 One of the things that’s a little different between these agents is their structure. Apalutamide and enzalutamide have a relatively similar structure. Both appear to cross the blood-brain barrier a little more frequently than darolutamide, which has a slightly distinct structure from the other 2. Sandy, in your experience, does that make a difference in your decision-making? Do you think the AEs [adverse effects] are any different? What are your thoughts?

 At least from the patients in whom I’ve used it in, darolutamide is better tolerated. There isn’t cognitive dysfunction. At least from the clinical trial point of view, there were fewer fractures and falls. In real life, it’s better tolerated compared with apalutamide or enzalutamide. That’s where perhaps this imaging becomes an issue, because if you look at those drugs, enzalutamide has approval across the entire spectrum, so it doesn’t matter if somebody has PET [positron emission tomography] imaging that’s positive if you’re going to treat them with an AR [androgen receptor]-targeted drug. But if you get into the nitty-gritty of drug approval and third-party payers, darolutamide is only approved in the nonmetastatic setting. Like Scott, I also use this to see how it fits. If I use conventional imaging and it’s negative, I advocate darolutamide for those patients.

 That’s a good point that the indications and FDA approvals are slightly different, so it can be more challenging to get access unless you don’t have that PET imaging, which, by the insurer, could shift your stage, even if not in your clinical practice. That’s interesting and important.

I should emphasize that none of these drugs have been assessed head-to-head, so we’re looking at AEs for each of these drugs as compared with ADT [androgen deprivation therapy] plus placebo, but we’re not able to cross-compare across the trials. We’re not advocating that anyone do that, but just trying to speak from our experience. We’re not comparing across trials, except the agent vs placebo, all with ADT. Scott, what are your thoughts on the same question thinking about the differences, at least as compared with placebo, for these agents, their tolerability, and even their drug-drug interaction profiles?

 To me, that’s the clearest. The twice-a-day dosing for darolutamide with less drug-drug interactions is a nice trade-off for me. For patients who are on multiple drugs in whom I’m worried about interactions, that’s the one I will use most confidently in terms of fewer drug-drug interactions. I agree with you that we don’t have any head-to-head comparisons in the nonmetastatic setting, but we do now have a comparison to this metastatic CRPC setting, which is just in abstract form. We don’t have the cognitive data yet, but there was no major difference between enzalutamide and darolutamide in terms of the AE rates and patient preferences for darolutamide. That’s preliminary. There are some cognitive data coming from that trial as well as multiple other trials, including one that you’re leading. I’m interested to see some head-to-head data within a randomized trial.

The other interesting part about the French trial was the crossover design. Each individual patient was their own control in terms of preference and exposure for both. Maybe there’s a little less fatigue and a little more preference for darolutamide, but in that setting, nothing major. Twice a day vs once a day is something that’s different. There are slightly fewer drug-drug interactions. I go back to the noncastrate setting. Two vs 1 is better, so the early addition of any of these for this nonmetastatic, particularly short doubling time castration-resistant setting, is important.

 I’d agree. That trial was interesting. Like you said, fatigue may have been a little different, but at the end of the day, these patients are often relatively asymptomatic, except for the symptoms that we’re giving them because of their ADT. Whatever we can do to keep them feeling as well as they can and not add onto that burden is going to be important. If they’re in agreement, we need to try to do whatever we can to get better disease control. From my perspective, that’s why it’s important to intensify when we can for the survival advantage. Your thoughts have all been interesting. Thank you all for your time and your expertise.

Videos

An in-depth discussion regarding experience treating nonmetastatic castration-resistant prostate cancer (CRPC) with apalutamide, enzalutamide, and darolutamide, and factors that impact treatment selection.

Nonmetastatic CRPC: Treatment Selection

 Let’s talk about our next section, which is management of nonmetastatic castration-resistant prostate cancer [CRPC]. Sandy, we’ll start with you on the clinical trials that led to the approvals of enzalutamide, apalutamide, and darolutamide. What are your thoughts on these trials? Can you give us an overview of all 3 and talk about their primary and survival end points?

