We're running short on time. We have about 10 minutes left, and I know Eleni has been really quiet. It's really great. I appreciate it, Eleni. I know this is a topic here that you really want to talk about. You brought up the Jean Hoffman-Censits, MD, abstract at ASCO . When we think about the promising emerging therapies for prostate cancer for the future, lead us through where you think 177Lutetium-PSMA-617 is.

Honestly, I like the comment, “I appreciate that you’ve been quiet.” I think it created the segue by Ben, who said that he considers radium-223 more precise than not, versus how Chuck presented it. I think the next step is exactly that. It's the treatment that would be more precise and to the point with a radiopharmaceutical. It's a great segue.

While we're waiting for phase 3 trial data that are probably going to come out at ESMO [the European Society for Medical Oncology annual meeting] or at least this year, hopefully, I think that this first look at the phase 2 study that was designed very elegantly by Hoffman, et al, gave us a first view of those men who are further along in the disease course gave us a promise of what may happen. They actually looked at a randomized schema of men who had progressed through other approved agents but had undergone PSMA PET and an FDG PET. That's really important.

I don't know how feasible that will be in the future in this country, but they did both, and they looked at accruing men who had mCRPC and had concordance of both of the PSMA PET and the FDG PET findings. If there was discordance—let's say there was an FDG PET positive but negative on PSMA PET for that lesion—they didn’t go on trial. It was a more homogeneous population. I love that. Then, they randomized. Let's go for the 177Lutetium-PSMA-617 versus the cabazitaxel. The primary end point was what you would expect from a phase 2 study. They’re looking at the PSA value.

They're looking at rPFS. These end points were well-met. The secondary was OS. I think their data were positive for that, too, even though they weren’t mature. It was a first glance at their data set, but the important part was a staggering response by PSA criteria to favor the use of 177Lutetium-PSMA-617 versus cabazitaxel, which looked like it was underperforming.

To Chuck's point, it’s because that is not as precise a treatment, so it might be a more all-inclusive disease approach to life. That's why I like the study a lot, and it speaks to the fact that if you pay attention to the details, you might get to your point quicker.

Fantastic. Any thoughts on that, Chuck or Tanya?

I think it's a key finding that the 177Lutetium-PSMA-617 is potentially hitting both of those themes. It's a targeted and precision therapy. I wonder if patients are going to be more likely to be able to take 177Lutetium-PSMA-617 than chemotherapy or would be willing to take it. I do have to say, I find cabazitaxel to be a relatively well-tolerated therapy, with regard to chemotherapy.

I don't necessarily see us replacing one drug with another, but I do see that there will be patients that might be more responsive to one strategy or another. I think this is where some of our biomarkers would be helpful. Obviously, the VISION study is what we need to see. We don't have those data yet. We'll do another program when that comes on and be able to discuss that, and it’ll be interesting to see where the imaging falls for this, because we talked about PSMA PET imaging as a way of looking for metastatic burden.

Now, we'd be doing it differently. We'd be looking at it in terms of a biomarker for selection. Tanya, does that change how you think about using PSMA PET, if you're thinking about it from a biologic profiling rather than a tumor burden perspective?

It’s very exciting to view it as a theranostic where you can do the diagnostic testing and show the phenotype. This is a cancer that’s expressing the target, as opposed to all these genomic strategies where we're looking at what the DNA says. There's something very appealing about that. I'm seeing the target in this patient, and I'm going to apply the treatment. I do worry whether the imaging component is going to be lost in the application of that agent. I think a lot of attention, as Eleni pointed out, to concordance, intensity of uptake, and who does well might be important in maximizing the impact of this agent, which we're all very excited to have added to our therapeutic toolbox.

Engaging its relative merit for an individual patient, I think we'll need to refine the biomarker. If anything, that makes me more enthusiastic. We always want to choose the best treatment for a patient. We always want to have a biomarker that helps us do that in a more scientific way. We’re scientists at heart, and data junkies, too.

Absolutely. I want to thank you all. This has been an incredibly informative and rich discussion. I really appreciate everyone’s input and insights. Before we conclude, I thought I'd give each of you a chance to summarize what you think are the most important takeaways from this session today. Chuck, do you want to start us off?

Obviously, we're seeing a lot of incremental progress on a lot of different fronts. It's really encouraging. We're, for the first time in my career as a medical oncologist focusing on castration-resistant prostate cancer, we're talking about people who are living so long that prostate cancer is fading a bit as a cause of death for these patients. When you talk about big shifts in our field, they don't happen overnight. But when you think about what we talked about on these types of meetings 5 years ago, it's a very different situation. That's really encouraging. We have a number of key studies underway.

We have our first genomically guided targeted therapy that just got approved. It's a very exciting time. It's a challenging time because while we get excited about these new agents and their ability to treat patients, we also get humbled by the fact that they don't always work in everyone. Even the people in whom they do have efficacy, it's not as long as we'd like. I am inspired to continue to study the biology of this disease, its evolution in patients over time, and how that can be applied to the population. I'm always delighted to work with you, my colleagues, on these projects.

Awesome. Tanya, do you have any closing thoughts?

To bring it back to the patient who’s at the center of all of this, it's so gratifying and important that these studies look at patient-reported outcomes and take into account quality of life. That has to be part of our discussion with patients when we're talking about the benefits and experience. There's also that third component of financial toxicity and concern, so it becomes more complex in our jobs to try to guide patients through.

It is important for us to look at all those aspects. There are so many great new treatments. Patients are living longer. They're largely living better, too. It's increasingly our job to help patients navigate and translate what these studies show us into what they will experience, what their day-to-day life will be like, and what it means for their lives and their PSA levels not just now, but 5 and 10 years from now. Those are challenges for us, but I know we can rise to the occasion.

I don't want to be repetitive. I want to add one more point that I believe comes across from all of us. We all feel privileged and have had the opportunity to try a lot of these drugs firsthand. In a way, we're also privileged in our practices being mainly academic settings. It is also our responsibility to reach out to the community and offer a hand of trying to get everyone on board, because it will mean nothing unless it gets to every single patient out there. I think that's what we all agree on.

Fantastic. Finally, Ben, from the urology perspective.

 I appreciate Eleni’s comments there, because I think the mission for us is clear. Whether as urologists, we're deciding to treat these patients or not, we have to be dedicated to finding them and understanding that these options are available for patients. They're better when we identify them as early as possible and get them on the right road.

Also, I'm very fortunate that I get to dedicate my time and efforts to this, but a big part of what I'm trying to do is help my partners make sure that we're finding these patients and offering all of the therapies that we can, because it doesn't do anyone any good if the patients aren't getting to the therapy. I really appreciate the discussion. It's been very enjoyable, and I look forward to future talks.

Fantastic. Thank you to you all again, and to our viewing audience. We hope you found this 

® discussion to be useful and informative, and look forward to having you join us again in the future. Thank you.

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Emerging Therapies for Advanced Prostate Cancer

It really dovetails into this next topic I want to talk about, and that concerns sequencing and some of the other novel agents that we haven't necessarily studied in the context of trials like CARD, but follow that same paradigm, meaning it's mechanistic switch.

We're not going from one hormonal agent to another, but from one modality to another, and that would be radiopharmaceuticals. In particular for today, that's radium-223. That may be something different in the future, but for today, radium-223 is a unique class of agent, in terms of being an alpha particle and being a targeted therapy toward bone. In thinking about it mechanistically, it's not tied genetically to any phenotype. It can kill indiscriminately, regardless of RB [retinoblastoma] status, TP53 status, or others. In thinking about radium-223, where do you sequence that now in the context of your chemotherapies and of your hormonal therapies? Where do you see that falling optimally? Chuck, do you have any thoughts on that?

