects of ADT, it’s morphed into our advanced prostate cancer clinic. Bone health is part of that. We start bone health at day 1. As soon as they’re introduced with the idea of androgen deprivation therapy, they are standardized to see our nurse practitioner. They get a vitamin D level at baseline, because being in the north we see a lot of low levels of vitamin D. As Jorge mentioned, we get testosterone levels at baseline. Well, guess what, if a guy [is] hypogonadal, he’s at increased risk to get a fracture right off the bat.
We take a more in-depth, bone-oriented history. We will basically fill out the FRAX [Fracture Risk Assessment Tool] calculator and then ask a number of questions about bone health. Then we put that all together and we say, “OK, they’re going to need a DEXA [dual-energy x-ray absorptiometry] scan. For us, the DEXA scan is done sometime within the first 6 months, maybe even the first year. The curves in terms of fracture risk don’t really go up until they’ve been on the ADT for about 6 months if you look back at the Vahakn Shahinian data from years ago  in the New England Journal of Medicine.
But once we got that data, it was pretty easy to segregate out that osteoporotic patients get treated automatically. Patients with osteopenia get put in the FRAX calculator, and we come up with an idea of what their risk is and if they need to be treated. What’s changed that is, really, the nonmetastatic castration-sensitive patient and the data on the oral agents. Because the second-line androgen receptor antagonists introduced fracture risk that is pretty significant. If you look at their safety profiles, they’ve got about a 10% fracture rate within 3 years. And if you look back to the FRAX calculator, that would suggest that that’s an independent predictor that they should be on treatment probably as soon as they start that drug to be treated for nonmetastatic castrate-sensitive disease. That’s a new thing that wasn’t in our armamentarium just a couple of years ago, and we’re looking at these people with a different viewpoint now.
Raoul Concepcion, MD, FACS: Basically, what you try to do is risk stratify these patients either before they get their first dose of ADT or very soon after. Correct?
Paul Sieber, MD: Correct.
Raoul Concepcion, MD, FACS: You’re looking at osteoporosis, osteopenia, and in that select patient who may not have that T-score [bone density exam], you have to make a decision whether or not, because obviously you do have approved agents for this patient type that can reduce the amount of bone-mineral-density loss.
Paul Sieber, MD: Correct.
Raoul Concepcion, MD, FACS: OK.
Jorge Garcia, MD: If I may, Raoul, I think the bigger question and to the point you guys made earlier, is that when we think of bone health in men with prostate cancer, I think there are 3 fundamental concepts that are important to remember for everybody listening to or watching this video. No. 1 is bone loss, which is what we talked about. No. 2 is do we have any data that the bone health agents or bone-targeted therapies that we have can delay time to skeletal-related events—or for that matter, time to metastases? And the third one is in the context of castration resistant, whether you can delay an SRE [skeletal-related event]. For bone loss prevention, I think that all of us over the last probably 3 years and 4 years with the advanced data you mentioned, we have come to realize that we were underappreciated in the importance of bone health.
The bigger question in my mind, as you pointed out earlier, is when do we start? And more important than that, there are many agents out there that we can use. I think it becomes a question of practicality, what patients do have access to IV [intravenous] therapy and subcutaneous agents. And that I don’t think we really know that data yet. What we do know is you can lose 6% to 7% bone mass loss per year, which is significant.
Raoul Concepcion, MD, FACS: The point here, especially for the average practitioner who’s managing prostate cancer—whether it’s the radiation oncologist, the urologist, or the medical oncologist—is that we have neglected bone health from the get-go. We as practitioners need to take ownership of that.
Raoul Concepcion, MD, FACS: The other thing that we’re obviously seeing a tremendous amount of interest in—from a research standpoint, from an observational standpoint—as Jahan mentioned, are the toxicities related to androgen deprivation therapy [ADT], short term and long term. When we started using LHRH analogues, we said, “Oh, this is an easy drug. It’s better than getting castrated. But now, over time, we’ve recognized some really, potentially serious adverse effects. Gordon, 1 of the things I think people are really interested in—and it’s just not getting enough attention—is the potential increased cardiovascular [CV] risks associated with LHRH agonists versus antagonists.
Gordon Brown, MD: Yeah, it’s an interesting question. I think it’s a very important question because as urologists, historically—to your point—we’ve utilized these drugs. I don’t want to say we’ve used them with abandon, but with much less concern than we probably should have. There have been some recent data published in The Journal of Urology from a group in Israel that looked at a randomized trial of antagonists versus agonists. It was a very small patient population. Their end point was, actually, looking at endothelial dysfunction and whether you got an antagonist or whether you got an agonist.
In that report, their primary end point was not met, but they did look at secondary end points of increased risk of cardiovascular events. And what they reported out was there was a 20% risk of cardiovascular events in the agonist group when compared with the antagonist group, suggesting that potentially from a mechanism-of-action perspective, those patients in the agonist group were at highest risk or higher risk for CV events.
Obviously, this is something that’s going to have to be played out and proven in randomized clinical trials. But it does call into question our need to monitor these patients more effectively and even to prospectively risk stratify them into patients who might be at highest risk prospectively for events during their course of therapy and potentially even engage a cardiac oncologist during their care.
Raoul Concepcion, MD, FACS: And it happens pretty quickly.
Gordon Brown, MD: It does.
Raoul Concepcion, MD, FACS: I mean, that was the 1 thing that that study…
Gordon Brown, MD: This was the study of the year.
Raoul Concepcion, MD, FACS: Right.
Gordon Brown, MD: One year follow-up.
Raoul Concepcion, MD, FACS: Those events happened within a year. Jahan, you’ve got a pretty big hematology-oncology group in New York, as Gordon mentioned, and a few academic institutions have brought on cardio-oncologists. Clinically, are you doing that? And I guess more important, should we be really looking at risk factors, vis-à-vis with history of cardiovascular disease, hypertension, and diabetes, before making a decision at the institution of ADT and who should get an agonist and who should get an antagonist?
Jahan Aghalar, MD: Within the prostate cancer realm, we have not been using cardio-oncologists in particular. We’ve been reserving that subspecialty mainly in patients who are going to be receiving anthracycline-type chemotherapies and women with breast cancer. In terms of prostate cancer, my goal is to ensure that the patient in the room understands that their cancer diagnosis does not mean they only have to follow their oncologist, or their urologist, or their radiation oncologist and that’s it.
On the contrary, if anything, they already have a good relationship with their primary care physician. They need to make sure that they continue that relationship and go there for their annual or perhaps even biannual checkups to monitor their lipids, blood pressure, and blood sugar. If they have a cardiac history, that’s more reason to make sure that they are being compliant with the medical therapies that they are on. That’s a very, very important topic that I go over with all my patients at the initiation of androgen deprivation therapy, letting them know that I’m very confident that we’re going to be able to be controlling their cancer going forward with the hormonal therapy that we’re going to be providing. At the same time, we have to keep in mind that there is a real risk to their heart health that we can’t ignore.
Raoul Concepcion, MD, FACS: I think there are more and more data, and it’s going to be interesting to follow this, especially now that potentially within the next year or 2 we may actually have an oral LHRH antagonist. Paul, I know you were on the clinical trial looking at this. Tell us a little about this new potential oral LHRH antagonist, which I believe just reported some data out recently.
