Bobby Liaw, MD

 I’d like for us to take this opportunity to share final thoughts. Let’s start with you, Bobby, and then Vivek and Ash. What are your closing thoughts on this field of mCSPC [metastatic castration-sensitive prostate cancer] and nmCRPC [nonmetastatic castration-resistant prostate cancer] and role for urologists and the multidisciplinary team?

 With the limited discussions today, we see that the treatment landscape is evolving very quickly. There are so many more “advanced therapeutic agents” that were previously reserved for metastatic CRPC [metastatic castration-resistant prostate cancer] are making a lot of inroads into earlier disease settings. We talked more about hormone-sensitive prostate cancer and nonmetastatic CRPC, but we’ll start to see inroads in more locally advanced disease like early-stage disease as well. There are going to be continued discussions on how best to optimize treatment timing, selection, sequencing, and even combinations. More than ever, multidisciplinary care is going to be important, and how we come together to help our patients and as well as us advance our field. With that, I just want to thank you so much for the opportunity to take part in this panel.

 I’ll offer some thoughts about the mCSPC setting. But as we talked about earlier, it’s a more involved conversation now when we have men with mCSPC presentations and what we highlighted today is that with longer-term follow-up from various clinical trials and more real-world data sets that are emerging, we’re beginning to see that across the spectrum of mCSPC. Whether it’s de novo or previously treated, hybrid, low burden, etc, we’re seeing a clear role for the use of AR [androgen receptor] inhibitors in this population with demonstrated long-term survival benefits. The take-home message is that we need to be incorporating this into the majority of patients with prostate cancer.

 Thank you very much. I want to echo what Vivek was saying and talk to the urologists out there. We’re the people making the diagnosis for the first time, and we want consistent and evidence-based messaging so patients are prepared for what’s going to happen next. Our messaging with all these data we presented is that we’re going to put you on combinatorial systemic therapy. It’s going to be androgen deprivation therapy [ADT] plus something else. Oftentimes, we’ll elicit a multidisciplinary team to do that. That way, we have the messaging up front that this is the standard. That’s the category 1 evidence. And you have to ask yourself questions if you’re doing ADT alone. We want to prep the patient for that. That’s why we’re doing combinational therapy, so the messaging—whether they stay with us or go to a medical oncologist and a multidisciplinary approach—is consistent and they’re not being surprised. They realize we’re doing this because they’re going to live longer on that therapy.

 Great points. Extremely well said. Bobby Liaw from Icahn School of Medicine at Mount Sinai, Vivek Narayan from UPenn [University of Pennsylvania], Ashley Ross from Northwestern University Feinberg School of Medicine—what a star panel. Thank you so much for your great insights, interpretation of the data, and advice to our colleagues. I hope everyone finds it informative. I learned a lot. Thank you very much, and good luck moving forward and taking care of your patients.

Videos

Bobby Liaw, MD; Vivek K. Narayan, MD, MS; Ashley E. Ross, MD, PhD; and Neal Shore, MD, FACS, provide closing thoughts and advice for the optimal management of advanced prostate cancer.

Future Directions for the Management of Advanced Prostate Cancer

 Getting back to the PSMA [prostate-specific membrane antigen] PET [positron emission tomography], the 18F-DCFPyL [Pylarify] was approved in the United States in May. The first dose was given in June, and multiple states have access to it. The folks rolling this out at Lantheus are doing a great job. There’s Medicare reimbursement in several states. The competitor PSMA PET, the gallium [Ga-68 PSMA-11] by Telix, is probably going to get FDA approval by the end of 2022, certainly by end of first quarter. I can’t imagine a state that’s not going to have PSMA PET capabilities. There are some differences in the molecular agents or generators vs cyclotrons, but that’s another conversation.

Ash, you were talking about a nice paper by Wolfgang Fendler and Dr Boris Hadaschik that was published in CCR [

]. They took 200 patients who qualified for the SPARTAN, PROSPER, or ARAMIS, with negative conventional CT scan who all had PSMA PETs. Lo and behold, 99% found that 45% had disease confined to the pelvis and 55% above, but their technetium scan and bone scan and CT were negative. Ash, would you do anything different if you have that patient now, tomorrow, or in 2022? How will you treat that patient?

 There were 2 important things that paper stated when I put it all together for myself. As a urologist, I was an early utilizer of PET PSMA because it was being developed by Marty Pomper and others at Johns Hopkins University, and we had early access. I’d always think about the BCR [B-cell receptor] space, and we’d be thinking about spot welding these metastases. The nmCRPC [nonmetastatic castration-resistant prostate cancer] space or the PET-positive or the metastatic space in the CRPC [castration-resistant prostate cancer] spending is different. What ARAMIS, SPARTAN, and PROSPER teach us is that those people need systemic therapy. They’re not on the phase 2 ORIOLE trial or other ones you could spot well. They need systemic therapy to benefit.