You brought up a really interesting point, which has come up a couple of times now. Our field is dividing our therapies into the precision therapies and the imprecision therapies, and both have value. Killing indiscriminately is the way you put it, and that's a good thing, right? That’s one of the key ways we need to think about things. When do we need a targeted therapy? Early. We want AR [androgen receptor] therapy, or PARP inhibitors if it’s a 

, etc. Whether we like it or not, more than occasionally, our patients get into a situation where they have disseminated disease, and we don't know what the biology is. This is where radium-223 fits in.

I'm typically using it in the symptomatic patient with obviously predominant bony disease but no visceral disease, or patients who have no option for chemotherapy available to them. It's typically being done with a palliative or survival intent, and it's very well-tolerated. That's one of the areas where it has its greatest value. As we continue the conversation about imprecision therapy, we may see a growth in other radiopharmaceuticals and whether there is a marriage of targeted therapy, imprecision therapy, and targeted radiopharmaceuticals, which is another area. For now, radium-223 is considered a standard option for patients with bony disease who have pain, typically, and bony predominant disease.

Tanya, do you think this follows the same paradigm as the other drugs? That is, when we use it later in high-volume, heavily pretreated patients­­—like where it was studied in ALSYMPCA—we see some benefit, but if we move it earlier in the disease where the disease burden is less, we might see proportionally greater clinical benefit?

Yes, that's a good point. There were toxicity analyses looking at giving radium-223 before or after chemotherapy, because you always want to be playing chess with your patients and making sure that you're not closing doors. I’m wondering what my next 3 moves are and not just about this next move for this patient today. Once a patient has anemia, which can happen as the disease burden gets greater, they don't tolerate the radium-223. They may not finish the 6-dose course, and of course you want to get in a full course if you can, so there's a lot of interest in moving it earlier.

There are a number of studies, including 1 at City of Hope Comprehensive Cancer Center that we're running in bone metastatic castrate-sensitive disease, to see whether adding it early will be beneficial. We obviously don't know the answer yet, and right now it's only approved in castrate-resistant disease. That's where we're using it clinically. At ASCO there was also the question, not just of when to use it, but whether to add it to abiraterone or enzalutamide. Neal Shore, MD, FACS, presented a study using the Flatiron Health database of concurrent versus layered trying to answer that question of whether the increased skeletal events that were seen in the ERA 223 trial with abiraterone and radium-223 would hold true if you layered.

The findings were a bit complex in that layered enzalutamide with radium-223 was associated with more fractures, and concurrent abiraterone and radium-223 was associated with more fractures. The bottom line from that presentation was, if you add the bone support agent and are giving them a bisphosphonate or denosumab, you will mitigate that risk. It's not standard right now to use them together, but certainly if you're going to do it, they've got to be on bone support whether you're layering or using them concurrently.

I think that's really great, and we’ve learned that from some of these studies the hard way. We didn't necessarily anticipate that this would be a significant limiting factor to the clinical benefits of combinations. It would make a lot of sense from our localized disease setting that hormone strategies and radiation strategies should play well together, and I think in the bone is where we see these complications in particular, not in other organ sites or other issues.

It's relatively well-tolerated except for this, and mitigating it with bone-strengthening agents is key. To your chess analogy, I really like that. Thinking ahead and using bone-strengthening agents early when you're starting treatment with drugs like abiraterone and enzalutamide in the castrate-resistant setting is an important aspect to this. Then, you've had some lead time to build up and strengthen those bones, and maybe prevent some of that. Not all the fractures are pathologic.

In fact, many of them may be more osteoporotic, so it’s important to recognize that strengthening bone broadly is critical, even if the bone metastases they show aren't necessarily weight-bearing. There are a lot of really important lessons learned from this, and yet it's still an agent we use. It's been beneficial in many of our patients. Ben, what’s the urology perspective regarding radium-223? Where do you guys see this in the continuum, and how does that sequence in regard to your referrals to medical oncology?

I think the critical question with all the discussions we've been having about somatic testing, consideration for chemotherapy, consideration for a PARP inhibitor, and consideration for radium-223 are all going to be occurring largely in the same timeframe. A patient’s failing their first oral therapy. Eventually, we'll be at a different place, but for the next several years, we're going to see those patients who have been on the oral therapies since diagnosis with metastatic disease and now are progressing. They're already at that point, whereas before, we had more options up front.

The way that I have been talking to people about radium-223 is that we were always looking for trials. Many of those trials were PARP inhibitors, so we're a bit beyond that now, but I would say we're going to be looking for the defects to treat for PARP inhibitors. For me, radium-223 is right thereafter for the bone-dominant patient. I think this is a situation where, with the clinical presentation of multiple bone metastases, we need to follow them differently. We need to prepare them differently. Frankly, as they show any signs of progression and some symptomatology, we really need to look at getting them on radium-223, because it is a treatment in which we have found that if we delay, we miss.

They don't get 6 treatments, they don't get to 5; they don't get the benefit. I think we have to be aggressive in looking for these, and it's interesting to hear Chuck describe it as imprecise treatment when it's frankly one of the more targeted treatments that we've had for a long time because it only predominantly goes where the cancer is. It's one that we look very aggressively for, and I put chemotherapy right with it, because Tanya made a good point about the symptom relief from chemotherapy. I think that's essential.

I think there were interesting data at ASCO this year about sequencing chemotherapy after radium-223, showing it’s fairly safe from a hematologic standpoint. Finding that sweet spot for radium-223 takes effort, but is well worth it for the patient. We're actively looking for the patient that can get radium-223 and working hard to get them on it, but it does take some effort. This is a subset of patients that are not all your patients. This is another one of those subsets you're really looking for.

 I would add that the imprecise comment was meant to say that it's a targeted therapy in a way, but it's not tied to 1 specific angle.

I understood it completely. I think it was totally accurate, but it is interesting that I still think it's one of the more focused therapies that we have.

Radium-223 in Metastatic CRPC

Let me follow up on that point, because I think one of the really challenging things is knowing the opportune time to check for these genetic alterations. It depends a bit on access to tissue; if it's an old archival prostatectomy from 10 years ago, how relevant that is; whether they have soft tissue to biopsy; or biopsying bone. If it's a blood-based assay, what’s the optimal time for that, in terms of having enough tumor burden to find these, and to your point, Eleni, being able to do it before you’ve exposed them to drugs that are unlikely to benefit them, so before chemotherapy? Where do you see this, and can you give me some broad strokes on your approach for genetic testing in castrate-resistant prostate cancer? I’ll open it up, but I’m looking at you, Eleni, because you're the biggest picture on the screen for me.

We can't tell who you're looking at, Dan.

You're talking to people who, including yourself, are all about doing biopsies every nanosecond, so it's unfair. You have to go with archival

 tissue. We have some data now showing clearly that at least if you find the

 defect there—it’s going to be there, right? We have proof of it, but ideally, you would want to go for a real-time and a liquid biopsy. I've had the experience a year and a half ago of a patient of mine coding while having one of those biopsies, and I thought, “I’m not touching this guy again. I'm not doing any biopsies. He's alive. He’s well.”

But all of a sudden, his disease has gone crazy on us and he's having low PSA levels with progressive disease. I did a liquid biopsy, the one that's commercially available, and I got an MSI-high result just like that. There is 2% chance of getting it. He just started today on pembrolizumab, so you have to go for whatever you can get right now that is at least validated to be CLIA [Clinical Laboratory Improvement Amendments]-certified. However, archival tissue, at least for practices out there, is something easy to go for. We have to be practical.

Any thoughts on that Tanya? Do you have any other things to add there?

Not really. I agree. I'm a fan of a metastatic biopsy. Bone doesn't always perform, so I prefer soft tissue when available, but the reality is that we use a lot of archival tissue and we use liquid biopsy. The timing is a really interesting question. If you get a ctDNA assay that's negative, did you do it at the wrong time, and when should you repeat it? That's a real nuts-and-bolts question that we have to try to answer.