Paul Sieber, MD: The investigators did. They just reported their phase III data, and I think the interesting thing was everything we’ve done to this point has been injectable therapy. If someone takes it out of the patients’ hands—in terms of compliance or other interactions that an oral might bring to the table—but the data on relugolix were that it did maintain testosterone and it did adequately castrate, that is tremendously exciting. Secondly, a little different in the head-to-head study here of this versus a standard superagonist was that recovery was much faster. Onset is rapid; recovery is faster.
As mentioned earlier from Gordon Brown, what’s that mean with cardiovascular? I think 1 of the limitations of our current injectables is they’re short-acting. That is, there’s only a 1-month depot, and that’s somewhat of an annoyance for patients with longer-acting depots available in the superagonist category. But now we have an oral that would totally go around that, so it’s really going to be interesting to see how that plays out. Then again, it’s an oral agent, which brings insurance issues to the forefront in the US because suddenly you’re taking drugs that are generally Medicare Part B and introducing a new drug that is Medicare Part D, which is going to be an interesting hurdle to overcome.
Raoul Concepcion, MD, FACS: I think that to wrap up this segment, it’s important that we are becoming more and more aware of ADT. There are going to be new choices. There are going to be new therapies. But we need to be very cognizant of the adverse-effect profiles and what they mean, given that ADT continues to be the foundation for all advanced therapeutics moving forward.
Raoul Concepcion, MD, FACS: That was a really nice discussion about current issues we’re facing with ADT [androgen deprivation therapy]. Again, I think most of us fundamentally believe, looking back at the seminal work of Charles Huggins and Clarence Hodges, that androgen deprivation therapy with the lowering of testosterone continues to be foundational. We’re going to talk a little more about that and why that’s confusing to some patients, especially once they come into this castration-resistant realm.
But let’s go to this next, because it seems to be gaining a lot of interest: is this patient of metastatic castration-sensitive prostate cancer? Obviously, these are patients who, in my thinking, can get here 2 different ways. They’re either the patient who has been definitively treated with radiation therapy—whether that’s external beam, brachy, or combination—and then lost to follow-up and, lo and behold, they show up, whether it’s in an emergency department, urologist, medical oncologist, and they have widespread metastatic disease. Or I think what has happened clearly over the past 5 years, because of the whole argument and discussion about PSA prostate-specific antigen and early detection, are these patients who are showing up with de novo metastatic disease having never seen a urologist or had a biopsy, and all of a sudden, boom, they show up in pain, and they have widespread metastatic disease.
Historically, the procedure has always been to do a biopsy, and if this biopsy is positive and they have metastases, go ahead and start them on ADT and see what happens. As we all know, over the past few years, we’ve had multiple trials that have led to the approval of the addition of other agents with ADT. Dr Garcia, walk us through the key registry trials that are changing the paradigm for the management of these patients?
Jorge Garcia, MD: Thank you, Raoul. Let’s first perhaps review the concept. I think you touched upon that, which is the definition of what we see. As you pointed out, for me, when I see someone with castration-sensitive metastatic prostate cancer, it simply means that either you have never received ADT, meaning you have never been castrated and developed metastatic disease, which were very uncommon in the past. I would argue probably the incidence of de novo metastatic disease after PSA became part of what we do routinely, and for follow-up of prostate cancer was in maybe the single digits in the United States compared with the European region.
If you look, then, at after 2012, I want to dispute the United States Task Preventive Force. Clearly, with the recommendation against PSA screening and prostate cancer screening in 2012, the incidence of prostate cancer patients walking into the office with de novo metastatic disease has substantially increased. I don’t think we have contemporary data to suggest what that number really is, but I would argue, at least based on my practice and what many of us have seen, it is probably going to be in the double digits, maybe 12% to 15%, maybe even mimicking what the Europeans have seen for many years because of the lack of PSA screening.
If a patient walks in the office with de novo metastatic disease, if they have not seen ADT, or androgen deprivation therapy, they’re castration-naïve. If they have seen it with the roughly 3 months or so and they’re already responding to treatment early on, they’re castration sensitive. But those 2 aren’t the same patient population. The other patient population, and you referred to it earlier, are those men who have received local definitive therapy for their prostate cancer. For whatever reason were not progressed biochemically, perhaps waiting until they developed metastatic disease. Then basically they walk into the office with metastatic prostate cancer.
When you think about those patient populations, the standard of care has drastically changed, at least for me, since 2013. That is when we released the ECOG data, called the CHAARTED data, that basically addressed a very simple question: if we do docetaxel-based chemotherapy up front in that setting rather than wait until men become castration resistant, who will live the longest, period.
It is important to actually home in on the definition of who those patients were. This is a bit more complex, but actually we’re talking about 2 different patient populations: those who are called low volume and those who are called high-volume disease. I tell my patients that right now volume is important, and intensification of therapy is needed. In the CHAARTED data, all comers had high- and low-volume disease, although the bulk of the patients on the CHAARTED disease were high-volume disease. The bottom line is that data demonstrated unequivocally that across all comers in that trial, men who received ADT and docetaxel-based chemotherapy, specifically 6 cycles of docetaxel given every 3 weeks—standard fashion, 75 mg/m2—had a superior survival compared with those men who only received ADT.
If you split the makeup of those patients, which was prestratified of the entry criteria, we recognize that the patients who benefited the most were those patients with high-volume disease, and the hazard ratio, which is the relative risk reduction in mortality, was almost 40%. That’s huge, right? We haven’t seen that in prostate cancer. That for me changed the paradigm in the management of our patients.
That was complemented also in the same year with the results from the STAMPEDE data. STAMPEDE is a very complex trial design, which is what we call a multiarm, multistage design where you have a backbone of a treatment—in this case ADT—and you add treatment that may actually complement that ADT. At some point, you can remove them or you can start building based on how the field is changing. They also demonstrate that the addition of docetaxel-based chemotherapy to ADT drastically improves survival. In STAMPEDE, they didn’t at the time divide patients based on volume. It was all comers. Later, they recognized actually that again, patients with both low-volume and high-volume disease benefited from the addition of docetaxel-based therapy. That’s the first pass of the data, and it changed how we practiced.
Then came LATITUDE, which is the French data that Karim Fizazi presented at ASCO [the American Society of Clinical Oncology Annual Meeting] 2 years ago, in 2017, whereby they specifically selected high-volume patients. And the definition they used for high-volume patients was a bit different, and we can talk a little more about what that definition looks like, compared with the American definition. In that data, they demonstrated that the addition of the biosynthesis inhibitor abiraterone acetate, or Zytiga, to ADT or ADT and placebo also drastically improved survival for those patients on the combination arm therapy. The hazard ratio was quite similar, almost 0.63, almost a 37% risk reduction in mortality when you add ABI [abiraterone acetate] to that regimen.
STAMPEDE also had an arm with ADT and ABI [abiraterone acetate], yet again they demonstrated that the addition of ABI [abiraterone acetate] in the British data also improved survival drastically. With those 3 big randomized contemporary trials, we know 3 things. We know what is the outcome of someone with metastatic disease, median survival around 44 months. We know what the median survival for someone with high-volume disease is, however one defines high volume in the French and American definitions. That is around 33 months, 34 months for both trials, respectively, and goes up to around 34 for the LATITUDE and 59 for CHAARTED. Hazard ratio unequivocal. That has changed the standard practice for us, and in my opinion what is sad for me to hear is when you look at that data in the United States, almost two-thirds of men with advanced prostate cancer or castration-sensitive or naïve-metastatic disease still are receiving ADT alone, which is, in my opinion, unacceptable.
