- 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.