Introduction: Overview of Prostate Cancer

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is the 4^th of 11 programs, all with the same format, we’re doing here at the ONS meeting. This is our 17^th year. Today, this afternoon, we’re going to be talking about prostate cancer. As in all the other sessions, so much going on and also another great faculty of nurse practitioners, Ms Monica Averia from the USC Norris Cancer Center in Los Angeles, Ms Kathleen Burns from the City of Hope Comprehensive Cancer Center, Duarte, California. And medical oncologist Dr Rahul Aggarwal from the University of California, San Francisco, in San Francisco and Dr William Oh from the Yale School of Medicine and the Smilow Cancer Hospital at Greenwich Hospital in New Haven, Connecticut.

We will, as in all these programs, be talking about the use of agents and regimens that are not currently approved, so please consult the package insert for more information on all of these agents.

Check out our new podcast, Oncology Nursing Update. If you go on your iPhone or your phone and hit podcast and just search for Oncology Nursing Update, you’ll find it. There are a couple of programs there right now on lymphoma and myeloma and we’ll be putting all 11 of these programs on that feed as well, so check it out.

These are the programs that we’re doing, and tonight we’ll be back here in the same room talking about chronic lymphocytic leukemia. We’re really here to listen to the faculty. I always loved making rounds when I was in training, and we really adapted that kind of strategy in our CME programs and CNE programs. We’re really thrilled to have the oncologists and the nurse practitioners here to sort of go through this with us.

Alright, so let’s get into prostate cancer. We’re going to just chat in the beginning, a little bit of an overview of some key basic principles, get everybody sort of up to speed. Then we’ll talk about the management of nonmetastatic disease and metastatic so-called hormone-sensitive prostate cancer, which we’ll define for you, and then the emerging role and current role of PARP inhibitors in prostate cancer. We’ll also be talking about PARP of course in ovarian cancer, program later on tomorrow, and finally the role of radiopharmaceuticals in metastatic castrate-resistant prostate cancer.

So first, just a little bit of an overview and Rahul, this is a slide you put together, really great way, kind of talking about the paths that patients take with this disease. Can you talk a little bit about sort of your vision of where patients are, how we sort of place them in different categories?

DR AGGARWAL: Sure, yeah, happy to. I think that, as opposed to other cancers, where we think about Stage I, II, III, IV, we really think about prostate cancer being localized or metastatic and castration-sensitive versus castration-resistant, and patients can fall in any 1 of those 4 categories. This was a clinical disease state that’s now about 15 years old, but you can really kind of see the progression of patients all the way from localized newly diagnosed disease all the way to metastatic castration-resistant prostate cancer. That’s the lethal form of prostate cancer. The arrow at the bottom is important. Many of our men die from other causes and so we’ll talk today about managing comorbidities and minimizing toxicity of treatment.

DR LOVE: And so William, of course a key issue in prostate cancer is the use of hormone therapy. Last night we talked about endocrine treatment of breast cancer and the mechanisms there. Interesting, this term castrate, which I know you’ve written about being maybe not the best possible term. But can you kind of talk a little bit about how the available hormonal interventions work, particularly the removal of testosterone, and then some of the newer hormonal agents that have come aboard?

DR OH: Sure, Neil. We’ve known for over 80 years now that this cancer is driven by androgen and it’s very parallel to breast cancer. And when this was first discovered, leading to actually a Nobel Prize, the first treatment was in fact orchiectomy, removing both testicles. We thankfully don’t have to do that very morbid procedure anymore and we have treatments that can lower testosterone. And what we’re going to talk about a little bit later is other ways of blocking or lowering testosterone, that have actually improved survival in these patients. So it’s an important principle. I call it targeted therapy. Just like an estrogen receptor is a target for breast cancer, androgen and androgen receptor is a target for prostate cancer and it’s transformed the field with better drugs.

DR LOVE: So William, in a second we’ll be talking about androgen receptor inhibitors, or I’ve heard the term lutamides, all these end with lutamides. Talk about what they are and how they work.