Raoul Concepcion, MD, FACS: Right, and I would echo that 100%. It is amazing that this data have been out there now. CHAARTED was published 4 or 5 years ago, right, and still less than 50% are getting a secondary therapy despite the data.
Raoul Concepcion, MD, FACS: Jahan, Jorge did a wonderful summary of sort of the data that [support] docetaxel and abiraterone. We have a couple of other agents that have been approved in the castration-resistant space and are now obviously moving into the metastatic castration-sensitive. Give us a little overview about what those trials are looking like and where we see these drugs essentially, hopefully getting approved.
Jahan Aghalar, MD: In the last 2 years, we’ve seen a handful of trials looking at other agents in this space, in the metastatic castrate-sensitive space, particularly in the TITAN trial looking at apalutamide, which was initially FDA approved for the nonmetastatic castration-resistant setting. We’re going to discuss this later, to see whether there’s any role in using this agent in the castrate-sensitive metastatic space.
A unique [point] with this trial was the fact that investigators did not necessarily discriminate between high-volume and low-volume disease, although they did stratify those patients. They also did allow lymph node–positive disease up to 2 cm. And they actually found that not only was there a progression-free survival benefit, but there was actually an overall survival benefit irrespective of the degree of volume of disease, whether there was low-volume or high-volume disease. Today, data for docetaxel have not been supportive, in terms of providing an overall survival benefit in the low-volume patients.
There have also been 2 large randomized trials looking at the usage of enzalutamide in the same setting, 1 being the ARCHES trial published by Dr Andrew Armstrong’s group in the JCO [Journal of Clinical Oncology] this year, along with the ENZAMET trial at ASCO [the American Society of Clinical Oncology Annual Meeting] this past year. Although the ARCHES trial did not show an overall survival benefit, many experts are confident that there is a survival benefit, the data just haven’t matured yet. The interim analysis did show a very significant radiographic progression-free survival of about 22 months.
The ENZAMET trial also did show benefit among multiple parameters. As of now, there is no FDA-labeled indication for enzalutamide within this space. However, there’s an NCCN [National Comprehensive Cancer Network] compendium category 1 recommendation in terms of using it. And there’s an ongoing trial by the name of ARASENS using the newest androgen receptor blocker, darolutamide, and we are eagerly waiting for the results of this trial.
Raoul Concepcion, MD, FACS: It’s important for the viewer to really recognize that. To your point—and it’s a very strong, important point—again, right now based on what Jorge presented, from CHAARTED, LATITUDE, STAMPEDE, and obviously TITAN, those are drugs you can readily use in this metastatic castration-sensitive disease. It’s still waiting to happen relative to basically ENZA [enzalutamide] and obviously darolutamide.
Jahan Aghalar, MD: One other point I would like to make is that we are now seeing patients who have already received docetaxel. I just want to point out as well, in the trials that I just mentioned, they did include patients who had previous docetaxel as well. In particular, in the TITAN trial, that group did not necessarily show an overall survival benefit, but that might be because of lack of maturity of the data.
Raoul Concepcion, MD, FACS: Right.
Jorge Garcia, MD: If I may expand on that a little, because I think that’s a very important point. There are 2 camps of practitioners right now for us: those who believe in chemotherapy up front and those who believe in an oral agent up front. I just don’t know that we have any data to suggest that 1 agent is better than the other agent, oral versus chemotherapy. I also want to actually comment that if you look at the latest STAMPEDE follow-up—and that data was presented by the British group at ESMO [European Society for Medical Oncology Congress] in Barcelona over a month ago or so—it does appear that there is no heterogeneity in the 2 volume patient populations, indicating perhaps that docetaxel still could be a viable option for people with low-volume disease.
Most of us in the United States probably feel that low-volume disease should get an oral agent, perhaps the perception of adverse effects of chemotherapy. But it’s important to recognize that oral therapy has toxicities even when you start early on. Chemotherapy also has unique toxicities when you start early on.
The second big question is the timing of utilization of these agents. By that I mean, did you do ADT [androgen deprivation therapy]–docetaxel? Did you complete docetaxel and did you follow up with an oral agent sequentially? Or who are the patients who may benefit from triple therapy, which to your point, Jahan, is the ARASENS data. ENZAMET had to run 40%, 50% of patients who were getting triple therapy. That data did not show survival benefit and all this immature data. There are a lot of concerns. I’m concerned about that data because I just don’t know if maybe the interaction between oral therapy and docetaxel, and perhaps liver metabolism, can influence PK [pharmacokinetics] and PD [pharmacodynamics]. One of those 2 agents may minimize the effectiveness of the triple regimen. We have to wait for that data to mature, certainly for ENZAMET and for ARASENS to actually get published just to really see who the patient populations are who benefit most from that triple up-front approach.
Jahan Aghalar, MD: The other way to interpret that data is that perhaps docetaxel in and of itself is enough to provide that overall survival benefit. If you want to add any therapy at that castration-sensitive setting and perhaps add an oral agent at that point, it may be a little premature. We’ll have to see how the data mature.
Raoul Concepcion, MD, FACS: You know, the other thing that we don’t know, because all the trials were designed, you either got ADT or you got ADT-plus immediately. What we don’t know is, can you get ADT, delay, and then add on? When does that take place? Because in all the trials, it’s all or none. It’s basically all or none.
Jorge Garcia, MD: But you would agree that you and I, and all of us as a group, would be very disturbed with this data today in 2019 if we find patients who actually get ADT up front, wait for the presumed benefit—which is probably seen in around 90% of patients or so—and the physicians or practitioners feel comfortable just keeping the patients on ADT because they’re benefiting from therapy. And I think although the PFS [progression-free survival] reduction is great, you are sacrificing mortality and you’re sacrificing the benefit of that survival improvement if you don’t intensify therapy.
Raoul Concepcion, MD, FACS: I think the data that you quoted with less than 50%, it’s the 30%-to-40% range of patients who are getting ADT that holds for both medical oncology and urology.
Raoul Concepcion, MD, FACS: Paul, Gordon, you guys are very active. Comment, if you will, about how this plays out: low-volume, high-volume, ADT [androgen deprivation therapy] plus the addition. How are you driving that home in your group, and how are you educating your partners? Because the reality is that in the United States, most of the ADT for this patient still gets started by urology.
Gordon Brown, MD: Right. It’s a great question. Within my group, we have internal mechanisms to identify these patients, and they’re shuttled internally to the right people to get the appropriate care. In our group, I think part of the care patterns are going to be dependent upon the tools at your disposal. Because based on the data, for the NHAs and the oral therapies, they’re agnostic as it relates to volume of disease. Whereas, DOCE [docetaxel] doesn’t seem to be as agnostic. Really, the benefit is primarily in those patients with higher-volume disease.
Because of that, my main message to my partners is that DOCE [docetaxel] isn’t for low-volume guys. We define that arbitrarily as 4 or more bone lesions, 1 being outside the spine or pelvis and/or visceral involvement as a high-volume patient. But the main message that we speak about when we go to the community and educate other providers is that patient ID [identification] is exceptionally important. And understanding that there are good, viable options that significantly improve the survival of patients is our duty as doctors—to identify these patients appropriately, even if we don’t choose to take on their care but get them with somebody who will.