One thing is I will scan those guys. If you recall, about 198 of 200 had a finding, but 25% had a finding where only the prostate or the pelvic bed lit up. I found that very interesting, and maybe a role for some of those guys for local therapy if they haven’t received it. In the other settings, if there’s metastatic disease, it helps me think about what agent I would reach for next. Technically, you could say that guy has mCRPC [metastatic CRPC], but I probably wouldn’t say to use docetaxel. That’s the guy who qualified for SPARTAN, ARAMIS, and PROSPER, so we should be using an AR [androgen receptor] inhibitor in that setting. My takeaway: don’t get fooled and not give more systemic therapy. Also, reach for something that has level 1 overall survival evidence. That‘s how I took it. I wonder what the medical oncologists think.

 Bobby, Vivek, what are your thoughts on it?

 I’m pretty much 100% in agreement. There are random cases where we get a PSMA PET scan, and we’re surprised that there are multiple spots of disease. That tends not to be the most common situation. Usually, when the PSA [prostate-specific antigen] levels are relatively low, when we don’t see much on a conventional CT bone scan, we’re not expecting to find widely metastatic disease. We’ve had a couple of cases like that, in which case I will absolutely treat those—even those silent on conventional treatment, I will still treat those as metastatic castration-resistant prostate cancer through and through. But for the ones who have a couple of spots of disease, like more low-volume disease, I’ll reach for intensifying their treatment with something that has efficacy in CRPC. Of all the drugs that are effective in nonmetastatic CRPC, like AR [androgen receptor] inhibitors, there’s only 1 approved for CRPC. I might reach for enzalutamide if I was going to reach for an AR inhibitor. But outside that, chemotherapy is an option, and abiraterone is still an option. It will be a game changer once we have more consistent access to PSMA PET scans. It’s going to cause a lot of some stage migration.

 I’ll be brief. Echoing what others are saying, the technology is phenomenal, and we’re going to see that what we’re describing is essentially stage migration or clinical setting migration. But we do need to be a little careful about how that informs the potential treatment and how that may affect our understanding of the biology of the patient’s disease. In terms of intensifying or deintensifying therapies, we need to be a little careful about what this means in terms of the patient’s individual prognosis.

Thank you. What great feedback and great pearls and great tips. There’s a lot more we could have talked about. We didn’t have an opportunity to get into genomic profiling—the role for germline and somatic testing. Maybe we’ll come back for another program.

Experts in prostate cancer review the role of PSMA PET imaging in advanced prostate cancer and its impact on disease management.

Role of PSMA PET in Advanced Prostate Cancer Management

Here’s the thing that I find myself saying more and more, especially to my urology friends: you can’t just start a therapy, whether it’s T [regulatory T-cell] suppression, an AR [androgen receptor] pathway inhibitor, or even a taxane, and say, “The PSA [prostate-specific antigen] went down. I’m declaring victory.” You mentioned fractures. There must be a strategy around avoidance of fragility fractures and metastases-related fractures, cardio-oncologic effects, neuro-oncologic effects, and fatigue. Fatigue is the bane of all cancer therapies. What are some pearls before we get to PSMA [prostate-specific membrane antigen] PET. Bobby, what are you doing with your patients? What are you teaching about these issues, these toxicities? We’re keeping patients living longer, we’re delaying metastases, we’re keeping them out of the emergency department, and we’re keeping them out of an inpatient facility. These are big cost factors, but what about fractures, cognition, and cardiovascular issues? What are your strategies?

 I wish I could tell you that I had the perfect strategy, but I don’t. As we’ve been working over the last couple of years in terms of intensifying AR-directed therapies for a lot of our patients, more and more I have to be more proactive in asking if you’ve had a bone-density test recently. If you haven’t, I’m going to get you 1. Are you taking supplements like vitamin D and calcium? If you’re not, I’m going to prescribe it for you. I’m no longer waiting for them to go back to their primary care doctors to have these things evaluated. For my patients who have a history of cardiovascular disease, whether it’s badly controlled hypertension or a history of some cardiovascular disease, I’m telling them to go back to see their cardiologist. There’s only so much that I can do myself. We still have to reach out to other specialties.

In time, we do need to have more of a network of people we reach out to and help manage some of these long-term toxicities. We’ve become very good for the multi-disciplinary areas like radiation oncology, urologic surgeons, and medical colleague. We’re good at working together, but a lot of these other adverse effects fall outside these disciplines’ purview. I don’t want to say everyone, but I’ll use myself as an example. In the past, I’ve been more relaxed in considering these things. It has to rattle around in your brain. As we help people live longer, we also must understand all the other things that we’re causing by prescribing all these treatments.

 I love your candor because it’s not enough to say T suppression, worry about hot flashes and sweats, decreased energy, ARPI [androgen receptor pathway inhibitor] drugs, a little more fatigue. There are other things going on. Vivek, what are your strategies? I love my colleagues who are in teaching centers because they’re being challenged. Now you’ve got your fellows and residents, who are saying what’s state of the art in terms of preventive care?