DR OH: Yeah. So obviously if you remove the testicles or you give a drug like LHRH agonist like leuprolide, which has been around for a long time, you lower testosterone. The insight over the past few years is that there’s still a little bit of testosterone floating in the body and I sometimes compare it to a cactus that’s able to grow in the desert. If you get rid of that last little bit of testosterone or water, you can actually kill the cactus. And the idea is that these cancers figure out how to grow with very small amounts of testosterone and these so-called lutamides, or we call them ARPIs sometimes, androgen receptor pathway inhibitors, they block that last little bit of testosterone and that has led to long-term responses and in fact, improved survival.

DR LOVE: So Monica, of course, endocrine therapy, we’re going to talk about some of the implications of that really unique scenario in all of oncology in terms of the tolerability and side effect issues. But you notice here in this graphic there’s something else, which is PSA. And there’s really nothing like this in oncology. For a long time we were looking for biomarkers, but there’s no better biomarker for cancer in general than the PSA assay. And we have a whole series of clinical trials and interventions we do with men with only PSA recurrence, for example. But this also leads to kind of, I think, a unique situation in terms of the patient and how they look at their PSA and sort of PSA anxiety. Any thoughts about how you see that played out in your practice?

MS AVERIA: I think patients view their PSAs in a very variable manner. We have patients that are quite fixated with their PSA results. Before I walk in the room, they already have a graph on their phone, before on their computer, now on their phone. And I have patients, when I would tell them I’m still waiting for their PSA, they would tell me, I’ll go home, give me a call. And there’s patients that don’t really rely on that. Everyone’s different.

DR LOVE: So Kathy, another thing that’s very interesting about prostate cancer that’s come out in the last few years is the scans. And we talked about PSA anxiety, there’s also scan anxiety, which of course you see in really every type of cancer. But the thing that’s interesting about prostate cancer is a new type of scan came along called the PSMA scan. It’s extremely sensitive and it’s picking up metastatic disease or picks up the cancer in situations where in the past, a CAT scan for example, would be completely negative. So now we have to go back and rethink, how do we manage these people who now have PSMA scans?

Again, any comments about how this plays out in your practice? Sometimes we have patients who have a positive PSMA scan, the CAT scan’s negative and maybe there’s only a couple of areas there and those areas may even be treated locally. Any comments on sort of this thinking in prostate cancer?

MS BURNS: Yeah. It’s definitely added a lot of technical information to our clinic visits. Patients really need to understand that it’s not a black or white scan. These PSMA PET scans can be very gray and there’s a lot of interpretation. So (1), there’s a great opportunity for patient education. I think, (2), there's a great opportunity for us to work along with teams in radiology and in other areas that we never really had that direct contact with that can help us interpret things and help us move forward with treatment.

Recent Advances in the Treatment of Nonmetastatic Prostate Cancer

DR LOVE: So we’re going to move on now and talk about, if you think back to what we just showed you in terms of the stages of the disease, we’re going to talk about the treatment in nonmetastatic prostate cancer but not localized. And these are patients who’ve had primary local therapy for their prostate cancer, either radical prostatectomy or primary radiation therapy, and then they’re followed looking at their PSMA levels to see: it should go down to nondetectable, which it usually does and then in some patients it starts to rise. And the quicker it rises the more likely it is or the quicker it is that we’re going to see metastatic disease.

And Rahul’s going to go through now all the interventions we think about in this PSA-positive but scan-negative space. So Rahul, a lot’s happening there. This is a typical scenario of a patient who has local therapy and now has a rising PSA.

DR AGGARWAL: Thank you so much, Neil. Yeah, we’re going to go through a case example, a patient of mine, running throughout this talk. So thank you everyone for attending and look forward to the discussion. So I’m going to talk about some of the advances in this rising PSA nonmetastatic prostate cancer space. We think back to our disease states, this is hormone-sensitive with a rising PSA after prior surgery or radiation.

But let’s start with a case of mine. This is an actual patient I’ve been seeing for a number of years, 67-year-old gentleman. He had presented to his primary with obstructive urinary symptoms, PSA was 24, had not had prior screening, underwent a transrectal ultrasound-guided biopsy, had, in fact, high-grade Gleason 4 + 4 prostate adenocarcinoma. We frequently stage these cancers now both with MRI and a PSMA PET. This did show a lesion that did extend beyond the prostate, so this is T3 disease, without evidence of nodal or distant metastases on imaging.