Raoul Concepcion, MD, FACS: Paul?
Paul Sieber, MD: I think you’re right when you said the patients come to us first because they’re coming in with symptomatic disease. We’re up in the double-digit numbers of people presenting with metastatic hormone-sensitive disease, so they’re coming to see us first. But I think the comforting thing for us, as Jorge Garcia said, the PK [pharmacokinetics] changes, so we feel like, hey, we want them on ADT, we want their performance to improve. Many times, they come in with urinary retention; a couple of months later, they’re better.
Our goal is to basically move on at 2 to 4 months, to say they’re ready for us. And the high-volume guys, as Gordon defined, they get docetaxel. And my oncologist and I work very closely together, and basically if the guy is a candidate for docetaxel, he gets it up front. Our feeling is that if he’s not a candidate for docetaxel now, when is he going to be a candidate? We’re fearful that so many people never see docetaxel, that if their best shot of it is up front and it’s defined, it is 6 doses. So they get it up front, and they typically start after a couple of months.
For us the paramount thing is we have a referral process, just like Gordon. They automatically get shuffled to the guys who were experts, the same thing as well. My expertise goes straight to my medical oncologist, and he’s on my speed dial. And we say this guy is ready, he’s tuned up, he’s had his 2 months, he’s way better. Typically, high-volume goes to docetaxel and low-volume always goes to orals, and that oral guy may never come back to docetaxel. That’s not what happens. We talk about it, but a significant number of people never see docetaxel.
Raoul Concepcion, MD, FACS: Right.
Gordon Brown, MD: That’s a very important point. I want to make just 2 comments. One is that there’s a perception that there’s no toxicity associated with the oral therapies, and that’s not true. There’s both real-world physiological toxicity in the patient, and there’s financial toxicity, and there’s a length of therapy. That’s an important concept that Paul articulates. The other thing I wanted to touch on was there are additional data from the STAMPEDE, what Dr Garcia mentioned earlier, relating to the role of definitive local therapy in patients with lower-volume metastatic disease and radiation. There’s a trend a little toward improvement of overall survival in that patient population. That does deserve at least a mention.
Raoul Concepcion, MD, FACS: From a time perspective, this whole concept globally—to your point of what we do with the primary—historically is basically [if] the cow, the horse is out of the barn, we don’t touch the primary. But I think what we’re seeing is that there are clearly some advantages to treating the primary, not only where a patient is symptomatic from an obstructed prostate but also from a molecular standpoint because these clones can go back and reseed. Basically the prostate primary acts as a reservoir almost. But I think the point for this segment is, Jorge, to your point, it’s an excellent point, that in 2020, if a patient has metastatic castration-resistant prostate cancer, ADT by itself is probably not the standard of care. We have to do a better job of educating our colleagues, our partners, to sort of encourage them to look at the additional drug that mechanistically is different but also taken into account the volume of disease.
Raoul Concepcion, MD, FACS: In this next segment, we are going to—let’s just review the progression of patients. Again, I am a big stickler moving forward, not even just for advanced prostate cancer but even for localized prostate cancer. Especially as urologists, we need to be talking about risk stratification—very low risk, low risk, favorable, intermediate, etc. But clearly, as we move into this advancing patient, of metastatic, nonmetastatic patients, to be able to identify these patients, understand the clinical trials that have gone into the “standard of care” for these patients I think is critically important.
We’ve talked about these 2 buckets of castration-sensitive patients. Now let’s move into an area that really started all this back in 2010, which is this concept of castration-resistant prostate cancer. Again, these are patients who historically we spoke of as hormone resistant and androgen insensitive. We’ve adopted this terminology of castration-resistant prostate cancer, understanding that these patients—despite castration levels of testosterone—will progress, and they will progress with rising PSAs [prostate-specific antigens].
To me, castration-resistant prostate cancer has a straightforward definition. It’s a patient with an ICD-10 [International Classification of Diseases, Tenth Revision] code of prostate cancer. They’re on an androgen deprivation therapy [ADT], whether LHRH analogues or bilateral orchiectomy. They have a rising PSA, generally by clinical trial, at least 2 or 3 consecutive rises taken on or 2 weeks apart.
And now, depending upon that, are they nonmetastatic or metastatic? Let’s first talk about, I think this is an arbitrary definition of nonmetastatic castration-resistant prostate cancer. These are patients who are on ADT. We know their testosterone is in the castration range. Their PSAs are going up, but with traditional imaging; traditional imaging being defined as bone scan, technetium-based bone scan and CT [computed tomography]. We’ll talk a little about the utilization of next-generation imaging and biomolecular scans. Gordon, walk us through the current trials that have brought various agents, which have really taken place over the past couple of years for this nonmetastatic castration-resistant prostate cancer patient.
Gordon Brown, MD: Thank you, Raoul. It’s an interesting topic. You did a great job outlining the disease state, understanding where we are in that patient with a testosterone of less than 50 [ng/dL] with a rising PSA and negative traditional imaging by CT scan and bone scan. As urologists, historically we really have had a dearth of therapeutic options. We really haven’t had anything to offer these patients. We basically had to watch them, or we’ve given them therapies that we know have been less than effective over time, waited till they developed metastatic disease, and now, you know, treated them in a landscape of new novel hormonal agents or sent them to medical oncology colleagues for Taxotere.
We do know, however, what the natural history of this disease is, trying to identify those patients at highest risk of progression based on the historical work of Matt Smith and Fred Saad looking at something called PSA doubling time. We know that those patients who have rapid PSA doubling times, defined usually as inside of 10 months, are at the highest risk for both metastasis as well as death from their disease.
These trials really focus on those patients who are at highest risk of disease progression and subsequently death from their disease and trying to really to modify the natural history of that disease. There have been 3 recently published trials. The first was the SPARTAN trial, which was utilizing apalutamide in patients who had castration-resistant nonmetastatic prostate cancer. I think we should note that all these look at PS [performance status] as conclusion criteria, PSA doubling times inside of 10 months. All of them have ECOG performance status of 0 or 1. All of them are nonmetastatic by traditional imaging. And they all use MFS [metastasis-free survival] as their primary endpoint, for metastasis-free survival.
Which for us, as urologists, is really the first time we’re seeing this commonly utilized in our literature to define end point for a clinical trial defining efficacy. We’re really utilizing that as a surrogate for overall survival based on the ICECaP [Intermediate Clinical Endpoints in Cancer of the Prostate] data.
From the SPARTAN trial, what we’ve seen is an improvement in metastasis-free survival of about 24 months and a reduction in risk of disease progression over time.
In the PROSPER trial what we’ve seen is an improvement in metastasis-free survival by about 22 months with the use of enzalutamide in patients with high-risk castration-resistant nonmetastatic prostate cancer. And most recently we have a report from the ARAMIS data that looks at the use of darolutamide, or Nubeqa, in the same patient population, showing a similar improvement in metastasis-free survival, about 22 months in patients at high-risk for progression of their disease.
This data, and it’s collected, suggest that we have to look for these patients within our practices. Right now we have data that really suggest that we could potentially extend the disease state over time and delay progression of disease. There may be implications with overall survival benefit, which are not mature yet. But now the burden rests on us in our advanced prostate cancer clinic to actively find these patients in our practice.