 Sure, Alicia. Nonmetastatic CRPC has been a big clinical bucket for us where—with our conventional imaging with bone scan and CT [computed tomography] scans—we’ve never had a drug that resulted in a meaningful end point, such as overall survival [OS]. Knowing the PSA [prostate-specific antigen] height as well as the PSA doubling time in these patients matters.

There were 3 large trials looking at enzalutamide, apalutamide, and darolutamide, all with almost identical trial designs, taking patients with nonmetastatic CRPC defined by conventional imaging and patients whose PSA doubling time was less than 10 months. All 3 trials aimed at showing an improvement in metastasis-free survival [MFS]. Remarkably, the results were almost identical. All 3 trials met the end point of improvement in MFS.

Last year, all 3 trials had a readout of improvement in [OS], which is important in this disease space where patients have no radiographic evidence and no evidence of symptoms. All 3 trials also demonstrated improvement in quality of life. These are compelling. Today, it’s hard to have a patient whose PSA is increasing sit in front of you and to just let them know that we’re going to watch them. It’s remarkable that we have 3 drugs all showing improvement in OS. For that patient with the rapid PSA doubling time, I wouldn’t hesitate to put them on 1 of these 3 drugs.

 Thank you for that overview. What a tour de force. That’s a lot of information. I appreciate that. Overall, even for patients in the control arms of all 3 trials who got intensification on progression, they found that earlier intensification led to a survival benefit, which means you cannot make up for that difference in time of earlier intensification. This message seems to be consistent with what we see in metastatic hormone-sensitive disease as well. Earlier intensification brings more bang for our buck.

One thing I’ve heard in conversations in practice is that there can be some confusion. Part of this comes from our imaging, because when we use things like Axumin PET [positron emission tomography], for example, or if we have access to the newer PSMA [prostate-specific membrane antigen] PET studies, we might find patients who, by conventional imaging, don’t have any radiographic evidence of metastatic disease, but on PET imaging, do have areas of metastatic disease. Phil, is this a common thing? Should we expect that these patients are going to have evidence of metastatic disease by PET imaging? How often do you think this might happen?

 Great question. We have some data that shed some light on this. When SPARTAN was first presented, there was another study that looked at a SPARTAN-like population. These patients would have qualified for SPARTAN, and had a PSMA PET-CT performed. In that group, 55% of those patients had M1 disease. Today, the real question is, what do we do with that information, and how does it impact management? I don’t think we know the answer. This is a good example of the potential phenomenon of the Will Rogers effect in this type of patient population.

In instances like this, we need to go back to the data. The PROSPER, SPARTAN, and ARAMIS trials used conventional imaging. Patients who are negative on conventional imaging would qualify for this, because in reality, all these patients who we classify as nonmetastatic probably have micrometastatic disease. It’s always been a limitation of the imaging. Even though the imaging has gotten better, it still can’t detect everything. That’s where we are today. This is another area where, now that we have this better imaging, we can do more research and investigations and have a greater impact.

 Great. Thank you. I tend to agree with you. Scott, I’d love to hear your thoughts on that. If you have a patient who appears to have nonmetastatic CRPC on conventional but somehow has PET imaging, either because you ordered it or the patient had it outside of your facility, does a positive PSMA PET change your treatment?

 Sometimes. I use the imaging how I want. I agree with Phil. Some might affect the PETs, but if they did, it was ignored. And some allowed some disease limited within the pelvis in the soft tissue. But ignoring that, these patients had nonmetastatic disease by standard cross-sectional imaging and bone scan. Especially those with a short doubling time, I have 0 problem offering any of these agents, whether there’s a PSMA or any other PET that’s positive.

