 and the Director of the Survivorship Program at Dana-Farber Cancer Institute.

Matthew Smith, MD, PhD, is the Claire and John Bertucci Endowed Chair in Genitourinary Cancers and director of the Genitourinary Malignancies Program at Massachusetts General Hospital, as well as a professor of medicine at Harvard Medical School.

Evan Y. Yu, MD, is section head of Medical Oncology and a professor in the Clinical Research Division at the Fred Hutchinson Cancer Center; medical director of Clinical Research Support at Fred Hutchinson/University of Washington (UW)/Seattle Children’s Cancer Consortium; and the assistant fellowship director and a professor in the Division of Hematology and Oncology at UW Medicine

 Sandy [Sandy Srinivas, MD], I'm just curious from your perspective, we heard a lot about the maintenance of quality of life by patient-reported outcomes during these trials, as we heard from Scott [Scott T. Tagawa, MD, MS, FACP], which I think is really important and helps us given that this is generally an asymptomatic patient population. But that isn't necessarily always the case when we see patients in clinic. From your perspective, how are these drugs treating patients when you see them on a day-to-day basis?

 I mean, I think just going back to the quality of life, I think it's 1 level to have the first end point, which was metastasis-free survival. And then, as Evan [Evan Y. Yu, MD] said, I think seeing overall survival, and now we have quality of life data from all 3 trials really showing that quality of life maintained, and patients are not having that much deterioration in the well-designed trials with end points that we have known for a long time, including health-related quality of life, the BPI [brief pain inventory] scores for pain, and fatigue. So, I think it speaks to keeping patients in this state where they don't have any metastasis. And that's been incredible to have something like 36 to 40 months of a period of not having any metastasis speaks well for these patients. For a patient in front of me, I think this whole ability to see their PSA [prostate-specific antigen] be undetectable is just so incredible to patients that I think they come in, they see their PSA being low that patients are willing to accept some level of fatigue. For the most part, I would say so long as they know that their PSA remains undetectable and there's no progression, patients are quite happy with the progress that they make.

 I think that all makes sense. And as we think about them and monitoring them over what tends to be hopefully a long period of time, I think it's important that we have strategies, especially because it's possible sometimes for patients to progress radiographically before they have a PSA rise, for example, and hopefully before they have clinical symptoms.

Videos

A brief review of the value of quality of life measures while managing patients on therapy for nonmetastatic castration-resistant prostate cancer (nmCRPC).

Nonmetastatic Castration-Resistant Prostate Cancer: Quality of Life Measures

 Matthew, can you go to the next step on that? What are the factors that describe the patient in whom you're going to do that intensification and you've decided that patient now needs to get that additional therapy?

 Of course, we all apply the same principle: when are we going to do more benefit than harm? That considers the disease characteristics as well as the age and health of the patient. There are patients who are older and more frail about whom you're going to have your reservations about intervening, whether it be for nonmetastatic CRPC or mCRPC [metastatic CRPC], but the disease characteristics are going to be close to meeting the criteria for the trial, which was PSA [prostate-specific antigen] greater than 2 and a PSA doubling time of less than 10 months. With a few exceptions, I'm going to intervene in those patients unless there's a compelling reason not to do so. Then in the lower-risk population, I think it's more of a judgment call, and those are typically patients who I might choose to initially monitor, but again, it's not a matter of whether, but when you'd intervene, and Scott [Scott T. Tagawa, MD, MS, FACP] made a really nice comment earlier, which is that we now know from PSMA [prostate-specific membrane antigen] PET [positron emission tomography] imaging, that nearly all these patients have metastatic disease, and that should come as no surprise. We knew that when the studies were designed that the terminology is a little problematic, and I like to say we chose the terminology “nonmetastatic CRPC” because the alternative of mCRPC was already taken in the labeled indications of the drugs that were approved in metastatic CRPC.

 That all makes a lot of sense. Thank you for walking us through that. Now, Evan [Evan Y. Yu, MD], there has been additional data that's been released on the SPARTAN, PROSPER, and ARAMIS trials related to quality of life, for example. I wonder if you can talk to us about the extended follow-up data that has been presented and maybe that quality-of-life data, as well as any comments on the subgroups that may respond. What are your thoughts as we have all of this additional data as part of these studies. How do those data points affect your decision making?