I like to do it while patients are progressing. If there’s 1 lesson out there, it is that once they've started therapy and they show some response, even if they've got tumor burden, I'm less likely to pick that up. Think about it as your patients are progressing, as you're seeing scans that show progression, and as you see symptom progression, as Tanya mentioned earlier. These are all opportune times to think about that before you make that next treatment. You can still go ahead with that next treatment, but check it, because you find things like Eleni pointed out, and that's a lottery ticket for that patient.

There was also a really nice oral presentation from Eric Small, MD at UCSF Hellen Diller Family Comprehensive Cancer Center where they looked at metastatic biopsies and they did methylation sequencing and methylation patterns. They essentially identified what looks like an almost new state of prostate cancer. That might be a bit of an exaggeration, but it's something that was distinct from standard adenocarcinoma, distinct from neuroendocrine tumors, and had a very different outcome.

I think it was a better outcome. That speaks again to the point that the more we look, the more we will see. Doing the biopsies, especially for those of us in the academic centers with all the tools that can be presented to us, is very valuable. But even when you're not doing things like methylations and genomic sequencing, understanding if a patient has transitioned into a neuroendocrine type is very reasonable, and that is not rare.

It may be that, by some estimates, 25% to 35% of the patients who are experiencing progression on abiraterone and enzalutamide have neuroendocrine disease. That should be brought out. We should study that, and we should be treating that differently.

Sometimes, it’s obvious, like liver metastases or lytic bone metastases, and sometimes it’s not. I’ve seen it in lymph node disease. I’ve seen it in regular blastic bone disease. In doing the biopsy, you used your cues, like the low PSA levels with visible progression, but I do think those biopsies are very informative.

The data, Tanya, suggest that it's not any more common in liver or less common in lymph node. It's everywhere, and some of the limiting factors are how good we are doing the biopsies and the pathologist who looks at them, right? You talk about a field effect. This is an effect that our whole field has to learn to adopt. Even the interventional radiologists who do these biopsies need to become experts at it, and our pathologists give us varying degrees of ability to detect neuroendocrine disease.

I want to bring up a couple of things. Tanya brought this up offline a bit earlier, and I wanted to put it on here and get everyone's thoughts on this. As we use more of these life-prolonging therapies in the castrate-sensitive disease state, the biology that emerges in the castrate-resistant prostate cancer is different. A number of the patients in the CARD study had treatment in the metastatic hormone-sensitive or castrate-sensitive state, and then progressed in castrate-resistant. Recognizing that our therapeutic history doesn't start at castrate-resistant disease, but earlier, and that those treatments have implications on how we manage these cases, is a critical aspect of this sequence biology. It impacts our thinking about this and when we do that testing.

One other point from me is that when I have a patient that I'm treating in the castrate-sensitive metastatic setting, I like to biopsy them if I can as they become castrate-resistant because that biology may be very different than had they come through, say, a nonmetastatic castrate-resistant pathway.

Genetic Testing in Metastatic CRPC

I happen to be a CARD investigator and the reviewer for ESMO on the discussion for the PROfound trial. I disagree a bit, Tanya, on the fact that I never considered shifting from one androgen signal inhibitor to the other as a valid option for our patients. I'm not saying that because we can’t disagree on the subject before this data, but when this trial started, I thought, “This is a no-brainer study. Why are we doing this study? Why are we doing it? This is a waste of our time.”

It turns out that you are absolutely correct. In practice, a lot of us, even today after 7 months, and within The University of Texas MD Anderson Cancer Center, people shift from one to the other agent. Now, we have clear data. If you look at both trials, for me, shifting from one to the other was the equivalent to placebo, based on the outcomes. Within 2 or 3 months, all patients progressed on both of those, if you look at them carefully. This is where I'm saying , we need to go out there, as you said, and educate more people to not first consider going from abiraterone to enzalutamide and from enzalutamide to abiraterone.

Think about it more. It’s more of a Ben question…because it's harder to do the referral. You have to go to a different doctor to do the chemotherapy. It's also the fact that the old TROPIC data with cabazitaxel was so scary for a lot of people. There were 5% toxic deaths, but still, for those of us who use it every day, many of us can say that cabazitaxel is so much better than docetaxel. We got the FIRSTANA data to speak to that point.

A lot of things that we sometimes have not processed enough until we actually get into the practice of using it came out of these 2 trials. The thing about PROfound that was a bit of an issue for a lot of physicians is that it didn't show an overall survival benefit, but 80% of the men who were on the placebo arm were immediately offered to go on to olaparib within a couple of months, so we can't judge anything from the overall survival data.

I was a bit surprised by the approval across the board, but that was to be expected. One of the things, as you pointed out, Tanya, is that they were largely 

 data, it was a bit of a mixed bag there, so we need to get better at it, but that was truly groundbreaking because it opens the door immediately for the approval of targeted therapy for prostate cancer. That's the first one. That ESMO session was for me, important, at least for 2019.

I would like to point out that although I'm very enthusiastic about the PARP inhibitors, and just as excited as everyone else, it's really important to notice that despite the presence of somatic 

 alterations, not everyone responded particularly well to these therapies. When I saw that, I wondered why. There were some really interesting data that are coming out. PROREPAIR-A was a study that was presented at ASCO this year, which looked at the presence of 1 or more of these alterations.

I think this is the next level we're going to get to. Right now, we're thinking, “Is there 

 mutation, yes or no?” If there is, great, we've got a PARP inhibitor. That's true, but when we see RB [retinoblastoma] loss and other genomic alterations, we know we're dealing with a different prognostic category. This gets back to what we said earlier, which is that we're beginning to talk in that language about the genomic complexity of the disease. It’s not simply whether a mutation is present or absent, but about the totality of the biology, which is really encouraging and exciting.

Doesn’t it also speak to your point about tumor volume and heterogeneity? All of those patients had to fail abiraterone or enzalutamide. They're not only metastatic castration-resistant, they're 1 step further. In the nonmetastatic, castrate-resistant setting, if you had someone with a 

, you would imagine that PARP inhibitors would work even better.

-altered prostate cancer before it loses 

, we're going to see better results. This is just the general theme that we're talking about, which is that earlier may be better. Simpler biology is better, etc. I think that the PROfound data, while really encouraging, and the rucaparib data also, opened the door to further questions and opportunities for us.

There’s also a lot of interest in combining some of these agents. There's this whole question about whether having those mutations also makes you more sensitive to immunotherapy with a checkpoint inhibitor, which we know has performed relatively poorly in prostate cancer in unselected populations. But the olaparib with durvalumab data are interesting, because you wouldn't have necessarily expected to see responses in an unselected population.

They had a 12-month PFS of 36% in patients without the mutations that you would use to predict sensitivity to the PARP inhibitors, and that's much higher than with checkpoint alone. It’s much higher than you would expect with PARP inhibitors alone, so is there some synergy there? I think that's one direction the field is moving in, in addition to the next generation of PARP inhibitors that may have broader effects or differential effects. Olaparib shows some responsiveness with 

. Rucaparib did not. I think we're going to have to get into the weeds, to Chuck's point, about how complex it is to understand the genomics and the heterogeneity, and what that means when we're choosing treatments.

Yes, it’s almost ironic, Tanya, because you're absolutely right. The irony is that we're also seeing data on the combination of abiraterone and PARP inhibitor in the PROpel data and in others. There are studies launching that are looking at PARP inhibitors plus AR [androgen receptor] inhibitors in the unselected patients. We may be going into the front door, saying we're going through all this genomic selection and have these targeted therapies, and then go out of the back door saying you don't need to do that in everyone.

You brought up the very nice experience we had at ASCO. There's one more thing that's coming out for the 

 patients, and again, we don't want to go into the weeds because the PROfound data went widely for anything you can pick out. Monoallelic was good to go since that specific assay, and we had some answers with regard to going from monoallelic coming out for some of the papers that had been published that actually supported that.