Raoul Concepcion, MD, FACS: Basically, in all these trials, these were nonmetastatic patients. To get into the trial, I think it’s important for the viewer to understand that, because this is where I think trial design and understanding trial design is very important when it comes time to clinically treat these patients. Correct me if I’m wrong, but pretty much for all 3 of these trials, to get in you had to be on ADP. You had to have a negative bone scan and CT. You had to have a PSA doubling time of less than 10 months. You had to have an absolute PSA value, though, of greater than 2, right?
Gordon Brown, MD: Correct.
Raoul Concepcion, MD, FACS: I think that, as you summarized very nicely, all 3 trials, although we can’t cross-compare trials, pretty much all of them showed with any of these androgen receptor blockers that there was clearly a benefit.
Raoul Concepcion, MD, FACS: Jahan, what if I have the patient with a PSA [prostate-specific antigen] doubling time of 12 or 14 months? How does that affect your decision making, understanding that we kind of know where these patients are going? Does it really fit the criteria that Gordon Brown just outlined? How do you look at that patient?
Jahan Aghalar, MD: You have to look at the individual patient and also consider what potential risk they may have and from the actual treatment itself. Apalutamide did show a significant risk of fall and fracture. If you are dealing here with an older patient walking in with a cane into your examination room, do we really need to put him on such a drug? First, he doesn’t fall within the trial eligibility criteria. Second, we’re not so sure whether there’s an overall survival benefit. There is a metastasis-free survival benefit, which I think is a clinically meaningful end point, but at the same time, if we’re putting that risk of having a fall and a potential fracture, have we done him a good service?
On the other hand, if we’re dealing with a younger patient in their 50s, with no major comorbidities, we feel pretty confident that his bone health is fine; he may have had a normal bone density recently. I think it would be worthwhile to introduce 1 of these agents for that meaningful end point, which as I mentioned would be metastasis-free survival.
Raoul Concepcion, MD, FACS: All right. Jorge.
Jorge Garcia, MD: I’m a bit more pragmatic about that. Maybe it’s the surgeon in me, who would tell me that if you look at the concept of M0 CRPC [castration-resistant prostate cancer], it’s something we have induced as a group, right? As you mentioned in an earlier segment, Gordon, someone who has undergone local definitive therapy, radiation, surgery, and the combination in a sequential manner, who has progressed biochemically and had a rising PSA or biochemical recurrence, you make the decision to start that patient on androgen deprivation therapy [ADT]. Whether you did it intermittently or continuously, what happened is you render that patient castrated. You castrated that man, and then basically a patient became castration resistant. More than likely, because the natural history is driven by PSA first for most patients, you will find that patient has M0 CRPC.
It would be very hard, in my personal opinion. I’m not saying that it’s right, but to tell a patient, “I started you on ADT when you had biochemical recurrence, after surgery or radiation therapy. And now that your PSA is rising again, despite you being castrated, I’m going to wait, and I’m going to wait for your PSA to really move faster.”
This is a pretty foreign concept to me, so I would argue that if I started you on ADT, because I felt the need for you to have ADT because of biochemical recurrence, it would be difficult for me not to put you on a therapy where you have a doubling time of 15 months, 10 months, 13 months, and so forth. I think it’s very important. You raise a great point. These agents don’t come without a financial toxicity, and without physical toxicity, diarrhea, and the adverse effects from all these agents.
It is a class effect, in my opinion. Right now, I also remind ourselves that if you look at the makeup of these drugs, 2 of 3 drugs did allow patients with up to 2-cm lymph nodes. Traditionally, if I were to get a patient with a CT [computed tomography] with a couple of 1½- or 2-cm lymph nodes, although that patient may have met the criteria for the trial, for me that patient really has metastatic disease, right?
But you know, a lot of people think that we think of our prostate cancer patients in a very linear manner, which means, what is your doubling time? Did you have it scanned, yes or no? And I think most of us will pay attention to how long it took you to fail. How long were you on ADT? What was your Gleason score from diagnosis? What was your primary treatment? There’s a series of features of your disease that would allow you and I, clinically speaking, to say, “You know what? Even if your doubling time is not moving that fast, I think it’s important for you to get on therapy.”
Lastly, as we have said before, this is the first time the regulatory agencies allow a different primary end point for registration outside survival. And we have come to a realization that delaying clinical symptomatic disease, delaying radiographic progression or time to death from any cause, may be more meaningful to our prostate cancer patients than whether you truly lead to survival improvement.
Matt Smith at ESMO [the European Society for Medical Oncology Congress] presented the earlier analysis for survival for TITAN, for the SPARTAN data. And that data would suggest that it’s very close to meeting survival improvement, right? If we finalized those trials and we have a survival improvement that we can see and demonstrate statistically, the community will adopt these agents far more with open arms than now.
Raoul Concepcion, MD, FACS: Jorge, great, great points. Great comments. Gordon, as you mentioned, 5 years ago, for all of us who were on clinical trials, if we had identified this nonmetastatic M0 patient based [on] the historic Matthew Smith data, within 2 years 50% of these patients would have ended up with metastatic disease radiographically. It was very frustrating if you did not have an M0 trial to just sit here and say, “OK, I know what you have, but I got nothing.”
Jorge Garcia, MD: Right.
Raoul Concepcion, MD, FACS: You can probably get away writing on compendia, but the grim reality was, that’s what we were stuck with. Paul, I’m going to direct this question to you, because I’m convinced that the urology community is probably the guiltiest. We have 3 agents with great trials, have benefit. But we still have a significant number of—and I’m just going to pin it on the urologists who are using first-generation anti-androgen bicalutamide. Is there a role of bicalutamide in this castration-resistant prostate cancer patient, nonmetastatic?
Paul Sieber, MD: If he suffers from severe PSA anxiety, maybe. But that’s about it. I think that’s what I would have argued even earlier when Jahan was talking about the guy who’s got a PSA doubling time at 14 months, 16 months saying, “Well, I’m going to about it”—no data, no data. We’re treating a number. The trialists I know from prostate cancer were in group 1 and then 2 and 3. PSA is nice, but there’s more that comes into play. I think I want to have hard facts. I don’t care what the package insert says; the study was less than 10 months. I stick to 10 months. I’m never going to fall back to a bicalutamide, because you have no data. We’re just playing with numbers, as we learned a long time ago. When you play with everyone getting superagonists to check a PSA recurrence, it’s the wrong thing. You’re hurting people.
I think you’re making a mistake, and I think you want to carefully individualize who gets treated even in this category as we talk about adverse effects, because we’re learning their adverse effects. Two of 3 drugs now carry cardiac warnings.
If I had a guy who’s had 2 angioplasties and the stents in the last 5 years, do I want to put him on a drug he’s going to be on for 3 years? He’s going to have to come off drug. I’m looking at adverse effects a lot more judiciously now. It’s in-depth history. I take a bone history now. I take a genetic history now. I take a neurological history. If the guy had a severe conclusion playing football, I worry about that guy. Maybe he’s the right guy to say, “OK.” But even now, I’ve got other agents that have other adverse-effect profile patterns for whom maybe not crossing the blood-brain barrier with darolutamide is going to make a difference. They did treat people with seizures. You have to think about a lot of factors when you’re saying who gets treated. But certainly, throwing a drug like Casodex—which has no data, just PSA response—is probably the wrong thing to do in 2019.