So it’s important to think about risk stratification in the newly diagnosed setting and this comes straight from NCCN. We think about low-risk favorable, unfavorable, intermediate, high risk, very high risk, node-positive or metastatic. And our imaging tools with MRI and PSMA PET have greatly aided our ability to accurately stage patients.

This is the disease states that Neil showed. I’m going to skip to the next slide here. Just to make the point that we’ve already started talking about PSMA PET, this is an FDA-approved imaging tool for newly diagnosed high-risk patients that improves upon the accuracy of staging compared to conventional imaging, which was a bone scan and cross-sectional imaging with a CT or MRI of the abdomen and pelvis. PSMA PET performs much better. You can see the improvement in accuracy from 65 to 92%, which is an aggregate of both sensitivity and specificity.

It's important not to forget about active surveillance. So for newly diagnosed but low-risk patients, to avoid overtreatment for men that may not ever need treatment for their prostate cancer, active surveillance really is the preferred approach. And you can see the characteristics that we choose that wouldn’t apply to my patient but it’s just important to remember that this is an important option for patients with low-risk disease.

In those with intermediate and high-risk, we have options of surgery, radiation, focal therapies. There’s not really great randomized trial data that tells us for sure 1 approach is better than the other, so this is where the individualized patient decision making comes into play.

So our patient opted for surgery. He had actually high-grade Gleason 5 + 4, had pelvic lymph node dissection, no nodes were involved. We checked the PSA post-op. It should be undetectable. That’s what makes it such a great tumor marker. His, in fact, did become detectable and it rose up to 0.56 with a relatively short doubling time, and we’ll talk about that. Had another PSMA PET scan that again did not show any distant or regional metastases.

It’s important to know that we can salvage cure in a lot of these patients.

So this patient did have salvage radiation to the prostate bed and the pelvis along with 6 months of androgen deprivation, had some mild side effects from that including hot flashes and fatigue. PSA became undetectable, did have some persistent urinary symptoms. A couple of years go by and patient’s PSA does start to rise again, up to 0.73, doubling time 2.4 months. This time around, he actually does have on PET scan a couple of new sites of oligometastatic disease. And this has really been a change in the paradigm in the way we manage these patients. We can do targeted radiation that may delay the need for these patients to restart hormone therapy.

And this just shows you a cross-sectional image of one of his metastases. This is a focal bright spot in his T5 vertebral body. This is not a lesion that we would pick up with conventional imaging. Patient did, in fact, get targeted radiation to his PET-avid sites of disease. PSA did respond, but as we see, it’s not a curative option. Patient’s PSA did start to rise up to 1.1, doubling time was short, had another PET scan. This time around, there was nothing really to target. So now we have this patient in front of us with a rising PSA, short doubling time. What do we consider for this patient? Do we watch him? Do we give ADT alone with leuprolide? Do we combine one of those ARPIs that we’ve heard about, or do an ARPI alone? The doubling time matters. The shorter the doubling time, the higher the risk of prostate cancer metastasis and mortality and that’s been shown some nice natural history data.

So let’s talk about the EMBARK study. This was really a practice-changing randomized Phase III trial specifically in this group of patients. Prior surgery or radiation, rising PSA, nothing really left to salvage a cure in the localized setting with a short doubling time of 9 months or less. Randomized to ADT alone, which is our standard of care, enzalutamide, which is one of these potent androgen receptor blockers or the combination of enzalutamide plus ADT. The nice thing about this study is it stopped therapy after 9 months in patients who had an optimal PSA response. And that reflects this intermittent therapy that we often use for patients.

The primary endpoint was looking at distant metastasis. And in both the experimental arms, so enzalutamide plus ADT versus ADT alone, there was a significant prolongation of MFS. And similarly and maybe somewhat surprisingly with enzalutamide monotherapy, so we’re not lowering testosterone, we’re just blocking the receptor, we also see a prolongation of metastasis-free survival compared to ADT.