That being said, if there’s a patient who I want to offer sipuleucel-T or something else that requires metastatic disease, I may say, “Hey, they have metastatic disease on this type of imaging.” I use it how I want to use it. But in the setting of relatively low-volume metastatic CRPC, in terms of not a lot of disease on CT, MRI [magnetic resonance imaging], bone scan, and 1 too many metastases on PSMA PET, these patients are appropriate for these drugs. These drugs clearly work in the long run. As Sandy pointed out, they have the overall viewpoint: MFS, OS data, maintenance of patient-reported outcomes despite an AE [adverse effect] rate that’s not 0. It says that these drugs work overall.

 Yes, I agree. It’s amazing how consistent these were in terms of their hazard ratios for MFS and OS, even though they’re done with different agents, different studies, and different populations around the globe. It’s impressive and quite consistent.

An overview of drug approvals for nonmetastatic castration-resistant prostate cancer (CRPC), and discussion regarding the potential utility of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) to guide treatment decisions.

Advances in Nonmetastatic CRPC

 There’s 1 other thing I wanted to hear both of you comment on before we wrap up this section. We have the approval of a new oral GnRH [gonadotropin-releasing hormone] antagonist medication. It’s different in that it’s an antagonist. There’s only 1 other antagonist on the market, and it’s oral. Relugolix was approved in 2020. What are your thoughts? Are you using this agent? Are there any challenges you faced because it’s an oral agent or because you’re transitioning patients to a new agent? Scott, what’s your experience and thoughts on relugolix?

 It’s great to have available. It came out during the COVID-19 pandemic. It’s important to have because there are some patients who are on long-term ADT [androgen deprivation therapy] in combination with radiation. Even though we have long-duration injectables, as well as an annual implant, most are getting an injection every month or every 3 months. For those patients who were scared to come in or didn’t want to come in, that gives it an advantage. Besides the start and lack of a flare, there may be some additional differences in terms of tolerance, particularly from a cardiovascular point of view. There aren’t exactly level 1 data, but they’re good enough for me across data sets across drugs, particularly those with extra risk factors, because they all have some risk factors as men.

As a medical oncologist who treats a lot of metastatic castration-resistant prostate cancer or advanced disease, it’s very important to have combination agents. In my mind, it’s not completely practice-changing for everyone because the ADT is in the background and I want to add to it. I’m much more focused on what I’m adding. There could be additional costs with the oral formulation, at least in the United States health care system. There are also probably more drug-drug interactions than with an injectable, although that isn’t always completely significant.

I agree with Scott. In my mind, the biggest asset relugolix brings in is the rapid testosterone recovery once you stop the drug. I think about the patients whom we give intermittent therapy to, especially those with nonmetastatic biochemical recurrence. With those patients, once you stop the LHRH [luteinizing hormone-releasing hormone] agonist, it takes a tremendous amount of time for the testosterone to recover. In that setting, I really like to use relugolix.

Like Scott, I’ve also used it in patients who have cardiac comorbidities. Even though the trial was done for only 1 year, some of the end points they picked were convincing that there was some decrease in cardiac comorbidities compared with an LHRH agonist. But I worry about the drug interaction, especially as we look at drugs such as DOACs [direct oral anticoagulants] and many of the arrhythmia drugs that our patients are on. I’d like a little more safety data on drug interaction. But in my practice, I will definitely use relugolix for patients whom I’m treating on an intermittent basis.

 Great, thank you. To the point that you’ve both made about cardiac issues, when we’re thinking about intensifying using an AR [androgen reception]–targeted agent with ADT, we know there are some cardiac risks for agents like abiraterone and enzalutamide. Perhaps combinations that include a backbone that has a lower cardiovascular disease risk may ultimately prove to be helpful. But these are data we’re still waiting to see. This was really great. Thank you all for this lively discussion.

Implications of treating patients with metastatic castration-sensitive prostate cancer with relugolix, an oral GnRH antagonist.