 I think I'll start off with saying that when these 3 trials first read out with apalutamide and enzalutamide and darolutamide, the first end point we saw was metastasis-free survival. It took a while for the field to really adopt that, but fortunately, we've seen from some other analyses outside these trials, like the ICECAP trial data, that we do believe that metastasis-free survival is a reasonable correlative end point with overall survival. First off, eventually, the first things that we needed to see after metastasis-free survival was that overall survival was confirmed in these trials, and it was in all 3 trials. Then, there are many other additional long-term follow-up reports looking at safety data. There were some thoughts initially that maybe in 1 of the trials, there might have been a little more cardiovascular events, but you also have to consider that the patients are on the study drug a lot longer, and they're exposed for a longer duration of time. There were some thoughts that we're not supposed to do this, but in cross-trial comparisons maybe some studies showed patients that had more adverse events than others. But when you look at the different studies and you analyze that, it all depends upon how often you ask the patient or how often you see the patient in regards to adverse events. I think the summary is that what we've seen with more long-term data and post hoc analyses and quality of life studies is that we don't see a major decrement in quality of life. These agents are efficacious and they do benefit the patients for multiple long-term outcomes and secondary outcomes. We don't see significant long-term toxicity from these agents. Of course, there are some adverse effects that we expect, like fatigue, for instance. There's always the tiny, tiny risk of seizures that is essentially negligible in these earlier disease states, but the long-term follow-up has been very, I think, beneficial for offering reassurance to all of us that we can start these agents earlier. We can treat these patients for many, many years and not see terrible things happen.

 Well, thank you for walking us through that, Evan; that's very helpful. I wonder from your perspective, Scott, as you think about the overall survival data that Evan and Matthew mentioned, what are your thoughts in terms of the control arm? Really, in most cases, for many of these patients actually getting additional active therapies that should be life-prolonging therapies against prostate cancer, and still we saw this overall survival benefit. How do you interpret that, and how does that affect your treatment decision-making in this space?

 Part of the question is, first off, the combination of not just prolongation-free survival, but also overall survival, plus the quality-of-life data overall with no significant detriment—that's how I'd interpret them all together, which would make me say that we should use these drugs appropriately. I agree with them that it doesn't mean that there are no adverse effects. But even if there is a patient that happens to have 1 of these rare fatal adverse effects, whether it's 100% related or not, but a seizure, a myocardial infarction, or something like that, it's very clear that the overall survival or all-cause mortality was improved. I would take it case by case; optimize the control of any comorbidities. If I think someone has a life expectancy for other reasons, and as Matthew mentioned before, if I don't think that's right for that patient, then I don't think that's a good idea. But overall, I think for this patient population, we have 3 trials and we know that they're beneficial. And these are on top of data that came from, like Matthew looked at before, some of the prognostic factors of PSA doubling time in this patient group, whether we're talking about bisphosphate, an endothelium inhibitor, or whatever else.

 The other parts of what you asked, if I remember correctly, Alicia [Alicia Morgans, MD, MPH], in terms of the context of crossover, whether it's direct crossover or an indirect crossover, is that they got those therapies, and in my mind, we've seen this multiple times in this setting. And now, in a noncastrate or hormone-sensitive setting, a good drug up front is going to have a bigger impact than we can catch up later. So, it's another reason in this setting, if I see a patient with a particularly rapid rise in PSA and I don't see anything on CT or bone scan, I'm going to start these drugs earlier. Not that they wouldn't work if I can see them on metastasis but I think they have a bigger benefit when they start earlier.

Comprehensive insight on selecting androgen receptor–targeted therapy for patients with nonmetastatic castration-resistant prostate cancer.

Factors in Selecting Novel AR-Targeted Therapy for Nonmetastatic CRPC

 Well, wonderful. I'm excited to move us into the next section of discussion where we're really thinking about nonmetastatic castration-resistant prostate cancer [nmCRPC]. Sandy [Sandy Srinivas, MD], I'm wondering if you can talk to us a little bit about the available treatment options for nonmetastatic CRPC [castration-resistant prostate cancer]?