So the take-home points here, both treatment arms improve MFS and actually improve overall survival as well. The magnitude of benefit was a little bit lower with enzalutamide. We absolutely think about a treatment break after 9 months of therapy in patients that have an optimal PSA response. We’ll get into the discussion, there’re some differences in side effect profile when we use enzalutamide alone versus the combination. Enza alone, you see more gynecomastia and breast tenderness and maybe a little bit shorter off-treatment intervals.

So this patient, just to wrap up, did get the combination of ADT plus enzalutamide, had an optimal PSA undetectable after 9 months. He’s currently on a break and actually testosterone’s recovered with still a relatively low PSA. So that’s a nice outcome for this patient.

DR LOVE: So in a minute, Monica is going to go through some more issues relevant to nursing considerations, particularly people getting androgen deprivation therapy.

But Kathy, I want to come back to a couple of things that Rahul was mentioning, one in particular is the use of intermittent therapy. In the past we often, particularly for advanced disease, would give the patient continuous therapy. In some situations we would use intermittent therapy. But in this EMBARK study, everybody, once their PSA went down after 9 months, they had the treatment stopped and they were observed and most of them at some point, the PSA came back up and then they were retreated. I’m just kind of curious how intermittent therapy plays out in terms of the patient. Obviously, Monica is going to go through a lot of the side effects that are seen but when they come off the therapy do the side effects go away immediately? Do they go away at all? What do you see?

MS BURNS: Yeah. There are 2 groups. The 1 group of guys that are on holiday and really appreciate it and enjoy it, and others worry about it, right? So there’s a lot of reassurance for folks that testosterone should rebound. It can take a while, depending on the hormone therapy agent that you’re using. So side effects resolve with testosterone recovery for the most part. Men are always looking for the hot flashes to abate and other things. So there’s a lot of support during that time but men need testosterone. They need that break for muscle health, bone health. It’s important.

DR LOVE: So William, I can’t think of any other situations of therapies in oncology, which really clearly have dramatic impact on sexual function. And it was really interesting when the enzalutamide monotherapy came out. Again, this had never been done before without androgen deprivation, just the lutamide, so to speak. And everybody was optimistic that maybe this would be better tolerated particularly in terms of sexual function and desire. What have you actually seen from that point of view, and what are we seeing in terms of the data?

DR OH: Well, you remember your sexual function at baseline is always the key part and for a lot of these men, having taken care of thousands of men over the years, a lot of them come in with compromised sexual function to begin with. But there are men who have both a very strong libido and an active sex life where this is a really important part of their lives. And unfortunately as a profession, doctors, we don’t always give it as much attention as we really should. I think the nursing profession may be more attuned to some of the quality-of-life factors that sometimes the doctors rush into the room and out. So I do think the idea — these men do feel better in many ways. They have a high testosterone, the testosterone doesn’t go down. They have more energy, they have more muscle strength, they have more bone strength, they don’t develop osteoporosis, and they do have more libido. Whether they can act on it to have, for example, sexual activity with their spouses or partners is always going to be an issue and they may need help on the mechanical side with regard to getting an erection.

DR LOVE: So for me, there haven't been many trials in oncology in any cancer like the EMBARK study. It was particularly again, this idea of not using ADT, which has been used for 20 years of standard of care, and while enzalutamide plus ADT had a very significant effect, we call these pelican graphs because the curves are so wide apart, dramatic effects. But enzalutamide alone was significantly better, as Rahul just showed, than the therapy we’ve been using for the last 20 years and the whole possibility that maybe it would have less toxicity was very, very intriguing and this is still playing out.

So Monica, let’s talk a little bit about life on androgen deprivation therapy. We’ll talk a little bit about with or without enzalutamide, but can you comment, can you go through your talk?