Oral GnRH Antagonist Therapy for mCSPC

 As we wrap this up, I’d love to hear your thoughts on how these intensification strategies may affect biology. Do you think it does? Does the cancer that comes out after these intensifications, particularly after a triple-agent intensification, become more aggressive? Does it change in terms of its phenotype? Does it change in terms of how we need to target it? What are your thoughts, Sandy?

I don’t think we know the answer for triple therapy yet. But we certainly know from patients who’ve had intense AR [androgen receptor]–targeted therapy that we’re seeing the price we pay for that. There’s the emergence of the neuroendocrine phenotype, which is certainly on the rise. Twenty years ago, even in my clinic, I’d see very few patients coming in with a PSA [prostate-specific antigen] that’s undetectable but a liver full of metastases. That’s becoming more common in our practice. We know the biology is very different for patients with low PSA who have an undifferentiated disease with hard-to-target treat areas, such as liver. The intense AR target the escape mechanism of what comes. We know for at least the AR-targeted therapy that it’s pretty difficult to treat, other than treating them with platinum-based chemotherapy. We treat them like we treat neuroendocrine tumors.

I don’t know what it would be when we do triple therapy. That’s why it’s really important, because these patients all have metastatic disease. We’re not curing them. This strategy might be very different if you’re talking about patients with localized disease where our goal might be to cure a larger fraction. It’s important to be cautious about what this is going to do downstream for our patients. That’s true even today, using all these drugs earlier when patients become castrate resistant. Even though our list of approved drugs exists, we have very few great options. This is a question that I’m looking forward to being answered and knowing what the field will shape out to be.

 That’s a great strategy. Certainly, changing the mechanism of action to hopefully target something that hasn’t already evolved resistance is going to be important from my perspective. Scott, what do you think?

 I agree. Not that I know the answer, but I don’t think there’s a major difference in biology for someone who got ADT [androgen deprivation therapy]–abiraterone for 3 years and then develops metastatic CRPC [castrate-resistant prostate cancer] vs someone who got frontline mCRPC [metastatic CRPC] therapy and a year and a half of ADT continuation plus the addition of abiraterone at the end. It’s probably similar. There may be some differences in underlying biology in those who present with metastatic disease vs not.

In any case, to respond to Sandy, the key point is what the tumors have become exposed to and resistant to. But I don’t think we should be following these metastatic patients with only PSA, especially now. I don’t know the right answer in terms of the exact imaging frequency. If you look at LATITUDE, it was every 4 months because we’re looking at rPFS [radiographic progression-free survival]. If you look at SWOG-S1216, it was at least 1 year. But there needs to be regular imaging for patients with noncastrate hormone-sensitive castration-sensitive disease who are treated, because there’s a bigger percentage having progression radiographically or clinically without PSA. It’s not the majority, but it’s an important subset.

 I agree. In an analysis of the PREVAIL trial, it may have been even up to 20%. This is absolutely something that we as a field need to think about. Hopefully it will be addressed in the next Prostate Cancer Working Group guidelines, which make recommendations for clinical trials. Hopefully they’re considered in our clinical practice a little, along with our NCCN [National Comprehensive Cancer Network] Guidelines, which is where we always have our clinical practice guidelines. Maybe it can be addressed explicitly there in the future.

Recommendations for integrating treatment advances in metastatic castration-sensitive prostate cancer into everyday practice.

mCSPC: Applying New Data into Clinical Practice

 We saw some interesting presentations recently, and 1 not as recently, on the use of triple therapy, ADT [androgen deprivation therapy] and docetaxel chemotherapy followed by or concurrent with either enzalutamide in the ENZAMET trial, or abiraterone in the PEACE1 trial. Both of these trials showed a pretty significant improvement in progression-free survival. PEACE1 most recently reported and showed a 2½-year difference in progression-free survival radiographically. I’m curious about both of your thoughts on triple therapy. It’s not recommended at this point. We don’t have survival data. But what are your thoughts and practices, Sandy?