Raoul Concepcion, MD, FACS: I think all of us would agree that it’s up to us to treat the disease and not treat a number. We have to treat the disease, and you have to look at it in its totality—what’s happening at the molecular level. As you said, Paul, understand the data in terms of risk-reduction benefits and those types of things.
Raoul Concepcion, MD, FACS: We have sort of mentioned—and I think we’ve done a very nice job of reinforcing this concept—that this whole nonmetastatic M0 CRPC [castration-resistant prostate cancer] patient is very arbitrary. The reality is, yes, using traditional imaging, they are nonmetastatic. But at a molecular level, at a cellular level, we know they have micrometastases.
Here we are now. What about the role of biomolecular scans and next-generation imaging? I’m going to open this up. Gordon, I’ll start with you. What are you using? Give us a little about what’s available to your practice. What do you think is going to be coming up, and how is this going to change management?
Gordon Brown, MD: Sure. We, as first-line treatment, still go with CT [computed tomography] scan and bone scan, and we go to second line with more sophisticated imaging, specifically Axumin scanning, which is readily available in our community and is covered pretty routinely by our payers.
We do that in patients who have an equivocal bone scan or CT, or in those patients we believe to be really at high risk in the presence of a negative CT scan or bone scan—where a positive scan will really make a therapeutic difference for us in terms of accessing available therapies. That’s how we’re currently utilizing Axumin in our practice. We don’t routinely get an Axumin on everybody, specifically from a cost, and in payer perspective that’s a little challenging.
We do see the advent of PSMA [prostate-specific membrane antigen] scans on the horizon. That’s going to allow us to open a whole new field of not only diagnostics but also potentially therapeutic options for patients with advanced prostate cancer. And that’s going to be the next wave of excitement here for these patients.
Raoul Concepcion, MD, FACS: Jorge?
Jorge Garcia, MD:I agree with Gordon. I think all our patients who have a rise in PFS [progression-free survival] after local definitive therapy have metastatic disease. The question is the ability to detect that metastatic site of disease. I think PSMAs are likely to become the imaging of choice in the future, but right now they’re not FDA approved; they’re quite expensive. Fundamentally I think the challenge we’re going to be facing is simple: whether to identify metastatic disease on a metabolic imaging test. If we act earlier, it affects whether we’re going to really impact the natural history of the disease. That’s No. 1. And No. 2 is to your point, Gordon. If you have someone with a bone scan that is negative and a CT scan is negative, and the patient has a rapid doubling time and you get an Axumin or you get a PSMA/PET [positron emission tomography] and you find disease, then you may be bound to treat that patient. The bigger question is, how are you going to follow that patient with imaging? You’re not going to be able to revert and look at a CT or a bone scan. You’re going to have to commit that person to a PSMA/PET or an Axumin. I can only imagine the cost when we do that follow-up.
Raoul Concepcion, MD, FACS: Jahan?
Jahan Aghalar, MD: At our practice we start with a traditional CT and bone scan. A PET Axumin scan, almost unequivocally we would order for the patient who is in the recurrent state and for whom we are considering salvage options, such as salvage radiotherapy, to ensure there’s no evidence of distant metastatic disease. There’s a role for a PET Axumin scan within that setting. Outside a clinical trial, we haven’t been using other tracers, but I agree totally with Gordon’s point, that it’s very exciting for the future, with the ability to have PSMA scans that may have therapeutic implications.
Jahan Aghalar, MD: The other role where sometimes a novel tracer may or may not impact outcomes is the treatment of oligometastatic disease. What do you do with a patient who has a slowly rising PSA [prostate-specific antigen]? You get the PET [positron emission tomography] Axumin scan, and you see 1 side of disease on PET L4. Do you go after it? Do you ablate it with radiation? Are we going to impact the trajectory of the disease? In those settings it brings up some interesting questions that will be brought up within the examination room and also hopefully within the realm of research.
Raoul Concepcion, MD, FACS: So Paul, Jahan brings up an interesting point. This concept—and I think this is going to become a bigger dilemma, especially for the busy clinical urologist—of oligometastatic disease at diagnosis. What do you do with the primary? The current definition by most people, although it’s not standardized, is less than 5 METs. Now we have the primary to deal with, we have mechanistically some different agents, and we have radiation. How do you see that playing out, basically with oligometastatic disease? Because we’ve talked about the deleterious effects of ADT [androgen deprivation therapy]. People necessarily don’t want to stay on long-term ADT, so for these patients, have you been using some of this next-generation imaging? How have you chosen? If you find somebody with a biochemical recurrence who, as Jahan said, maybe has an isolated lymph node that maybe you can go after. Are you going after them surgically and [spare] the patient ADT?
Paul Sieber, MD: Yes and no. If I have nodal disease, I’m looking at stereotactic radiation. If I have bone disease, I’m looking at stereotactic. In my most unusual cases—I had a guy with solitary metastasis to the testes, and now that he’s 2 years out with an undetectable PSA, with a rising PSA previously—I’ve got, oh my gosh. It’s all anecdotal data, but we’ve seen some real spiking responses in treating minimal metastatic disease with stereotactic treatments.
So yeah, for the moment I’m stuck with that. I also introduced a concept of immunotherapy. Immunotherapy works best when there’s low-volume disease, so I like a guy with low volume to introduce the concept of immunotherapy. Once again, I’ve seen some unusual immunotherapy responses in guys with that small volume of disease. It’s all anecdotal. The problem is, I don’t have data. But I don’t know what to do with it. Without data, I’m moving ahead saying, “I’ve got something to treat.” And I’ve got enough anecdotal cases to say, “I want to continue to do that.”
Raoul Concepcion, MD, FACS: I think it’s important for the viewers to remember that right now, fluciclovine, or Axumin, is currently approved. It’s approved in the United States, and it has to be a patient who has been diagnosed with prostate cancer and has been treated. It requires no other documentation. They don’t have to be CRPC. In a lot of markets, active surveillance is considered a treatment. Currently right now, as we sit here, that is the only FDA-approved biomolecular scan. As we talk about PSMA [prostate-specific membrane antigen], we think it’s going to be on the horizon. There are all kinds of issues obviously with PSA limitations and those types of things. But I think because most of us have discussed in this segment that this is an area, there’s a lot of attention and now there are obviously new therapies that are made available to our patients. Gordon, to your point, it is the early identification that’s important.
Raoul Concepcion, MD, FACS: Gents, this has been a great discussion. Let’s wrap up with the patient who started all this, the metastatic castration-resistant prostate cancer [CRPC] patient. To just give a definition for the viewer, CRPC is defined as a patient with prostate cancer who is on hormonal therapy, whether it’s ADT [androgen deprivation therapy] or bilateral orchiectomy; with testosterone in the castration range, currently defined as less than 50 [ng/dL]; and a rising PSA [prostate-specific antigen], generally at least 2 [ng/dL] rises taken at least 1 to 2 weeks apart.
We’ve had a robust discussion on the nonmetastatic patient. Let’s talk about this patient who—again, there will be more options—is a metastatic castration-resistant prostate cancer [mCRPC] patient. Dr Sieber, my friend, this is what started all this back in 2010. Give us a little bit of an overview. Give us the current landscape of approved agents for mCRPC. I’ll let you decide if you want to do it mechanistically or how you want to give us that summation.