MS AVERIA: Sure. So when we start our patients in clinic on ADT, I let them know that it’s a cornerstone therapy for patients with prostate cancer. However, it’s not without side effects. The goal of ADT is to reduce the male hormones in the body to stop and slow down the growth of prostate cancer cells that rely on androgens for survival. Because ADT has significant side effects, when we talk to our patients about it, we almost often include their significant others who will be part of the patient’s journey. The side effects include hot flashes, bone density loss, fatigue, depression, emotional lability, gynecomastia, erectile dysfunction, metabolic syndrome and cognitive changes.

Hot flashes is a common side effect of ADT. Some patients will tell us they have 1 every hour, while some would say once or twice a day. Medications, such as venlafaxine and gabapentin as well as acupuncture have provided a role in relieving our patients’ symptoms.

Bone density loss does happen to our patients as well. There’s benefit in performing DEXA scan for monitoring. We encourage our patients to perform weight-bearing exercises if they’re not already. We start them on calcium and vitamin D supplements. Osteoclast inhibitors have been shown to reduce skeletal-related events. So there’s benefit in starting patients on zoledronic acid or denosumab.

Fatigue is a common side effect of ADT. We encourage regular exercise and maintaining activity level. Emotional lability and depression does occur to patients receiving ADT and we monitor and explore this with every visit with our patient. Some benefit from counselling, others benefit from medications such as SSRIs.

Gynecomastia is another common side effect of ADT. For patients that want intervention, there’re surgical options and there’s also single-dose radiation therapy to the targeted breast area.

Erectile dysfunction and decreased libido is a huge side effect of ADT. It pretty much happens across the board with all our patients. We review the role of PDE inhibitors such as sildenafil and tadalafil. We often refer our patients to urology for further management of their ADT side effects. Mechanical therapy has been shown to work on some patients and if they’re interested, we refer our patients for sexual health support.

Metabolic syndrome in the form of weight gain, insulin resistance and dyslipidemia have also been shown to be a side effect of ADT. Again, we encourage exercise and diet modification.

Cognitive changes, dementia in particular, have been reported in multiple studies with mixed and conflicting results and this remains to be an active area of research. If further work-up is necessary, we refer to neurology.

So whenever we start patients on ADT, when they’re continuing to get it, we highly individualize our patients’ care. We consider the treatment demand on our patient. We assess baseline performance status, their comorbidities as well as potential barriers, financial impact, compliant issues as well as limitations, be it physical, mental, psychological and socioeconomic.

So CW is a 75-year-old Asian male with cholangiocarcinoma and prostatic adenocarcinoma. Just briefly, in September 2023, he presented to our institution with cholangitis status post ERCP with biopsy, which showed moderately differentiated adenocarcinoma. Same month, patient underwent Whipple resection. Pathology showed pT3N0M0 extrahepatic cholangiocarcinoma of the common bile duct, margins were negative. In December 2023, the patient underwent restaging scan, which was negative for metastatic or recurrent disease. From February 2024 to July 2024, patient completed capecitabine adjuvant treatment. Unfortunately, during his cholangiocarcinoma workup, his PSA was found to be elevated at 31.10 with a testosterone of 511. Biopsy of the prostate showed Gleason 4 + 5 adenocarcinoma of the prostate. PSMA scan showed metastases to the left pubic bone and right acetabulum. After extensive discussion with the patient regarding his options, he elected to start ADT.

DR LOVE: Could I just ask, and this patient’s now developed metastatic disease without having had endocrine intervention for the prostate cancer. This is so-called hormone-sensitive metastatic disease. And in your review of what patients go through on ADT, could you just, without kind of going through all the details of the case, just talk a little bit about how you prepared him to get the ADT and how he actually experienced it?

MS AVERIA: So by the time we met him, he had an idea he had prostate cancer because the GI oncologist talked to him about it. So he’s been in discussion. So by the time we saw him he already was aware of the additional diagnosis, and he was also briefed about what he is expecting to receive from us if he agrees to it.

DR LOVE: And what happened when he got the ADT?

MS AVERIA: So this man is a classic example of — we have 2 sets of patients, patients that say I know what I’m up against, I’m really not interested in receiving ADT. I need to preserve my sexual health. And I have to say, across the board, age is not a factor. I have a 93-year-old man who called me after the LA fire telling me, Monica, my pharmacy burned down. I’m going to give you a call where to reroute my medications to help my erectile dysfunction. And we have patients who are in their 50s, 60s or 70s who tell me straight up, I don’t care what it does to my erectile function, my libido, I need to live for my family, for my children, my grandchildren, so I will do whatever you guys tell me to do.