 I found that really interesting at this year’s ASCO [American Society of Clinical Oncology Annual Meeting]. Alicia, as you mentioned, we’ve seen ENZAMET from a couple of years ago, when it had become standard based on CHAARTED, and there were many patients getting docetaxel. Overall, that trial was interesting because those patients who had ADT-enzalutamide and docetaxel had an improvement in clinical progression, but there was no improvement in overall survival. For the group who had docetaxel, that benefit with enzalutamide was a lot lower compared with those patients who didn’t get docetaxel. Prior to this year’s ASCO, it’s been our standard to not do triple therapy, but we were looking forward to results from PEACE1. There’s 1 more trial using darolutamide with chemotherapy, so we were awaiting those results.

Coming to this year’s ASCO, I thought PEACE1 was really interesting. This trial looked at standard of care—they defined standard of care as ADT—and patients were on docetaxel. They had 2 cohorts of patients. The whole intent to treat was about 800 patients, and the group that had docetaxel had about 300 patients in each arm. As you said, they found a pretty remarkable improvement in radiographic progression-free survival at close to 2½ years for the group who had all 3. We didn’t even get to see a glimpse of the overall survival because it was premature. It comes with a price in terms of toxicity suddenly when you add 3. But considering our previous conversation, where we’re having difficulty in this country having patients do dual therapy, with just ADT intensification, the standard would be to do ADT intensification and not offer patients all 3 as we wait more on the overall survival. Especially because there was some difference between the ENZAMET trial vs PEACE1, I’d certainly wait until we hear more overall survival results.

 Thank you. That was a wonderfully well-thought-out answer. It’s really interesting, because I feel like so many of us have our own takes on these data. After Karim Fizazi presented at ASCO, the moderator started that conversation and it was a completely split panel. Some people said, “I’d consider doing this intensification of a third agent now.” Others said exactly as you said, “I really want to wait for that survival of understanding how this triplet will affect survival, given all the costs associated with it. Not just financial costs but also potentially in terms of quality of life.” Scott, what are your thoughts?

 I was very impressed with the PEACE1 data. It was a very well-done study that adjusted during. But unfortunately, it asked an old question. Meaning, in my practice, the most common therapy is ADT plus AR [androgen receptor] pathway inhibitor. In my mind, the question is, what about the addition of docetaxel to that? We’re not really going to get that answer, even with ARASENS. Longer follow-up and additional data sets will have a lot of prospective numbers, and then we may be able to look at that in a meta-analysis and see how much better it is than ADT-abiraterone, or ADT-apalutamide, or ADT-enzalutamide alone. I’m not sure it’s ever going to be the standard as an all-comers approach for me.

There are additional questions to answer. What else can we add to it? Whether that’s a PSMA [prostate-specific membrane antigen]–targeted radionuclide or a PD-1 agent. There are other PARP inhibitors in that setting that I find more intriguing, and I have hope for those. But for individual patients, that could be a right answer. I don’t think it’s necessarily ever going to be the right answer.

 We’ll have to see. I have hopes that we’ll get some follow-up overall survival data from ENZAMET, PEACE1, and ARASENS, which is chemotherapy plus or minus darolutamide, in the next year, or that we can at least answer whether an AR-targeted agent adds anything to chemotherapy. As you said, 1 of the main questions is, does chemotherapy add anything to AR-targeted agent intensification? We don’t know yet.

Potential implications for treating metastatic castration-sensitive prostate cancer with triple therapy based on recently reported data.

Triple Therapy Approaches for mCSPC

 We’ve seen a number of studies in real-world populations that have demonstrated that even in the United States, among medical oncologists, neurologists, and anyone treating these patients, there’s a substantial number of patients with metastatic hormone-sensitive disease, or castration-sensitive disease, who are getting ADT [androgen deprivation therapy] monotherapy alone. I’d love to hear your thoughts on this. I’ll start with Sandy.