 With nonmetastatic CRPC, there have been a lot of changes that have happened. I think the last, I would say 5 years, the definition that we have had currently uses our conventional imaging, which is really a bone scan and a CT scan, and for patients who are on hormonal therapy, having a rising PSA [prostate-specific antigen] with castrate levels. That's the true definition of nonmetastatic CRPC. Over the years, prior to our approval of many of our next-generation AR [androgen receptor]-targeted drugs based on a unique end point of using metastasis-free survival, we have had patients sit in front of us having this anxiety of seeing their PSA go up. What have we used in the past? We have had the earlier generation of AR inhibitors such as bicalutamide. I still continue to use that in an occasional patient who has a prolonged PSA doubling time just as was alluded to earlier. Somehow, I can't remember the last time I used drugs such as flutamide and nilutamide for this group of patients, but maybe there is a role for those drugs. But the most important thing that I think about is that we have to keep in mind that these patients are asymptomatic. They really have no symptoms. I'm always cognizant of that fact that I don't want to add a therapy that has any worse impact on their quality of life. We have a lot of drugs available to us. Typically, chemotherapy that's approved in prostate cancer, such as taxanes, are not used in this setting, because as we think about toxicity and quality of life, use of chemotherapy in this setting has not been appropriate. Similarly, I think while we are investigating immunotherapy and other novel agents, they are not standard of care in this. We are really left with patients staying on ADT [androgen deprivation therapy] as the backbone, and for those patients who are comfortable, clearly this is, again, a state where shared decision-making is really important. How comfortable is that patient seeing their PSA go up really slowly? For that patient, I think it's completely acceptable to have them just be on ADT. On the other hand, if somebody's really anxious, I think there is an opportunity here for us to discuss what would be the appropriate imaging schedule. Should we be offering them some of our next-generation, AR-targeted drugs?

 Well, that's a perfect segue. Thank you so much for that, Sandy, as we think about the next-generation AR-targeted agents that are actually approved at this point, based on several studies in the non-metastatic CRPC setting. Matthew [Matthew R. Smith, MD, PhD], would you mind walking us through those?

 Happy to do so. I think in some ways this has been an uphill battle to describe the importance of this disease state. I have a few additional comments to expand on what Sandy already said. If we look at historical data, and even data from the 3 pivotal studies, the control groups are a group of patients whose overall survival with ADT alone is similar to patients who have de novo metastatic disease to bone. This is a serious disease state. It's a fatal disease state. Most of these patients go on to die of their prostate cancer—at least those enrolled in the trials who were somewhat higher risk because of the shorter PSA doubling time. I think, and the fact that they're asymptomatic is important, but so are many patients with de novo metastatic disease, and we happily intensify therapy in that setting. This is an important disease, and most patients go on to die of their prostate cancer. We now have 3 approved drugs with level 1 evidence for massive improvements in metastasis-free survival, and important improvements in overall survival. When I intervene, I'm going to intervene with 1 of those 3 drugs—apalutamide, enzalutamide, or darolutamide—with the purpose of delaying metastasis development test is an improving overall survival. It's the consistency between the trials that I think is compelling as well as the individual trial-level data. We really have strong evidence to intervene in this patient population. You do have to choose carefully. There are patients who are at lower risk for progression, but in those settings, I just will monitor them on ADT alone, and intervene later. It's really a matter of not whether, but when I'll intervene with one of these life-prolonging drugs.

Focusing on nonmetastatic castration-resistant prostate cancer, panelists review the current treatment armamentarium and shared decisionmaking. 

Evolving Treatment Landscape of Nonmetastatic CRPC 

 Scott [Scott T. Tagawa, MD, MS, FACP], when you think about that, what are your thoughts in terms of the pros and the cons? The things that we appreciate, but the things that we also might need to be cautious about?

 With any new technology or treatment, in my opinion, it's great to have more options for our patients, but sometimes they significantly will change the landscape. I think that's true of PSMA [prostate-specific membrane antigen] PET [positron emission tomography]. As Evan [Evan Y. Yu, MD] mentioned, I think there's no question, particularly, let's say, in the biochemical relapse setting, if we can localize at least confined to the pelvis, ie, amenable to local salvage therapy, that might lead to cure or not. I think that helps us. Before we were a little bit shooting blind, at least when it came to radiation, although I will make the comment that any time a patient, let's say, has surgery, PSA [prostate-specific antigen] is up, and I am ordering a PSMA PET. I was telling that patient and his family, “I hope that we see nothing” because that generally leads to the lowest burden of disease. Those men probably have the highest chance of a cure with solid radiation.