DR LOVE: So another issue here, Rahul is actually ADT alone is not used very much anymore. We know that, similar to breast cancer, intensifying therapy, we talked last night about CDK inhibitors. But intensifying endocrine therapy always seems in prostate cancer to lead to better outcomes and very commonly it’s combined with a lutamide. You can actually see here that this patient actually ended up having enzalutamide on top of that. When you add in a lutamide on top of ADT, what kind of toxicities do you get? We’ll talk all week about the situation in oncology where you have multiple agents that have similar actions that are available to choose from and there usually aren’t trials to compare one versus the other, so you have to kind of indirectly compare. But based on kind of what we’ve seen with the — can you talk about the 3 major lutamides, and what characteristic toxicity or side effects you see with each?

DR AGGARWAL: Sure, yeah, absolutely. We have, in the hormone metastatic, hormone-sensitive setting, we have enzalutamide, we have apalutamide and darolutamide. So these are all androgen receptor blockers. We actually also have abiraterone, which is an androgen synthesis inhibitor, so really 4 agents to choose from, all of which have demonstrated either alone or with chemotherapy that they improve long-term outcomes. So our goal is always to intensify therapy. Sometimes we do it sequentially where patients get started with ADT first, see how they do and then we get the second agent added in. There isn’t good head-to-head randomized data that lets us know for sure, but we anecdotally have differences in toxicity profile, I’d say with enzalutamide and apalutamide being a little bit higher risk of fatigue, asthenia, sometimes a little bit of gait instability and a little bit elevated fall risk. Darolutamide might have a little bit lower risk of those things. It’s the newest agent, so I think there’s a lot of interest in whether the side effect profile is better. And then with abiraterone, typically a little bit less risk of falls but maybe a little bit higher risk of cardiovascular outcomes such as hypertension, rarely congestive heart failure, arrhythmias and so forth.

DR LOVE: So you mention abiraterone, and I should have asked William this, but can you talk about that mechanism of action as opposed to what we were saying with the lutamide, and also the fact that these patients receive low doses of corticosteroids as replacement and potential issues and complications that you kind of alluded to? Rahul, can you talk about abiraterone?

DR AGGARWAL: Sure, sure, yeah, absolutely. So this is an androgen synthesis inhibitor. So as William said, when you give leuprolide you block 80, 85% of testosterone production but there’s still a little bit left. And that little bit left comes from the adrenal gland as well as the tumor itself can make androgens. So abiraterone blocks that little bit left of synthesis to really drive the testosterone production down to a very, very low level. It’s a CYP17 enzyme inhibitor so the feedback loop in the adrenal gland you can get sometimes mineralocorticoid excess, so hypertension, fluid retention, low blood potassium levels. We have to give prednisone along with abiraterone to counteract those set of side effects. Prednisone can then in turn have its own related issues in hyperglycemia and so forth.

DR LOVE: Yeah. And we’ll talk later about some of the newer agents that have come along that actually affect glucose metabolism, whether or not the steroids there are going to be an issue.

Treatment Approaches for Metastatic Hormone-Sensitive Prostate Cancer

DR LOVE: So William, we talked about metastatic disease where the patient hasn’t received any hormonal therapy, or at least not recently, so-called hormone-sensitive metastatic disease. Almost every stage of prostate cancer has seen amazing revolutionary changes, particularly including this one, multiple huge trials looking at patients in this situation. So can you talk a little bit, patients may present either with prostate cancer, typically a man who’s not engaged in prostate cancer screening might present with symptoms of metastatic disease. Or the other pathway to metastatic disease can be a patient who gets local therapy, like Monica’s patient, and then develops recurrence and metastatic disease. So William, can you talk a little bit about how we manage it today, much, much differently than a few years ago?