Some of the other approaches have been more purist in going for biallelic alone. I think we want to walk away a bit from being so selective moving forward. The approvals that we got from the FDA are speaking to a specific assay, but maybe we want to comment that moving into the future, we might be using other assays, as well. Cost is an issue and we don't want to be bound. For now, the approval for olaparib was for a specific Foundation Medicine assay companion diagnostic. The Myriad Genetics, Inc, I believe, is for germline assessment.

I wanted to bring up one point that came up from ASCO, as well. It is likely that those men who have tumors that harbored 

 alterations may not be at all responsive to taxanes, and that had come out in a retrospective analysis from Elena Castro, MD, et al. There was a poster about looking prospectively at such candidates where cabazitaxel really underperformed. It performed as badly as transitioning from abiraterone to enzalutamide and from enzalutamide to abiraterone. There’s more to look into in the future about selection of these types of patients who have more aggressive phenotypes based on molecular characteristics.

Impact of Clinical Data on the Treatment of mCRPC

I want to pivot to our last section because this is our largest section. This is probably the area where we’re seeing the biggest changes in the field now in 2020, and that is in metastatic castration-resistant prostate cancer. Just to set the stage, we’re all aware of the progress that’s been made over the last 15 years with taxanes like docetaxel; in just the last 10 years with a number of newer agents, like cabazitaxel, sipuleucel-T, and radium; and over the last 7 years or so in our androgen-targeted strategies like abiraterone and enzalutamide in this metastatic castration-resistant setting. There are now some new developments going on in the field, and we’re beginning to understand a bit more about sequencing of drugs and recognizing the impact of that. When we sequence from 1 drug to another and 1 of those agents doesn’t work, we’ve essentially delayed the time to the next therapeutic benefit.

As Chuck mentioned earlier, those delays can have significant impact on overall survival. We’ve learned that from some of these crossover studies, so I want to spend some time talking about that. We’re moving beyond the 1 or 2 classes of agents and into a field where we have multiple targeted agents. We’ve just gotten some newer targeted agents with PARP inhibitors, and we’re getting potentially new targeted radiopharmaceuticals in the future. These classes of drugs are going to continue to expand, and it’s going to be ever more important that we make the right decisions, in terms of order, sequence, or combinations in the future.

Let’s dive into some of the data that have come out in the last 12 months. The first couple of studies were presented primarily at ESMO , but they’re still relatively fresh on our minds, in terms of the clinical implications of the CARD and PROfound studies. Tanya, I wonder if you could walk us through these studies and give us your initial thoughts on the clinical implications of their results.

The CARD study was super practice changing for me, personally. This was a study in which men with metastatic castration-resistant prostate cancer who had already been through abiraterone or enzalutamide were randomly assigned to cabazitaxel or the opposite AR [androgen receptor]–targeted therapy—abiraterone or enzalutamide—which was essentially the physician’s choice. I should mention that these men had also received docetaxel. What the study showed is a significant prolongation in radiographic progression-free survival, which was the primary end point but also a trend toward overall survival—11 months for AR-targeted therapy versus 13.6 months for cabazitaxel.

What really struck me, and you alluded to this, is they had a significant improvement in pain. One thing that was unique is most of the patients getting onto the study had not progressed just by PSA . Something like 70% of them had progressed based on pain, so it was a symptomatic progression. That’s a bit unique when we’re thinking about how to apply these data in our practice. Given that so many had pain, 45% of the cabazitaxel patients had pain benefit or pain relief, compared with 19% on the abiraterone or enzalutamide. We’re trying to help our patients live longer, but I always emphasize that we’re trying to help them live better, and that can be counterintuitive when you’re thinking about chemotherapy.

A lot of patients think of chemotherapy as something that’s going to make them feel worse. It’s important to emphasize that when we’re picking, we’re picking not just to help people live longer but to deal with palliation and control symptoms and skeletal-related events. Again, not to beat a dead horse, but that’s what drives morbidity in this disease, and overwhelmingly as these men suffer from bone metastases. So I found it very compelling.

Then you have PROfound. This was also very exciting, to see a new class of agents, PARP inhibitors, go head-to-head against a second-line abiraterone or enzalutamide. Again, this was a very similar population that had progressed through 1 of those agents and the control arm was physician’s choice. All these patients had to have a DNA-repair mutation—primarily 

, and a number of other mutations were eligible.

To find a progression-free survival advantage and overall survival benefit with an active comparator is really exciting. There was more placebo control here, but what we would consider a fairly active alternative choice. This really establishes the role for PARP inhibitors and speaks to the need for genomic testing and genetic testing in these patients, both germline and somatic. We need payers to cover this because there is a real survival implication for patients if we discover these mutations.

The CARD and PROfound Trials for Metastatic CRPC 

 I want to get your opinions on the differences between these drugs because we now have 3 drugs in the same class. Obviously, you’re going to pick only 1, and we don’t have head-to-head data comparing these drugs and may not for a while. How do you decide which agent to use? Are there real differences between these drugs, in terms of their pharmacology or biology, that would influence who you might prescribe 1 to versus another? Eleni, do you have any thoughts on that?

This is a great point. I think we would all agree, for the purpose of not going into a lot of detail, that we’re looking at a class of agents that have a very similar efficacy across the board. You can have your personal preference, and then it boils down to how you are going to adapt in your clinic. You would like to be equal in giving all 3 a chance to see how they work, and this is an important thing to take into consideration.

I’m in an everyday practice, not in an academic practice, and I’m going to reach for what I know how to use. We know that 1 of the 3 drugs has been around forever. Ben will speak more to it, but we’ve got a newcomer in here that actually has, in my mind, clearly proven from the preclinical and ongoing data that it does not pass the blood-brain barrier. That may give it an advantage because we all have to admit that the other 2 agents, enzalutamide and apalutamide, do pass the blood-brain barrier. Maybe apalutamide does not as much. That is debatable.

Maybe the ensuing fatigue is less, but then you get a bit more of the rash coming in that has been a nuisance for some of the practitioners. It all essentially boils down to safety. Now you have 1 agent that’s been around for almost 8 years and 2 that are newcomers: apalutamide and darolutamide. I can tell you, I have not used darolutamide a lot. I just started the moment it got approved. I haven’t done any research on it; I’ll be honest. Other colleagues have. I have limited experience to date, and it has been positive. It lives up to the claim of not having as much fatigue.

If you look at the 3 trials and don’t focus on the little details—how much fatigue here or there—but look at the differences in discontinuation due to adverse events versus placebo, that’s your comparator in each of these trials. You’ll see that you do get that difference in percentage in the SPARTAN trial, which is the apalutamide 1. You get the same difference in the PROSPER trial, which is enzalutamide, but there is no difference between the darolutamide arm and the placebo arm when you look within ARAMIS.

It’s about 8.5% discontinuation due to adverse events, which in this case are obviously more associated potentially with disease progression and maybe a bit of darolutamide there. As an overview, until we all get more hands using it, I would say that these data would actually persuade me to reach out and try the darolutamide agent more, especially my older patients. As you said, you want to make sure they’re not going to have more falls or instability in their gait, especially if they also have some backbone of neurological deficit there. I’d like to hear everyone’s thoughts on that.

Tanya, I see you nodding your head. Is this your way of thinking, as well?

Yes, I will say that the treatment discontinuation rate is a good tool to judge how much your patient is going to struggle with adverse effects and how often they will get bad enough that they’re going to stop the treatment. There is a difference, I would say. My own experience is that darolutamide is very well tolerated. I don’t see some of those CNS–type effects that I see with the other agents. This is not to say that apalutamide and enzalutamide are not well tolerated. They are, and the quality-of-life data speak to that.