But to share my own perspective, we need to think of every patient as getting ADT plus something. Then our second response should be: Is there a reason they can’t get that intensified therapy? And only if they can’t get it, should we back off to ADT monotherapy? Patient preference can be a reasonable reason to use only ADT monotherapy. But that intensification strategy needs to at least be considered. Sandy, what are your thoughts?

 I agree. Alicia, I’m surprised about all these papers that have come out about the real world. You think about practice changing. Nothing in oncology that we’ve seen has resulted in this impactful change in overall survival. If you think about a trial like CHAARTED, to have close to an 18-month difference in overall survival, it’s hard to see it with any other oncology trial we’ve had. That has been consistently shown with not just chemotherapy but abiraterone, enzalutamide, and apalutamide. The NCCN [National Comprehensive Cancer Network] Guidelines have this as a category 1 recommendation, so it’s really surprising to see in the real world that there have been repeated papers saying that fewer than 10% to 15% of patients end up getting either chemotherapy or 1 of these AR [androgen receptor]–targeted drugs. We agree that AR intensification should be the norm, and there should be an absolute reason why they can’t get it. For some of our patients, it may be that these drugs are expensive, or there may be co-payment reimbursement issues.

In my practice, there may be a patient who’s in their 80s—an older patient with multiple, especially cardiac comorbidities—and you may be concerned about what this addition would do. I thought the SWOG-S1216 trial, presented that at this year’s ASCO [American Society of Clinical Oncology Annual Meeting] was intriguing. It was an overall negative trial looking at TAK-700, which is a drug very similar to abiraterone. Overall, the surprising part about that trial was that the standard-of-care arm with just ADT plus bicalutamide outperformed what we’ve seen before, about 70 months, compared with the TAK-700 at 80 months. There may be a small group of patients for whom ADT may be OK. But for the majority today, there is level 1 evidence that ADT intensification, with 1 of these AR-targeted drugs or docetaxel, should be the standard of care. It’s hard to understand why that hasn’t transformed into an adaption.

 I agree. SWOG-S1216 was inspiring because it speaks to subsequent therapies being effective and really shifting that survival curve that we saw. But those patients were all in a clinical trial, so my expectation is they probably did get those subsequent therapies, hopefully relatively quickly, at each point of progression, which isn’t always the case in the real world. I always favor earlier intensification unless, as you said, there’s a reason not to. Because if we don’t do it early, we may miss that opportunity to do it ever and certainly miss that massive benefit in terms of survival. Scott, what are your thoughts on this?

I haven’t been able to figure out why at least the 5 days that I know of that have been presented—Medicare data sets, a VA [Veterans Affairs] data set, and 3 commercial internal data sets—all point clearly toward less than 50% of patients getting escalated therapy. Some of them were as low as 13%. Part of it is timing. The VA data sets ended in 2017 or 2018. It does look like there’s an improvement in terms of the percentage who are getting ADT plus. We can look at the 2019 data, but there are still less than 50%. It’s clear in my mind that it’s not even close to 50% who aren’t eligible for these drugs.

One of the data sets that Stephen Freedland presented showed not only that but even, unfortunately, increased disparities by race and ethnicity in terms of who’s getting them and who’s not in the world setting within an insured population. Luckily, 2 of these drugs are generic. Generic abiraterone in terms of lack of assistance co-pay may or may not be cheaper out of pocket, but docetaxel certainly is. It’s chemotherapy, so not everyone wants it or is appropriate for it. But at least that’s a very cost-effective drug. They’re actually all cost effective, but on a practical basis, it’s about how much the individual patients are paying out of pocket.

The rationale for treating metastatic castration-sensitive prostate cancer with androgen deprivation therapy as monotherapy as the field advances with newer combination approaches.

ADT Monotherapy in mCSPC

Sandy made a comment on this previously. Scott, before we move on to some imaging-based biomarkers, I want to hear your thoughts on how you’re testing for somatic mutations in particular. Because as Sandy mentioned, many of our patients have bone metastases. Not as many have accessible lymph node or visceral metastases that we can easily biopsy and sequence. What are your thoughts about bone metastases and tissue biopsies vs using prostatectomy specimens vs using liquid biopsies, which are available but not always concordant with our tissue samples?