Anyway, getting back to your question about what other questions do we have. Some of the time we see patients that have either high-risk or intermediate-risk localized disease or have a biochemical recurrence that we think then we see metastatic disease on PSMA PET, that we may not have seen on conventional imaging. We have a lot of data that we'll talk about in terms of therapeutic advantages with multiple drugs in that non-gastric metastatic disease setting, but that's for conventional imaging. So, if you see something on PET only, but not in conventional imaging, what does that mean? It's led to an extrapolation of data. Sometimes I will go back and get a bone scan after that, in the setting of what has been termed M0 CRPC [castration-resistant prostate cancer], or nonmetastatic CRPC, but I believe we're also going to talk about some therapy advances. Nonmetastatic was based on CT, MRI, and bone scan, and we know that the majority of the time, particularly in higher-risk groups that were enrolled in the clinical trials, with a shorter doubling time, we almost always see something, whether it's only in the pelvis or outside is a little bit different. These drugs probably work whether we can see them or not. Then 1 additional item that I think is an opportunity is that we have very clearly been able to look for metastatic disease, metastatic CRPC, and more specifically, we’ve been able to follow progression radiographically in everyone, and that’s led to some of the drug approvals, radiographic progression-free survival, but only a minority were eligible to see a radiographic response, because in bone scans, we can't really see response, only progression. I think that we might be able to see this with molecular imaging, whether it's PSMA PET or others, depending on the specific situation. I think that leads to opportunities to be able to do that. But my goal is not to make a PSMA PET better unless that's clearly associated with other outcomes like survival. At this point, that is something that I'm very interested in investigating but not something that I'm clinically using right now.

 Those are all such great points. I appreciate that, Scott, and I also just want to emphasize 1 of your first points, which is that having a negative PSMA PET is actually a great thing in biochemical recurrence because we still do, I think in most cases, want to do the standard of care, which would be radiating the pelvis in a postprostatectomy patient who now has biochemical recurrence. We might add something on if we see something on a PSMA PET, but the less disease that we can see, the less disease hopefully there is. That's a good thing. Thank you for that. I think your other point about how making the PSMA PET better is not necessarily our goal. Our goal is to help the patient live longer and feel better or improve an outcome. Whatever that outcome may be is also important. As we think about the other things that we follow for our patients in the biochemical recurrence space, there are other things that we think about, including things like PSA doubling time. Matthew [Matthew R. Smith, MD, PhD], I'm wondering from your perspective, are you still using PSA doubling time? How does that come into your decision-making practice when you're thinking about the biochemical recurrent state in particular?

 Sure. It's unavoidable, right? We have a lot of PSA data on our patients, and a faster rate of PSA rise or shorter PSA doubling time has been consistently linked to worse clinical outcomes, including shorter time to metastasis, and in the CRPC setting, shorter overall survival. It's there to stay. I think it'll help. It'll continue to inform other decisions, including about the timing of imaging, whether it be conventional or PSMA PET imaging. There are very nice data from the registration studies for the PSMA PET imaging agents that a higher PSA is associated with a higher rate of positivity, to no surprise. I don't know that they have the same data for PSA doubling time, but I would speculate that the same would be true, meaning that a shorter PSA doubling times is likely to be linked to a higher rate of PSMA PET positivity. So, I think PSA kinetics are going to remain an integral part of decision making, particularly for patients with biochemical recurrence.

Shared insight on the respective roles of PSMA-PET imaging and PSA doubling time in the current prostate cancer treatment paradigm. 

Optimizing Use of PSMA PET Imaging and PSADT in Prostate Cancer

 Peer Exchange titled "Recent Advances in the Treatment of Prostate Cancer". My name is Alicia Morgans and I'm a GU [genitourinary] medical oncologist at Dana-Farber Cancer Institute in Boston. I'd like to welcome my esteemed fellow panelists and ask them to introduce themselves, starting with Dr Matthew Smith.