I agree that darolutamide not crossing the blood-brain barrier is significant. In my own practice, it’s not just cognitive, but it’s also sometimes anxiety or depression or just this ill feeling that can lead to discontinuation. I take that to be a CNS effect. Importantly, there are ongoing prospective formal studies to look at cognitive changes, so eventually we will have level 1 evidence that can guide us when we’re concerned about that particular aspect of toxicity.

Are there other ways to quantify this kind of stuff. Are there things we can do in our practice to recognize potential risks in our patient population?

Absolutely. This is where we need to learn from work that’s being done in the field of geriatrics and neuroscience. There are a lot of tools available to look at cognitive function. Whether we can integrate those into daily practice in an oncology or urology practice is another question. Fall risk is something that has been associated with a couple of these drugs. Assessing the risk for falls is actually quite easy to do.

The timed up-and-go test is very easy. Anyone can do it in any clinic if they know what they’re doing. It’s just having a person walk about 10 feet and back and timing that. We need to get the word out about these tests, provided that we think there is a significant difference among the drugs.

Building on Tanya’s point, we have to do those studies and prospectively look at whether there are differences. If there are, and all the therapies are still available, we have to make those tests available and teach our field how to do those tests so that they can use them in their decision-making. It’s really no different from using a genomics test to make an action.

Even if there is not a huge difference between these drugs and it’s a class effect, it’s important for us to recognize because it would factor into our management decisions in these patients. If there are differences by drug, that’s even more important to know going forward.

As our patients are living longer, as we just got done saying, and maybe their risk of dying of prostate cancer is slowly decreasing as we give better therapies, attention to these types of factors is more important.

Right. I was just going to say that because it is a class effect and because they’re still on hormone therapy or castration therapy, paying attention to what we can do to mitigate any potential fall risk, for instance, is important. Talking to patients about the importance of exercise and making referrals to physical therapy when appropriate are part of our job as we’re using these agents earlier and longer.

And prove to the payer world that these things are worthwhile and should be covered.

Yes. I think from not having the internal medicine background, encouraging our teams to be looking into cardiovascular risk and risk of metabolic disease and other things that we know these agents can contribute to is all part of the same thing. Falls and fractures are the dramatic events that we know we need to avoid, but just because more patients are dying of cardiovascular disease doesn’t necessarily mean that it’s not related to their prostate cancer, since we’re using these agents. Understanding that we have to incorporate all these risk assessments into our practice is definitely a focus.

I want to make that comment, mainly for you, Ben. It’s a matter of streamlining it and building an algorithm. You guys are urologists. You don’t have the time to mess with that. You want to have an algorithm where you send the patient to the cardiologist for a checkup and do the bone density. Breast cancer has done it. Do that bone density every couple of years. Assess the risk of fracture. You don’t even have to do it, but if it’s building the algorithm checklist, you do it.

That’s exactly what we’re trying to do.

It’s survivorship, and it’s building in that survivorship model in these patients. No, they’re not cured. But they may not die from prostate cancer, so these are the competing survivorship issues that we have to balance. Thank you, Ben, for bringing that up. It’s a great perspective for urologists, and I like that analogy, Eleni. We can do this in our field as well.

Differences Between AR-Targeted Therapy in Prostate Cancer 

Chuck, do want to update us on some of the data that have come up this year regarding OS ?

The data from our most recent presentation essentially confirm that all these studies that had met their primary end point for MFS also met an end point for overall survival. The question of whether MFS is a surrogate end point for an improvement in survival is something that is continuing to be thought through. It’s fair to say that we’ve now demonstrated that improving MFS in the nonmetastatic setting is both a provability end point and is clearly associated with a long-term outcome benefit for the patient in terms of overall survival.

My interpretation of this also is that MFS—apropos of what I said previously—is really PFS [progression-free survival]. It’s just going from a radiographically invisible metastasis to radiographically visible metastasis. It’s not a wholesale qualitative change in the state of the cancer. How these data will integrate into further studies in the nonmetastatic space will be curious to see. I’m wondering if the nonmetastatic CRPC [castration-resistant prostate cancer] space itself may go away with a lot of the newer imaging modalities that we’re seeing tested and presented, as we did at ASCO this year. It’s going to be an interesting area, and I also think we won’t be able to see any more placebo-controlled studies in this setting, either.

That’s interesting. Some of these studies actually allowed pelvic lymphadenopathy, so the reality is that what we called nonmetastatic was low-volume metastatic disease. In many respects, maybe our novel imaging is just going to reinforce it. Maybe it’s not as low volume as we thought when we do this novel imaging, but at least by these standards, it’s still relatively responsive. That will be 1 of the questions.

Tanya, what do you think about that? How is some of the novel imaging going to influence your thinking? You mentioned earlier in the castration-resistant setting that imaging probably isn’t going to change how you think about that disease biology. Will it influence it here in this castration-resistant setting if the novel imaging is showing perhaps a higher volume of disease than what our standard imaging is showing?

I’m not sure it would, given that we would already intensify treatment either way once we get to castration resistance. Now we have these approved drugs that have proved metastasis-free survival and overall survival benefit. I’ll add that quality of life was preserved in these trials, which is quite remarkable for that amount of difference between metastasis-free survival of 40 months versus 15. That’s a huge difference, and for people to be feeling well during that is really important.

If you have a well-tolerated agent that’s highly effective in castration-resistant nonmetastatic disease that’s also available for metastatic disease, I don’t think the imaging adds much. Just because we see more spots, do we treat it differently? Some differences that it could impact are whether you might add bone support if you saw something in the bone that you didn’t see on traditional imaging, but that’s a huge gray area. There is no research on that yet. Maybe we need to look to our European and Australian colleagues, as Eleni mentioned earlier, and learn from how they’re handling that type of situation.

It’s a great point. It’s another setting where I think this novel imaging isn’t necessarily going to drive a change in our therapy. What it might point to is another class of therapy that’s evolving, and we’re going to get to that subject later. It may be more useful as a biomarker for preparing for future therapy than it is for changing the current therapy in these patients, so I think that’s reasonable.

Can I make a comment on that? It’s very interesting. We are a bit trapped in this administrative term 

. We have the data from the Hadassah Medical Center group, where if you took patients who would be accrued on this trial and did the PSMA [prostate-specific membrane antigen] PET, 75% of these men would have findings, whether localized or metastatic. For the purpose of the FDA approvals and the like, we use these terms. But as physicians, we know well that it’s earlier CRPC versus later.

Even though we can’t compare trials, we even have Chuck, who was the lead in the COU-AA-302 trial. If you look at those survival benefits, even in absolute terms in this later chemotherapy-naïve disease versus earlier disease, as Tanya brought up, the difference in what you get is quite big as long as you’re good at monitoring these patients and taking care of them. That’s our duty.

I think it’s a no-brainer. I’m saying that because people will then be saying, “Of the 3 drugs, only 1 has approval in metastatic CRPC.” These are agents in the same class, and then you go into the safety and tolerability, and adapt it to your patients. That’s where you make the decision. You don’t go by just the sheer administrative label. That’s my take, and I’d like to know your thoughts.

I like that thinking. I think back to what Chuck said earlier about disease heterogeneity and how these agents are going to work so much better in that castration-sensitive setting, when we knock down the tumor burden with ADT [androgen deprivation therapy] and then wait for the castration-resistant setting. This is like that, because here, we’ve got a low-volume, chronic development of castration-resistant disease. It’s unlikely to be as heterogeneous as our patients who have high-volume metastatic castrate-resistant disease.

We see that a 30% survival benefit in this setting, when patients are going to live for 5 years or more, is way more impactful than a survival benefit of 30% when a patient has 1 year to live. Recognizing that hazard ratio in the context of the overall natural history is really important, and in recognizing that, it makes sense that these drugs would have a more lasting, more durable, and greater benefit in this setting.