DR OH: Yeah. We already started talking a little bit about how fast this field is changing, both because of imaging, because of new treatments. But this is a 60-year-old man who presented with urinary retention, fatigue and a poor appetite. His first PSA ever was 150 ng/mL and he had a biopsy that showed a Gleason score of 8, which is high-grade. He had a PSMA PET scan, which is shown here, which showed multiple bone lesions as well as liver lesions. So the bone is pretty typical. Ninety percent of men with metastatic prostate cancer will have cancer in the bones, about half of them will have lymph node disease, but only 5 or 10% will have liver mets. This is considered a very negative prognostic factor. He had no family history, no genetic testing, was abnormal and he just had high blood pressure. So we’ll get back to him at the end.

Now this is my version of the same slide that Dr Aggarwal showed earlier, and what you see here culled out is the area that I’m going to be talking about. And as you said, Neil, you can come into the metastatic situation either de novo, that is in that yellow box, you could just be presenting like my patient did first with metastatic disease. But many of the patients in this country actually first have clinically localized disease, progress and then move into this metastatic setting. And as Dr Aggarwal mentioned earlier the key here is that these men live a long time. So the same intervention in the category of nonmetastatic, you’re going to expose those patients to long periods of treatment, whereas metastatic patients, they’re farther along in this pathway. So the benefits of treatment may actually be higher for these men than in the nonmetastatic or biochemical recurrence.

The biology here is that prostate cancers are heterogeneous and what we mean by that is, within a single man, within a single person, they may have multiple kinds of cancer cells so that just doing ADT alone may not be able to get rid of all those cancer cells. And so what we’ve learned is combining it with ARPIs such abiraterone or apalutamide, darolutamide or enzalutamide or chemo or both, have shown added benefit by basically killing off some of those more resistant cancer cells that are shown in that cartoon. And this is really amazing. Over the past decade there have now been 11 clinical trials. Thousands of men randomized to either ADT alone for metastatic HSPC or ADT plus a doublet, which is one of these ARPIs, or a triplet, which is one of these ARPIs with chemotherapy. Now, unfortunately these studies did not actually have an arm which just got chemo so we still don’t know who should get chemo. We’re going to talk about this when I talk about my patient.

And the most recent study is right there. I actually had to add it on because this review article didn’t have this most recent study called ARANOTE, which is with darolutamide. So this is an example of the kinds of studies that have proven that adding an ARPI to ADT, like leuprolide, improves outcomes, including progression-free and overall survival. So you can see, your randomized with metastatic HSPC, or hormone-sensitive prostate cancer, to ADT plus a placebo versus ADT plus, in this case, darolutamide.

And if you look on the left side you can see very significant improvement in progression-free survival, that is, how long did it take for a metastasis to show up in one group versus the other and the significant benefit with the group that received darolutamide up front. If you look at some other endpoints, like how low did your PSA go or how long did it take for your PSA to rise, again, very favorable. And then, just as a reminder, this has already been shown with the other lutamides or ARPIs. On the left there you see the TITAN study with apalutamide, on the right ARCHES with enzalutamide and one thing you’ll see is that all of these slides look very similar. So this gets to the question of why you might choose one or the other. It's not based on their effectiveness. The effectiveness seems to be similar across all 4 of those categories of drugs, but what’s different is, of course, their side-effect profile. That’s why it really matters.

So what about chemo? There’s actually been 2 large studies that looked at chemotherapy plus ADT plus an ARPI. This was PEACE-1. So everyone got either ADT alone plus chemo with or without abiraterone. So you can see, if you add abiraterone to a patient who received ADT plus chemo, they do significantly better, both in terms of progression-free and overall survival. That’s what you see on the right side.

And there was a second study called ARASENS that did the same thing. Instead of using abiraterone they used darolutamide. And you can see again, very strong benefit in terms of overall survival and progression-free survival. This was in time to castration resistance with the combo.

So I want to make sure that this group goes home with 1 important lesson. For many years ADT alone was the standard of care. And then we started adding a second drug, either docetaxel or an ARPI such as abiraterone or enzalutamide. And now we have these triplets with chemo plus ADT plus abi or darolutamide. But you should no longer be giving ADT alone unless the patient is contraindicated to receive one of these second drugs. And you should no longer be giving docetaxel plus ADT alone. So there’s really only 3 groups of options here. You either decide a patient needs chemo but almost everyone should get at least 1 more drug.