Paul Sieber, MD: It’s so much easier mechanistically. There aren’t that many I have to go through, right? I have only 4 different classes to talk about. I could talk about cytotoxics, which include docetaxel and cabazitaxel. We’ve got 1 immunotherapy, Provenge. We’ve got 2 orals—slightly different categories but 2 orals. We’ve got both abiraterone and enzalutamide. And we have 1 radiopharmaceutical, radium-223. In the category of designed agents to treat metastatic disease, that’s pretty much it for the moment. But everyone is knocking at the door.
Raoul Concepcion, MD, FACS: Correct. Again, just to be clear, they’re all monotherapy trials. Maybe the only 1 that has a little bit of an exception is cabazitaxel because for those patients, you cannot use cabazitaxel up front unless they have been exposed to docetaxel. Right?
Paul Sieber, MD: Right.
Raoul Concepcion, MD, FACS: There have been all those approvals. Obviously, docetaxel in 2003, 2004; everything else came onboard from 2010 to 2015. And now, Paul, as you said, there’s a host of agents knocking at the door. Jorge, give us a little overview of what we’re expecting in 2020.
Jorge Garcia, MD: I certainly don’t speak for the regulatory agencies or what the regulatory agencies will do. But I think, perhaps to me the most exciting trial in 2019 for prostate cancer is PROfound. The PROfound data actually tackles a very simple question, and that is, DNA repair-deficient patients. For many, many years, we have known that patients who have a DNA repair defect—ie, most commonly people are known as BRCA1, BRCA2 or ATM-mutant patients—can have pretty poor outcomes and oftentimes have quite aggressive disease.
The incidence of true germline mutations, which is ATM, BRCA1 and BRCA2, and many other ones, is pretty low in the United States. You can probably look at the data from Seattle, Washington. The true incidence of germline for men with prostate cancer is probably under 9%, 10%. But there is another series of somatic changes, or epigenetic changes, that also are DNA repair by nature and can also be exploited therapeutically. I think that’s the genesis of these data that started with Joaquin Mateo with what we’ll call the PARP data, which suggested that actually men with metastatic castration-resistant disease who were receiving an oral PARP inhibitor—in this case, olaparib—had a significant improvement in progression and also good PSA declines. When you tease out who these patients were, it appears they were those who had true ATM, and BRCA1 and BRCA2s, so true germline patients.
That was the genesis for the PROfound data that Dr Maha Hussain presented at ESMO [European Society for Medical Oncology Congress] in Barcelona. I wouldn’t say it’s complex, but it’s a randomized trial that basically addressed a simple question. If you have progressive disease in the metastatic castration-resistant setting, you get randomized to get either olaparib or an oral agent, the 1 you have not seen before. If you had ABI [abiraterone] for M1 CRPC, and you get randomized to oral therapy, you will get an oral therapy, the 1 you didn’t receive—and vice versa, enzalutamide followed by ABI [abiraterone].
But the important part of that randomization was that those patients were selected patients based on the type of DNA repair deficiency that they have. Group 1, or cohort 1, was patients with BRCA1, BRCA2, and ATM mutations randomized to olaparib or the oral agents that they haven’t seen before. And the in Group B were patients with any other different DNA repair deficiency outside BRCA1, BRCA2, and ATM. So there’s 8, 12, other DNA repair deficiencies that we isolated. Those patients were randomized to the PARP inhibitor and/or to an oral agent or AR [androgen receptor] inhibitor.
The primary end point of this trial was not for cohort B. It was cohort A, which was actually what I would call the true germline patients. It’s the first time a biomarker-driven approach clearly demonstrated RPFS [radiographic progression-free survival] improvement, and a survival improvement to a PARP inhibitor over an oral agent in that patient population. When you included those groups—cohort A and cohort B, which is basically all the DNA repair deficiencies—that benefit was maintained.
Some of us were a bit concerned as to the impact of that second cohort of patients because there were not ATM, BRCA1s and BRCA2s. But it appears that the hazard ratios were maintained for our PFS [progression-free survival]. We do know that BRCA1 and then BRCA2 are exquisitely sensitive to PARP inhibitors. We do know also that not all DNA repair deficiencies are responsive to PARP inhibitors. That’s something that once this agent hopefully gets up and we can put our hands on this class of agents, we’re going to start teasing out the true patients who may benefit the most from this class of agents.
For me that really is going to revolutionize how we manage patients with DNA repair deficiencies. And it will also add the question as to the utility of platinum-based compounds for those patients. We know that those patients with DNA repair deficiency may benefit from carboplatin- and cisplatin-based therapy and may have some behaviors like neuroendocrine or small cell phenotypes for that matter. That is a pivot on the management of prostate cancer in 2020, and hopefully many years after that.
Lastly, perhaps what a lot of people are enthusiastic about as well, is moving away from the ribonucleotide set of all agents, the alpha emitters, and trying to use PSMA [prostate-specific membrane antigen]—not only as a diagnostic tool, meaning that we don’t use Gallium-67 just to tap PSMA and label someone, but also for therapeutic purposes. And that’s sort of data with lutetium-177. The VISION trial is the largest randomized phase III data that we have. That also is completed, fully accrued, and that data basically were randomized in patients to lutetium PSMA when they have Gallium PSMA-positive disease or standard therapy, dealer’s choice. That data will demonstrate whether this class of agents would really pan out to be part of what we do in the future.
Raoul Concepcion, MD, FACS: Circling back to the PROfound trial versus TOPARP. My recollection is TOPARP required metastases-directed biopsy, correct?
Jorge Garcia, MD: Correct.
Raoul Concepcion, MD, FACS: In PROfound, did they do both germline and somatic testing?
Jorge Garcia, MD: That’s a good question. PROfound used a specific assay that was part of the entry criteria. It was a foundation acid that is not actually part of—obviously, it’s not a standardized FDA approved test. Basically, that can include either liquid, cell-free DNA, an archived material, or a new biopsy. You know? But what I think is important—and we were talking earlier about the importance— is looking for that old material, archived material, because you still can capture some patients and find their DNA mutational changes in archive materials.
You may not need to be restricting your patients to cell-free DNA. Because as we know, some patients don’t have circulating tumor cells. You can rely also on archived material, which has its own complications and logistical challenges. But I think we want to capture the bulk of the patients, because if you look at germline, there’s only less than 10%. If you add on somatic changes, we may be able to actually capture around 15%, 20%, even up to 25% of patients who may be able to benefit from these agents.
Jahan Aghalar, MD: One very interesting point that came out of this trial is not only the results of the trial but the results of the screening that went on with this trial. Out of all the patients that were screened, believe it or not, 30% ended up having either a somatic or a germline mutation to indicate that they would benefit from these, from such an agent. In the clinic, when we’re facing a patient who’s progressing and they’re castration resistant, we should start having that in mind, in terms of somehow or another painting the archive tissue. Or perhaps even ideally getting a repeat biopsy. Or even if that’s not possible, there are liquid biopsies available that can screen these patients appropriately.
Jorge Garcia, MD: That’s for you guys, urologists, because the NCCN [National Comprehensive Cancer Center] Guidelines have changed and put that pressure on and you’ve seen that identifying those patients early on for germline testing.