I’m curious for the group to comment, because of this question of using hazard ratios or time in how we communicate with one another or with patients. As you’ve said, we can’t compare trial to trial. But you do now have these overall survival benefits of 11 months with enzalutamide and 14 months with apalutamide, compared with 4 months with enzalutamide in the metastatic castration-resistant space. That tells the story as dramatically as anything. I’m curious if that is something you find to be a differentiator in explaining it to colleagues and patients. I’m curious how you’re finding these data are helping you.

Can I make a quick point on that? It’s a really interesting point. One of the things I’ve been reflecting on in looking at the survival data and thinking about the more aggressive treatment of low-volume disease is that we are beginning to see the other causes of death competing with prostate cancer as a cause of death in these patients. That was unimaginable when we were treating postdocetaxel patients with enzalutamide and everyone was dying of prostate cancer. Not only that, but they were suffering a lot before they did.

Now we have taken these drugs into a much earlier phase, where we’re beginning to see that the risk of dying of prostate cancer is going down and is being almost eclipsed in many cases by the risk of death from cardiovascular disease. I think there was a slide and Neal Shore’s presentation, which showed that for a man diagnosed with prostate cancer, the risk of dying of cardiovascular disease actually exceeds the risk of dying of prostate cancer.

That has huge implications for how we would talk to a patient in that we can actually say, “Not only are we going to delay the progression of your cancer, but this may be your chronic therapy moving forward, and prostate cancer may not threaten your life.” It’s a long way before we can say that to every patient, but I see that beginning to creep its way into the conversation.

It’s a great point, and these nonmetastatic castration-resistant prostate cancer patient populations were generally older than the populations of patients we’re studying in these castration-sensitive and even metastatic castration-resistant settings. Again, it speaks to the natural history of this biology, but probably 20% or 30% of these patients are 80 years old, and average age is about 75 years old. We’re dealing with a population of patients in which cardiovascular risk is only increasing with time.

Ironically, this is what statins and beta-blockers did to cardiovascular death a couple of decades ago.

Overall Survival Data Presented at ASCO 2020 for nmCRPC

I want to move on. This is another narrative of prostate cancer. This is the nonmetastatic castration-resistant prostate cancer. We talked about the patient who has metastatic castration-sensitive disease. We pick them up by imaging, or they present de novo with widespread metastatic disease. It’s almost a different clinical path. In the patients who present with localized disease, they get localized treatment, at some point recur, PSA level rises, and they get put on hormonal therapy and respond for a long period of time. The natural history of these patients that evolve into nonmetastatic castrate-resistant disease might be 8 or 10 years.

We’re looking at a pace of disease that’s much more chronic yet largely neglected until recently. There’s been a series now of 3 large, international phase 3 studies to demonstrate an improvement and a new end point of metastasis-free survival. Ben, can you walk us through these studies—PROSPER, SPARTAN, ARAMIS—and what have they taught us about this disease’s biology? Tell us about some of the newer findings we’ll get to from ASCO [American Society of Clinical Oncology Annual Meeting] this year?

Thanks. It’s interesting because this is a disease state that didn’t really name before. It was defined when we had options to treat it. These were the patients who had been put on ADT [androgen deprivation therapy] at some point purely because of a PSA, because of a biochemical recurrence, and because by definition, they didn’t have metastases. Some of them may have experienced early failure of treatment with radiation and had been on an ADT, but a lot of these were patients essentially treated for PSA levels before.

There’s a whole discussion to be had about whether we should have these patients much anyway. Should we have started them on ADT? That rewinds the clock a bit about who these patients are to begin with. That being said, eventually, many of these patients were failing. That’s when we had the head-scratching moment of looking at a patient and saying, “You don’t have metastases. I can’t find metastases. At this point, you’re on standard ADT, and I don’t really have anything else for you. It doesn’t make sense to offer you chemotherapy.”

Even the newer novel agents weren’t for this, at that time. It feels like a long time ago, but it was only 2 years ago when we had the readouts of several trials that were looking at the highest risk of those patients. These were not the patients who had a slow PSA, but those with doubling times of less than 10 months. All 3 studies use that same indicator, and that predicted that they were likely to show metastasis within the following year. All those patients are very high risk in this subset.

First was the SPARTAN trial with apalutamide, closely followed by PROSPER and enzalutamide, and then about a year later, it was darolutamide. They all showed a significant improvement in metastasis-free survival, or MFS. MFS made news because it was a new marker. It was an acknowledgement that to wait for overall survival is not practical if we’re trying to deliver on a treatment option for patients who have high-risk disease. Although now we know how long it would have taken to do that, at the time, it allowed for these studies to be framed in a more reasonable, although somewhat controversial, framework.

Metastasis-free survival was deemed to be a reasonable exploratory end point by the FDA, which allowed these trials to move forward. They all showed a significant reduction in the risk of metastasis with an approximate—all the data were relatively similar—2-year benefit over a placebo in metastasis-free survival, and hazard ratios that were 60% to 70% risk reduction. It’s a remarkable set of trials that showed an improvement that we don’t typically see, in a disease state that we knew was worrisome but didn’t have any options for before.

It was groundbreaking from that perspective, to understand it, but it was a bit of an unproved end point. Tying that to overall survival, which is a very proved end point, has been the missing link until just recently.

FDA Approved Agents for Non-Metastatic CRPC

 Ben, do you have any thoughts on the real-world experiences? I’m sensitive to what Eleni says, because I think about my own practice, and we use a lot of these drugs in this setting. But I realize that Duke Cancer Center doesn’t necessarily represent the real world. The patients we’re seeing in the academic centers aren’t necessarily the populations you’re treating out there in community settings. Do you want to speak to that a little?

It is a great point, and for the most part, where we’re falling short is in the de novo patient, which arguably is the highest-risk patient, who shows up metastatic. For a long time, the standard has been to get them on ADT [androgen deprivation therapy] and watch them, and we’ve had enough time to adjust. Many of us have. The first 2 agents, abiraterone and docetaxel, came with potentially a bit more baggage. I don’t want to disparage docetaxel. It’s a very tolerable drug, but it may have scared a few people off. I’m speaking very much in conjecture.

The discussion that I have now with my colleagues is that we have many options for better hormonal therapies, and you shouldn’t think of this as anything other than that. In many ways, this goes back to what we had before with total androgen blockade. It wasn’t really adhered to then, when we had data that there was some advantage to adding agents. Now we have better data and more agents. For many of my colleagues who are so used to having these patients in their practice, they’ve either embraced this or they haven’t.

For those who haven’t, they’ve created their referral patterns, hopefully. It’s all a bias on the part of the provider. A patient will go where they want, where they’re directed, when they have a clear direction to do so. Many providers are still getting onboard with the real level of difference that Eleni and Chuck referenced between early and late. To get this done earlier is such a differentiator that there is no excuse, and we’re going to keep working toward getting better.

I do think there is a real question about whether you go to cytotoxic chemotherapy or an oral. Is there ever a patient where there’s a clear right or wrong answer? That is still being discussed. I think the high-volume patient with bone metastasis is the 1 that I make sure gets a discussion about chemotherapy, without question. There is further discussion about some of the lower-volume metastases and then certainly visceral metastases. I’m curious if anyone else has any input on that part of it.

 It’s a great question. Tanya, I wonder if you could address that for us, and also the idea that perhaps it isn’t always an either-or. Maybe there’s a rationale for either a combination of docetaxel and AR [androgen receptor]–targeted agents or a sequence of these before disease progression. Any comment from the clinical trial data we have? I think there is an ongoing study asking that question.

From ENZAMET, which was the up-front enzalutamide study, about half the patients got docetaxel and then either enzalutamide or placebo. What we saw in that trial was that it did not look as though there was added benefit, so maybe 1 agent to intensify up front is enough. But it wasn’t a study that was formally designed to answer that question. In the ARASENS trial, which is ongoing with darolutamide, everyone is going to get the chemotherapy, and then there’s the randomization between darolutamide or placebo.