 Hello, I'm Matthew Smith. I'm a medical oncologist at Massachusetts General Hospital Cancer Center in Boston.

 Hi, my name is Sandy Srinivas. I'm a GU medical oncologist at Stanford in California.

 I'm Scott Tagawa. I'm a medical oncologist at Weill Cornell and NewYork-Presbyterian Medical Center.

 Hi everyone. I'm Evan Yu. I'm a medical oncologist at the University of Washington Fred Hutch Cancer Research Center in Seattle, Washington.

 Well, thank you everyone for being here and joining me. Today we're going to discuss a number of recent updates in the treatment of patients with prostate cancer. These have been presented at recent conferences over the past few months. We will discuss the data in the context of guidelines, the treatment landscape, and its impact on clinical practice. Let's get started with the first topic. Sandy [Sandy Srinivas, MD], this question is for you: We're really thinking about the overall treatment landscape of prostate cancer, and there have been so many advances in the recent past. From your perspective, what is the greatest and most exciting thing in terms of systemic therapy that you're on the lookout for in terms of use in your clinic in the next few years?

 Thanks, Alicia [Alicia Morgans, MD, MPH]. There has been a lot of progress made, and I think about it in several different ways. I think, first of all, do we have new drugs that we can use for our patients? Examples of those have clearly been the introduction of PARP inhibitors for our use in prostate cancer. We are looking forward to the much-awaited lutetium-177 for our patients with advanced disease. I also think a lot of progress has been made with existing drugs that we have had for a long period of time. I think over time, we have just learned how to use them more wisely and have moved them up in the earlier lines of therapy, which has resulted in significant impacts in improving longevity.

 Wonderful. I think we're all excited just as you are. I'd love to hear from you, Evan [Evan Y. Yu, MD], in terms of technology, which has also been rapidly evolving. What are you excited about in terms of technology related to prostate cancer care?

 Well, I'm very excited about the new advances in PET [positron emission tomography] imaging. Some of our colleagues overseas, for instance in Germany and Australia, have been using PSMA [prostate-specific membrane antigen] PET for many years, but in the United States, we have not had accessibility. Just recently, we now have access to both PyL [18F-DCFPyL (piflufolastat F-18)] and gallium 68 PSMA PET, which I think will have a lot of utility, especially in early stages of disease. For instance, for staging initially for patients with high-risk localized disease, it has the ability potentially to change both surgical and radiation fields for planning prior to local definitive therapy. I think that another area where PSMA PET will contribute significantly will be for identifying the target. For instance, with lutetium PSMA 617, it will be useful for identifying patients who will be eligible for such treatment and as new PSMA targeted therapies come down the road. I think that it'll be a good companion biomarker at least for identification of eligible subjects and patients that will be eligible to receive that. Finally, I think it opens up the question, can we help with furthering the field with doing oligometastatic directed-therapy? That's the 1 setting where I think outcomes are at this point in time lacking, but for patients who have had primary local therapy and have some biochemical relapse, the sensitivity of PSMA PET is quite outstanding and might be able to identify early oligometastatic disease that might be amenable to additional metastasis-directed therapy. At this point in time, the long-term outcomes are lacking, but trials should be done in that area. I'm really excited about the potential for that to contribute to better outcomes for our patients.

 I completely agree, and I think as we try to integrate these new PET imaging strategies into our treatment plans, whether it's related to early-stage disease, biochemical recurrence, or potentially, as you mentioned in the mCRPC [metastatic castration-resistant prostate cancer] setting, there are going to be pros and cons because this is certainly a more sensitive imaging strategy. It allows us to see things that were previously invisible.

Broad discussion on the evolution of care in prostate cancer from both the therapeutic and imaging standpoints.

Alicia Morgans, MD, MPH

Articles

Nonmetastatic Castration-Resistant Prostate Cancer: Quality of Life Measures

Factors in Selecting Novel AR-Targeted Therapy for Nonmetastatic CRPC

Evolving Treatment Landscape of Nonmetastatic CRPC

Optimizing Use of PSMA PET Imaging and PSADT in Prostate Cancer

Overview of Improvements in Prostate Cancer Management