Optimally, for any given patient, it’s best to use a plethora of different tools. On a practical basis, I agree that getting a tissue-based biopsy at any given time is often the most invasive and difficult. There’s a fairly large percentage of patients, at least by standard imaging, who have bone-only metastasis. That being said, we can get information. About 5 years ago, we published our bone biopsy series, and I believe 85% of the bone biopsies were diagnostic, with 82% able to do whole-exome sequencing and a little less in terms of RNA-seq [RNA sequencing]. So it’s possible.

The caveat is the patients who we thought we probably couldn’t do, like those with a very small rib metastasis, for instance. But that being said, it’s possible. And at least as of today, we get the most depth of analysis from a tissue biopsy. But as I tell patients—you mentioned heterogeneity—we get a great depth of whatever is in the needle, and that’s it. The same tumor in a different location may be a little different. That’s where I think of the addition of blood-based biomarkers, which are clearly the easiest in my mind, as long as someone doesn’t have a hematological malignancy for germline.

I would clarify circulating tumor DNA a little differently than cell-free DNA. Circulating tumor DNA, where we have a germline-matched sample, is very good. It’s not as sensitive, but we can really trust those results. When we have cell-free DNA without a germline sample, we have to worry about clonal hematopoiesis. Just a thought. But we want to take every test into context and at least give prognostic information, which will help guide treatment choices, but also, particularly in the setting of different therapeutic interventions, it can probably give some predictive information to a subset. That subset is 0 if you don’t test.

I couldn’t agree more. And to emphasize that there can be challenges with those cell-free DNA assays having CHIP, or clonal hematopoiesis of indeterminate potential, particularly on genes like 

, it’s so important to make sure you can match with a germline sample. All patients with advanced prostate cancer, high-risk localized or metastatic hormone-sensitive and beyond, are eligible for germline testing at this point in time. They’re not just eligible, it’s recommended. Thank you for clarifying that.

Dr Scott T. Tagawa comments on the pros and cons of liquid and tissue biopsies used to assess patients with advanced prostate cancer.

Tissue and Liquid Biopsies in Advanced Prostate Cancer

 titled, “Evolving Management Landscape for Advanced Prostate Cancer.” My name is Alicia Morgans, and I’m an associate professor of medicine in the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, Illinois. Joining me today in this discussion are my colleagues and friends, Dr Phil Koo, the chief of diagnostic imaging at the Banner MD Anderson Cancer Center in Phoenix, Arizona; Dr Scott Tagawa, the medical director of the GU [Genitourinary] Oncology Research Program at Weill Cornell Medicine in New York; and Dr Sandy Srinivas, a professor of medicine in the division of oncology at Stanford Medicine in Palo Alto, California.

As we are just past the midpoint of 2021, it has been another year stocked with practice-changing advances in the field of GU oncology. In prostate cancer, several recent FDA approvals have been granted. Today, we will discuss evolving approaches that are transforming how we think about precision medicine in prostate cancer, as well as how we’re using systemic therapies for advanced prostate cancer. We’ll focus on the latest research in the context of existing standards of care and highlight practical implications for patient care. Let’s get started on our first topic.

In our first segment, we’ll be talking about how we’re moving toward precision medicine in advanced prostate cancer. Let’s start by thinking about that topic in general. What is precision medicine? And what is precision medicine when we think specifically about prostate cancer? Sandy, what do you think when we think about this particular topic?

 It is individualizing therapies for patients. Our colleagues in lung cancer have done a remarkable job of biopsying after every single therapy, at progression, and tailoring therapy to what an individual needs. It’s been challenging in prostate cancer, given that our patients have predominantly bone disease. The field hasn’t yet completely gone into having a comfort of analyzing tissue from bone. But for the first time ever, we have therapeutics in prostate cancer based on mutations and altered mutations, so we’re getting there.