Raoul Concepcion, MD, FACS: I think it’s important to remember, because as we’ve seen, we’re getting the utilization and approval of a lot of agents earlier on in the course of the disease. Getting back to a point I made earlier, is 1 of the biggest questions from patients that we all have to deal with, right? The patients always ask, “Well, doc, I’ve been on this hormone shot, and you’re telling me I’m getting worse. Why do I have to stay on it?” I think patients clearly don’t understand it. I would venture to say some of our colleagues don’t understand the heterogeneity of prostate cancer, that we know there are certain clones that are going to still be responding to ADT [androgen deprivation therapy]. There are certain clones that are going to be still responding to first- and second-line therapies, but then mutational burden and treatment pressure selection are forcing us to get into all these other mechanistically different therapeutics.
Great discussion on PARPs, radioligands. Gordon, there’s also been some interest on the potential role—early on there wasn’t a lot of interest—of checkpoint inhibitors. What does that patient look like?
Gordon Brown, MD: That’s an interesting question, Raoul. There have been some preliminary data looking at the identification of patients with advanced prostate cancer who might be eligible for checkpoint therapy, in those patients who have mismatch repair that’s the MSI [microsatellite instability]–high patient. That patient represents only a minority, about 3% or so of the patients you know with castration-resistant metastatic disease. But the outcomes that have been published from PEMBRO [pembrolizumab] exposure have been compelling with respect to durable responses in this patient population.
It has received approval for therapy in this same patient population. It speaks again to the need to identify and test these patients for the presence of germline somatic abnormalities, which might open new therapeutic options for them that previously didn’t exist. To Jorge’s point earlier, it’s an exciting time in prostate cancer because we’re truly getting down to an individualized or a personalized approach to therapeutic options that can really maximize patient outcome as opposed to much dirtier, for lack of a better term, approaches historically.
Raoul Concepcion, MD, FACS: I think your point, which is really well taken, is that PEMBRO [pembrolizumab] is the only drug that’s tumor agnostic.
Jorge Garcia, MD: NIVO [nivolumab] too. NIVO [nivolumab] and PEMBRO [pembrolizumab].
Raoul Concepcion, MD, FACS: Again, so MSI-high, the Michigan folks last year reported on CDK12 by allelic loss—you know, all those patients. Now it’s going to come down to…finally catching up with molecular testing to have some testing panels to direct us to…the appropriate next line of therapy based on a panel of tests. Paul, you have been active in looking at the use of testing for hereditary panels and DNA damage repair genes. Give us a little bit of insight about what you think might be the optimal panel. What testing should be included if we have a patient with metastatic castration-resistant prostate cancer who has been through 1, 2, 3 lines of therapies, is still doing great, wants to continue to be aggressive? What should the viewer be looking at in terms of testing to determine the next line of therapy?
Paul Sieber, MD: Do you want this week or next week?
Raoul Concepcion, MD, FACS: Right now.
Paul Sieber, MD: It’s going to change. It’s going to change. I think the only thing I’m doing that segregates people out is if I have a patient who comes in, and I’m going back to my family history, and I find out that his brother had transitional cell, and I find out his sister had breast, and I find out his uncle had pancreatic, I might start to look at a broader panel.
I’m going to broaden it out and say, I want a broad panel. And there are a number of players out there that are offering these 40-, 50-gene panels to look at things that are going to include some of the typical DNA repair-defect genes that we’re looking at in our clinical trials and others. I think that’s a challenge to say, “Is that what everyone should have?” I don’t know. I do a more directed panel if I have a guy who walks in with more isolated disease, and I’m pretty much at this point looking at isolated panels that are going to also lead me then to a clinical trial, because I don’t know what to do with the data.
If I got something like PALB2, I want that in my panel because I’m using that, because I could put him in clinical trials right now. Is that going to be the case when these drugs are approved? I don’t know if they’re going to be approved, but that’s what I’m doing because I have panels that encompass clinical trials for the patient right now.
We will probably see next year the approval of a PARP inhibitor, but there will be a limited panel of people who are eligible. Or there will be a diagnostic, and maybe they’re required to go with that. For now we’re just kind of dabbling. I think we need a genetics counselor involved. They certainly want a broader panel on everybody because they’re going to do an in-depth history. And they’re going to say, “We want a broad swath of people that’s going to include a number of different genes,” versus just those isolated ones that were looking at for trials for right now.
But it continues to be confusing. I mean, now we’re talking about how BRCA is wonderful. Well, now I go to meetings and say, “Well how BRCA-y is he?” Because there are people that I’ve had on PARP inhibitors who are BRCA-positive who have been amazing, and I’ve had other people on PARP inhibitors with BRCA and they’ve just done—worthless. There’s got to be some difference among all these guys who are PARP treated yet they don’t all act the same. And this term BRCA-ness is out there because there are multiple defects. In the beginning of the term, I am BRCA positive.
Raoul Concepcion, MD, FACS: People should remember that there are about 20,000 to 30,000 variants of BRCA. It’s not this isolated, “Oh, you’re BRCA positive.” There are 20,000 or 30,000 variants out there, and some of them—as we’ve talked about off camera—[are] VUS: variants of unknown significance.
I want to circle back a little because you’re a huge institution [Cleveland Clinic], Jorge. You treat a lot of patients. What are your thoughts about metastasis-directed biopsies? To me, you know we talk about CTCs [circulating tumor cells], cell-free DNA, circulating tumor DNA, micro RNA, all these liquid tests. At the end of the day, should we be more aggressive? I realize that bone is a difficult place to biopsy.
Jorge Garcia, MD: We all strive for perfection, but clearly we fall short of it. I think there are very few institutions in the country who will have been successful at doing biopsies to metastatic sites. No. 1, I think that we have not as a group, and it’s fundamental the reasons why. It’s not a lack of effort, lack of interest. You know, patients want something as an exchange, right?
If I’m going to change your treatment basically on the biopsy that I do, I may pursue the biopsy. As you pointed out, 80% to 90% of our patients have boney metastases. They calcify the bones. It’s just complex, right? Half of them will have lymph node disease and very few will have visceral metastases. I biopsy all patients with the visceral disease because I want to get a histology. But I also want to get tumor genomics in that context, and it may change how I treat this patient.
But from the mentality for those men, which is probably the most complex population, boney or very small lymph node disease, it’s very hard to convince them to get a biopsy, unless you do it in a clinical trial. I think for my group at least, we’re going to rely on germline testing, somatic changes, somatic tumor testing in archive material, and in rare exceptions cell-free DNA. I don’t think we’re going to push that agenda of biopsies unless we do it on a clinical trial.
Perhaps if I can summarize, my answer is that I fundamentally think that any man in America walking in a clinical practice with metastatic prostate cancer has to be tested genomically. The NCCN Guidelines are clear, but they have changed over the last few years. As of March of this year, men with localized disease and with high risk disease, also should undergo therapy in addition to what you said, Paul—any man with a family history. The complexity of us just seeing patients, and not paying attention to family history, is no longer something we can accept in our practice. I think every man with prostate cancer should be genomically tested.
Raoul Concepcion, MD, FACS: I think that’s right, and I think we can no longer sit back and say, “I don’t want to do that because there are not enough counselors.” I think everybody is looking at different solutions because, as you said, Jorge, there are 2 reasons to test. No. 1, there’s a recent test because in that advanced prostate cancer patient it could potentially direct you to the next line of therapy. But also for the newly diagnosed high-risk patient potentially with significant family history, it provides significant counseling to family members.