 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.

Videos

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

Evolving Treatment Landscape of Nonmetastatic CRPC

Optimizing Use of PSMA PET Imaging and PSADT in Prostate Cancer

Overview of Improvements in Prostate Cancer Management