I think that’s going to give us more definitive evidence. But right now, based on the evidence we have available, I tend to pick just 1 drug. I agree with Eleni that the real battle is getting providers in the community to adopt that. There’s been this mentality of “Let’s save an arrow in our quiver. Let’s wait.” I find that the patients also talk about it that way, and I really have to emphasize that most people on the placebo arm crossed over and got these life-extending therapies after they progressed. We saw this very dramatic difference, so there is something about intensifying and getting a better remission by killing more cancer right up front.

The neoadjuvant studies presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year by Rana McKay and others really speak to the fact that we kill more cancer when we add abiraterone, for instance, in the neoadjuvant setting. We can look when we pull out the prostate. Some men have no cancer left. We don’t achieve that with the ADT-alone standard. I talk about it in those terms with patients. We know we kill more cancer with these drugs, and that’s going to keep you well longer. It’s going to delay the time to you having pain or feeling sick from your cancer or needing chemotherapy if we’re starting with a hormone agent.

Those are some ways around that conversation that can be helpful. There is that financial cost, and there is some concern about whether that intensified hormone therapy will lead to more toxicity over such a long period of time. But at the end of the day, the survival is markedly better. There’s a delay in skeletal morbidity. These are very meaningful clinical end points. More education and more communication with all our colleagues is necessary to really emphasize this. Then we’ll learn whether we want to choose both chemotherapy and an AR-targeted agent when we get the ARASENS data.

 That’s really good advice about recognizing the need to follow that clinical data. That’s where the survival benefits are.

May I make a quick point on this, Dan? It’s such an important point. Tanya nicely addressed the issue of the clinical data, the crossover, and this change our mentality from “Let’s do the easy thing first and the hard thing later.” But the other piece that is happening is that in our literature, our knowledge of the biology of castration-resistant prostate cancer [CRPC] is exploding. What we’re finding out is that that is a disease that is much more complex, much more heterogeneous, and associated with many more lethal mutations than the earlier-stage untreated disease.

We’ve seen this with data on loss of RB [protein]. There was a whole oral presentation at ASCO on methylation, CRPC, and neuroendocrine small cell cancer. That conversation with the patient shouldn’t be about just what’s the easier therapy. It has to be that we’re trying to prevent or treat when you have a low-volume, less complicated disease rather than wait to have a higher volume, more complicated disease when things become really challenging.

There is a practical problem that happens. Everyone gets on their injection first. They get on their ADT first, and if you haven’t had the conversation almost right then, what ends up happening? At the next visit, they get a PSA [prostate-specific antigen] that shows that they had a great response. Then the patient says, “Well, why do I need another therapy?” The enemy is that PSA, and it’s why you have to plant the seed very early.

It speaks to the need for early referral if you’re not doing it yourself, or certainly incorporating that into the very first discussion. I’d say that, associated with the financial cost, ends up being the big hurdle, because they say, “What’s the differential? My PSA can’t go any lower; it’s down from 83 ng/mL to 1 ng/mL.” That’s the issue.

Any oncologist out there who treats triple-negative breast cancer is going to know the model for how this works. You identify an aggressive biology. You have an aggressive treatment that has multimodal therapy associated with it, and you improve outcomes. No one would ever dream of starting with something easy in that setting and allowing the disease to evolve, so we need to shift our mentality. I think we are shifting our mentality in prostate cancer.

This is an important point that you brought up, Chuck and Tanya. It has been my passion, as you know, to actually be able to characterize that disease. Where we’re stuck is, unfortunately, we have these options, and we don’t really know how to best guide and how to provide the sequence. We don’t know if it would be chemotherapy. We know that volume and risk are more like the low-hanging fruit that we use as a surrogate for the biology we’re looking for, but the bottom line is that everyone needs to understand that there is progress.

There’s no perfection. It’s just progress, and I want to tie something in here. We have clear guidelines that all men who walk in with de novo metastatic disease, or even any metastatic disease, should be offered germline testing. We’re probably going to get to that a little later. You get a lot of second opinions because of your position and where you are. I can tell you that maybe 1 of 20 of my second opinions have received community germline assessment mutation.

You may not be able to act on it, but just the sheer knowledge is valuable, especially with what’s happening. Most practices would be advised to at least have this type of algorithm where they’re trying to maximize benefit up front, when the patient is also in a better performance status. Get a hold, and actually account for all comorbidities and make these decisions. Then maybe it’s a little harder for urology practices, but they can pair up with either oncology or even involve internal medicine when it comes to these interactions.

Germline testing and better risk stratification should already be in the discussion for some patients with presumed localized disease. It’s not something that’s solely for the metastatic world, and I think it’s just another of those things that we have to get better at quickly. That’s true across all of what we’re doing in all cancers and all specialties. Understanding what we understand now: That’s the challenge.

Clinical Trials in the Community Setting for Prostate Cancer

 I want to shift gears to therapy and consider our earlier use of chemotherapy and novel androgen receptor–targeted therapy in the metastatic castration-sensitive prostate cancer setting. Those agents have really changed the landscape of not just castration-sensitive disease, but the biology that emerges in castration-resistant disease.

Eleni, I was wondering if you could walk us through some of the data regarding the rationale for chemotherapy. I want to address some of the updated data from CHAARTED, some of the rationale for abiraterone from STAMPEDE and LATITUDE, and then some of the newer studies that have been coming out around enzalutamide, apalutamide, and others. Where are we today with the management of metastatic castration-sensitive prostate cancer?

 Thank you, Dan. Before we go into that, I want to add a comment on the previous topic. Tanya, great comment. A lot of us are trying to do studies along these lines. Ben, I liked your attitude about knowledge offering the way forward. There are a lot of naysayers still saying we won’t be able to use it. The bottom line is that none of us has had this extensive experience that we’re seeing in the rest of the world. We need to look more toward Europe and Germany, where they all started to understand better how they’re actually using it.

One thing that Chuck might come back to later when we speak about the Hoffman data is that with the PSMA [prostate-specific membrane antigen] PET [positron emission tomography], we get a lot of specificity. We’re going up to 95%, but we’re still not there with sensitivity. That’s what I’m going to use to segue into the hormone-naïve castration-sensitive space with regard to heterogeneity. It could be that PSMA, being a more molecular-based imaging assay, is not picking up the disease to the extent that we want because of that heterogeneity.

With that in mind, I think we’re very privileged, compared with even 5 years ago, to have this option right now in the clinic for what is metastatic castration-sensitive disease. Even though we’ve had these data—starting from 2014 or 2015 with CHAARTED, STAMPEDE, LATITUDE, and TITAN, and are waiting on other data sets like ARASENS to come forward—the problem we’re having is a disconnect with real-world practice.

Even in this country, where abiraterone has become generic, the numbers may be a little skewed, but they don’t look like we’re reaching even 50% capacity in treating these men with castration-naïve disease with any of these agents. The numbers for chemotherapy are actually quite low at less than 10%, and Ben Lowentritt might want to comment on that. We have strong data to support that the use of cytotoxic chemotherapy in the name of docetaxel or any of 3 FDA-approved agents—abiraterone, enzalutamide, apalutamide—has an impact in all primary end points, including RPFS [radiographic progression-free survival] and overall survival, and all secondary end points.

Why are we not using them yet? Is it part of the learning curve? Is it part of the difficulties of access in the clinic? Are there still those who believe that later may be equivalent to earlier? That’s my main point. Given all these trials—especially when you look at 11 positive phase 3 trials with enhanced androgen signaling inhibition for pointing to the fact that it’s 1 of the main drivers—it should probably be your first choice with exceptions that we can comment on. Earlier is better, and we’re going to get to this data.

This is my main concern. We’re all embracing the fact that we can treat hormone-naïve disease regardless of risk or volume. We should take into consideration the comorbidities that may be impacting the quality of life of these patients. We are now understanding better how to cater to bone health, and a lot of you were doing research along the lines of generalized health index. My main concern is, where are we standing with actual real-world practice?