 The discussion I often have with patients is that there’s this duality—what patients worry about when they read about the medications, and things like fatigue, hot flashes, etc. But from the medical standpoint, in treating prostate cancer, we have to worry about all the symptoms patients may not have, and we have to monitor them from a medical comorbidity standpoint. What I described to fellows is this frailty complex that can occur with this potent energy suppression for prolonged periods of time. This is sarcopenia, loss of bone mineral density, the potential for fracture fragility, fractures and falls, potentially neurocognitive issues—it’s those effects. Although patients may not notice or complain, we have to be attentive to them.

That alludes to what Bobby said about the importance of being proactive about doing the DEXA [dual x-ray absorptiometry] monitoring in men with metastatic castration-resistant disease and bone metastases. We know in ADT [androgen deprivation therapy] plus these AR inhibitors from studies like PEACE III and the radium-223 study that there’s a high rate of fractures in this population. These men need to be on some sort of bone supportive care, taking the calcium and vitamin D supplementation, engaging in some weight-bearing exercise, and monitoring their cardiovascular risk factors. Increasingly, this is part of the domain of treating prostate cancer that we all need to be comfortable with.

 I fully agree. Great comments from both of you.

Bobby Liaw, MD, and Vivek K. Narayan, MD, MS, share clinical pearls for the management of adverse events from ARI-directed therapy in advanced prostate cancer.

Managing AEs for ARI Therapy in Advanced Prostate Cancer

: Ash, let me ask you, now that all 3 of these drugs, apa [apalutamide; Erleada], enza [enzalutamide; Xtandi], daro [darolutamide; Nubeqa] are available can you talk about the PSA [prostate-specific antigen] kinetics of what we saw in these trials and how that influences using these drugs. Many of our patients and families are incredibly wedded to the PSA. And then we will want to get into your earlier raised question about the role of PSMA [prostate-specific membrane antigen] PET [positron emission tomography] in this population.

 The PSA certainly declined dramatically compared to placebo in these agents, which is obvious and it was expected. That’s why it was nice to see the overall survival benefit drive home. For the patients, seeing their PSA decline is a meaningful thing for them. And then the morale they have is meaningful, particularly when you’re telling them that, “Hey, at the same time, we’re going to do this combination therapy. You’re going to live for a while. And you must have a high brow. You want to see your PSA decline. Take that positive attitude into preserving your bone health and your cardiovascular [CV] health by doing exercise, doing strength-bearing measures, by us taking a look at how we’re using—if applicable, thinking about your bone protective agents, etc.” They can optimize that longevity and prevent some of the potential toxicities, like falls and fractures. The interesting thing is that all of the agents, to me, could there be nuances in the mets [metastasis]-free survival? Could there be nuances? It’s hard to compare agents to each other. There’s biases in all the trials and the populations, and it’s impossible, unless there’s an actual head-to-head to compare agents to each other. This wasn’t in this setting, but as we’re talking about quality of life and tolerability, the ODENZA trial was just a phase 2, but recently reported in meetings, [and] was looking at people taking enza [enzalutamide] then daro [darolutamide], or daro [darolutamide] then enza [enzalutamide] in the CRPC [castration-resistant prostate cancer] setting, metastatic, and what would be their preference. And this was on the idea that all these drugs, apa [apalutamide], daro [darolutamide], and enza, [enzalutamide] may have different properties in terms of how they cross the blood-brain barrier and how they affect fatigue and cognition, etc. I’d like to hear the other panelists’ thoughts on that. But the results were, I thought, “Well, maybe daro [darolutamide] was going to be great,” but it wasn’t as strikingly. The ODENZA favored daro [darolutamide] a little bit. The results weren’t striking, and it’s hard to know, for me, which agent do I reach for, when? It’s a very difficult thing for me to figure out. And for me, as a urologist, the most important thing as we intensify therapy is do I maximize cardiovascular health, bone health, metabolic health, as I intensify these agents? And I can’t tell which to do. And to me, what the ODENZA trial told me is if someone’s having a tolerability issue on 1 drug, it’s not inappropriate to switch to a similar agent which may or may not be more tolerable by them. Usually, we switch due to disease progression, but here we’re switching due to toxicity. Those are my thoughts there. It’s a complicated, nuanced thing. And I know we’ll get to the PET issue soon.

Ashley E. Ross, MD, PhD, comments on the clinical significance of PSA response in patients with nmCRPC.

Bobby Liaw, MD

Articles

Future Directions for the Management of Advanced Prostate Cancer

Role of PSMA PET in Advanced Prostate Cancer Management

Managing AEs for ARI Therapy in Advanced Prostate Cancer

Role of PSA Kinetics in nmCRPC Management