But there’s tremendous heterogeneity for patients with prostate cancer. Patients respond so differently to the hormonal therapy ADT [androgen deprivation therapy], which we’ve had for decades. Some patients have a dramatic drop in PSA [prostate-specific antigen] and a long duration of response, and then we have others who have barely a couple of months of response, and they progress. There’s such significant heterogeneity that our ability to pick therapy for a given individual should be based on some selection, and that’s what precision medicine means to me.

That’s a great start. As you said, precision medicine goes back to the time of ADT, because targeting the androgen receptor was one of the very first precise ways of targeting a cancer. It’s really interesting to mention that and to also comment on the heterogeneity of this disease.

Scott, what are your thoughts? In prostate cancer and across cancer, we’re trying to move into precision medicine. Where do you feel that stands in prostate cancer? How do you think we can improve on that and target some of that heterogeneity, including things like racial diversity, that we know may be contributing and is a particular challenge in prostate cancer?

I agree, it can be quite complex. Precision medicine, which I would broadly define as the right treatment for the right patient at the right time, is fortunately in play in all fields of medicine, whether it’s internal medicine with diabetes and who needs insulin, etc. There are many more diabetic drugs than when I trained, so I’m glad that we have that help. In a way, precision medicine has been in prime time within prostate cancer for a number of years. We’re further refining it, and it’s true for all stages of disease. With patients with clinically localized, low-risk disease, I’m considering imaging, blood-based and tissue-based biomarkers to help me give the best advice I can in the context of a patient and their comorbidities and wishes for active surveillance vs interventions.

We have moved to much more sophisticated types of diagnostic tools, which nicely has been matched with advanced disease to many more treatment options. Not just ADT, although that’s the backbone for everything, and not just taxane chemotherapy, but we now have a number of different choices, which makes it much more important. One of the relatively new factors in the longer-term scheme of things is germline alterations. If you think about racial disparities, it’s not just germline genomics, exposures, or access to care, it’s a little of all those and much more. There are some factors that look like they may cut across all the other factors, such as a germline 

, but there are others where we need to take all the other factors into account.

I couldn’t agree more. To comment on germline and somatic mutations, these are things we can target at this point with a couple of FDA-approved therapies, including our PARP inhibitors, and we have things like 

, as you mentioned. Sandy, are you thinking about other alterations at all, like tumor mutational burden or MSI [microsatellite instability]-high status, when you’re seeing patients with very advanced prostate cancer? That would also be a way to enact precision medicine, right?

 Totally. Immunotherapy has been such a welcome change in so many different cancers. In prostate cancer, just monotherapy with checkpoint inhibitors hasn’t been that promising, so we’re fortunate to have FDA approval for pembrolizumab, for instance, which has an approval across all cancers for tumor mutational burden greater than 10 and for MSI-high. I’ve looked very hard, and I can’t tell you the number of times that, especially for patients post-AR [androgen receptor] therapy, where you’re looking for something besides chemotherapy. It’s at that point that I’ve definitely looked at prior tissue and liquid biopsies, but I haven’t yet found that patient who has MSI-high. But certainly, that’s a time to look for these markers, because those patients who have this will have such an amazing therapeutic option where they could have a response that could be more long-lasting.

Absolutely. It’s only 1% to 3% of our patients who are going to have that MSI-high status, and that’s in the mCRPC [metastatic castration-resistant prostate cancer] setting, so these are truly patients who are needles in a haystack. I have 1 patient who I inherited from someone, but haven’t identified any on my own, despite testing as much as I possibly can, just as you mentioned. But despite this being a rare situation for our patients, it’s absolutely imperative that we identify those patients if they’re in our practices, because there can be an option in pembrolizumab.

A panel of physicians who work in the field of genitourinary oncology comment on the evolving role of precision medicine in advanced prostate cancer.

Phillip Koo, MD, MD Anderson Cancer Center

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