 If I could comment, Dan. Eleni touched on this also. Part of what we’re trying to do is attach a binary tool to a continuous variable, and that metastatic disease is probably a continuum. Eleni mentioned the sensitivity of the gallium Ga 68 PSMA PET not being as high as we would like. That’s because it’s higher: The higher the PSA [prostate-specific antigen] gets, we don’t really need it. Where we really want to have it is when it begins to lose a bit of its sensitivity, but the idea that we go from having no metastases to some metastases as if we’ve jumped over some border is not really the case. They’re always there. It’s just a matter of the volume.

 It’s a great point, and our coding makes everything black-and-white, but the reality is that we see this disease as a continuum.

Data for Metastatic Castration-Sensitive Prostate Cancer

 Ben, do you have any thoughts from the community urology perspective? Do you see this becoming widespread in your preoperative work-ups and your high-risk patient population as a way of decreasing our volume of treatment of patients or maybe expanding it?

 It’s great question, and I’m very excited to see the application of these novel PET [positron emission tomography] agents in the staging standpoint. From what we’ve had available, outside some of the locations that have an agent they’ve been studying, the commercially available agents are only for biochemical recurrence. This idea of moving into the staging will help us because there’s a lot of variability in how we’re treating high-risk cancer.

It’s personal preference. Everyone is doing the best they can for their patients. It’s not easy to make it data driven when you have what you strongly expect is metastatic disease but you’re hoping might be localized, and you’re getting those patients who can be cured. Anything that gets us to a point where we can be more accurate with our staging is a positive, so we would absolutely want to use these agents for better staging of our high-risk patients when available. I don’t know that it’s going to lead to less overall treatment.

It will just be more specific treatment and even more localized treatment. A lot of people who write some of these patients off because they strongly suspect they have metastatic disease. I also suspect there might be opportunity for cure in a lot of the next-generation, imaging-only, positive lymph node, localized regional disease patients if we treat them appropriately. It’s going to allow us to better evaluate treating and studying these patients going forward. It’s nothing but a positive.

 Tanya, when we think about metastatic disease, we think about systemic therapies and now combinations—ADT [androgen deprivation therapy] plus systemic therapies. Do you think you’re going to be comfortable doing that on PSMA [prostate-specific membrane antigen] level alone, if there isn’t more traditional bone scan or CT [computed tomography] scan findings? How do you think that’s going to impact our threshold for aggressive combination systemic therapy?

 Personally, I think having PSMA-positive disease that’s not visible conventionally and then labeling that patient metastatic and treating them with lifelong, intensified systemic therapy is hard to sell. The added value will be if we can apply local therapy like focal radiation to areas where we see early micro-metastatic disease and try to get back to more of an intermittent approach, which is what we would be doing if only we had the conventional imaging.

Even the modern trials like the Alliance Foundation Trials’s androgen annihilation trial [AFT-19], which is looking at intensified therapy in the setting of biochemical recurrence, are ignoring PSMA PET findings and basing therapy on conventional imaging. At very, very low volume, maybe we don’t need to make that leap. At the least, it needs to be studied before we shift our treatment paradigm.

 I think that’s right. We have to be careful not to overreact, or patients might overreact. It’s going to be important that we don’t overreact to what these findings are and what they biologically represent, compared with how we’ve traditionally defined high-volume disease and whatnot.

Conventional Versus PSMA Imaging in Prostate Cancer

®: “Prostate Cancer Evolving Treatment Approaches.” I’m Dr Dan George from the Duke Cancer Institute in Durham, North Carolina. Joining me today in this discussion are my colleagues Dr Tanya Dorff from the City of Hope Comprehensive Cancer Center in Duarte, California; Dr Eleni Efstathiou from The University of Texas MD Anderson Cancer Center in Houston, Texas; Dr Ben Lowentritt from the Chesapeake Urology Group in Towson, Maryland; and Dr Chuck Ryan from the University of Minnesota Medical School in Minneapolis, Minnesota. At the midpoint of 2020, it’s been another exciting year in the field of genitourinary oncology. In the field of prostate cancer in particular, we have made significant progress with several recent FDA approvals.

Today, we’re going to discuss a number of the systemic therapies for advanced prostate cancer. We’ll highlight the latest research in the field and discuss practical implications for patient care. Let’s get started with our first talk. We’re going to start out with emerging data around metastatic castration-sensitive prostate cancer. We’re going to follow this up with a segment on nonmetastatic castration-resistant prostate cancer, and then finally end with a segment on metastatic castration-resistant prostate cancer. We’ll discuss both the therapies we have today and some of the emerging treatments and how they are going to impact our care.

Let’s start with metastatic castration-sensitive prostate cancer and exactly how we get there. Many of these patients are presenting with biochemically recurrent prostate cancer after being monitored. The question I have first is, what’s the optimal timing and frequency of imaging? Is that imaging modality changing now with some of the newer PET [positron emission tomography] scans? What are the data around that? Where do we see that emerging now in our regular practice? I’ll start with you, Chuck. Could you walk us through this next generation of imaging and the impact of the timing of diagnosis of metastatic prostate cancer? Can you talk to us a bit about some of the PSMA [prostate-specific membrane antigen]–targeted imaging and where the data are pointing us, in terms of that implication?

 Sure, Daniel. Thank you. It’s really important, before we have a conversation about how to treat castration-sensitive metastatic prostate cancer, to figure out what that clinical state is. As you alluded to, it’s becoming a wider range of clinical entities because our imaging is getting much more sensitive. This is 1 of the areas with the most rapid change in our field. As you said, PSMA-targeted imaging is leading the way. We had 3 presentations at ASCO [American Society of Clinical Oncology Annual Meeting] that helped us with this concept.

Two of the abstracts looked at a molecule called fluorine F 18 DCFPyL, which targets PSMA. Another looked at gallium Ga 68–labeled PSMA-11. They’re using different isotopes for imaging. More important, they looked at different clinical states. The OSPREY trial that was presented was with a pretherapy, newly diagnosed group of patients. Virtually all those patients had negative CT [computed tomography] and bone scans. When they went through the PSMA imaging, we found that 15% of the patients imaged with this new modality actually had N1 disease, and almost 11% of the patients actually had metastatic disease that was entirely missed by the standard imaging.

In that group of metastatic disease, 9% had M1b, or regional disease, and 1% or so had distant metastatic disease. That means that potentially 25% or even more of the patients who are currently diagnosed as having localized prostate cancer will actually have some element of metastatic disease, so that’s something we should discuss. The other study is the CONDOR study, which used the same imaging modality but looked at patients who had a rising PSA [prostate-specific antigen] level after local therapy. CONDOR demonstrated that these images do change the therapy.

That was the key end point of CONDOR. Do we change what we do with the patient based on novel imaging? About 69% of the patients who were imaged had positive scans, and in 64% of the patients who were imaged, treatment was affected by the scan. What was interesting about these changes in imaging is that they led to systemic therapy in about a third, focal therapy in about a third, and observation in about a third. There is a lot to discuss there.

Finally, as for gallium Ga 68–labeled PSMA-11, there is obviously a lot of work going on with regard to metastatic disease and how we’re going to see it integrated into oligometastatic detection, etc. This study, presented by Thomas Hope from University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center looked at preoperative, pretherapy patients. It suggested a very high sensitivity and specificity for gallium Ga 68-labeled PSMA-11 with PET, so that is also an imaging modality that’s going to drive how urologists and radiation oncologists are going to approach localized disease and who they’re going to include as having metastatic versus localized disease.

 There is a lot to digest there, because it really is a paradigm shift, especially when we think about it in a preoperative, prelocal therapy setting. How much of this is going to impact treatment? How clinically relevant is that? Or is this just another way of characterizing microscopic spread of disease?

Charles Ryan, MD, University of Minnesota

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