And then just the last 10 seconds, there are new drugs coming down the pike and this is an important pathway called PTEN. PTEN’s a tumor suppressor and it activates something called AKT, which drives prostate cancer, about one quarter of prostate cancers. So they just put out a press release. We now learn about new drugs through press releases, and about a quarter of men who present with PTEN-deficient tumors actually benefit from this drug that blocks — capivasertib blocks the PTEN AKT pathway. And this drug is already active in breast cancer so you’re going to see more about this.

So the good news is our treatment landscape is really full. There’s a lot of options. And what did we do for this man? Because he was relatively young and strong, we gave him ADT, chemotherapy with docetaxel and darolutamide. His PSA did respond and paradoxically he gained weight. You remember he was losing weight because men with liver mets actually lose weight and now he’s doing well with a PSA that’s actually in remission.

DR LOVE: So just to follow-up on the last thing you mentioned, capivasertib. Of course, we talked about that last night in the breast cancer session. We’ve been talking about capi for a couple of years now in breast cancer and general medical oncology have used it a lot. A lot of issues with glucose intolerance that have to be looked at.

We’re about to do a program in 2 weeks, the American Urologic Association on AKT inhibition, these patients with PTEN loss. And in breast cancer we don’t know. We see this press release is positive. We won’t know how positive it is until we see it actually presented, most likely in the next couple of months. But the thing that’s really interesting, because prostate cancer is not only taken care of by medical oncology offices but also in urologic oncology offices. Urologists know nothing about capivasertib and all of a sudden we’ll see what this trial shows. It may end up getting approved and all of a sudden they’re going to have to figure out how to use it and particularly how to deal with some of the tolerability, although it has really a great impact.

One other point I just wanted to bring up here too is, we talked about the tolerability issues. And Kathy, I’m curious, one of the agents is apalutamide. I’m curious what your experience is. Again, as Rahul said, these agents seem to be very similar efficacy-wise but slightly different in terms of tolerability. And I’m curious what you’ve seen with apalutamide, particularly in terms of dermatologic issues.

MS BURNS: Yeah. I think that’s our 1 challenge. It has this classic rash, which can be fairly significant. So when someone calls in with some skin issues, you want to get right on those calls. It doesn't happen often, but when it does it can be quite alarming.

DR LOVE: Alright. Well, you actually have a talk prepared looking at these issues so we can take a look at some of your slides and get into more depth about how to manage patients getting this therapy.

I’ll also mention that there’s so-called real-world studies where we go out and we try to look in the really the electronic medical records to find out how people are being treated. And 1 thing that’s very concerning is, we keep saying at these meetings, you rarely give ADT alone anymore and yet you see plenty of people in practice, maybe even 25% of these men who are only getting ADT. The message has not gotten across. So if you see somebody who’s only getting ADT and they’re not getting one of these other agents, it might be interesting to just bring up the question of why they’re only getting the ADT.

But anyhow, Kathy, let’s talk a little bit about these implications from a nursing point of view and particularly from the patient’s point of view.

MS BURNS: Thanks, Neil. All the pictures on my slides except for a couple are City of Hope in California. It’s a really beautiful place. So I’m talking about nursing interventions for APIs. You’ll also see the abbreviations A-R-S-I and A-R-T-A, ARTA and ARSI. And as we know now, they intensity single-agent ADT. When a patient starts on these, it’s important to talk cost, insurance coverage and adherence. These men might be people that don’t take any medicines at all, or you might find that they’re on 15 different things. And I really think it’s important 1, to discuss, is it affordable? The cash price of these drugs is high but there’s lots of good coverage and assistance for patients so I think it’s important to know, is it affordable and what is their plan for taking it? Especially abiraterone and prednisone is a combination that adds pills you take on an empty stomach and a full stomach. So I like to walk guys through, okay where do you put your pills? How are you going to remember? It’s an important thing because it’s surprising how many people come back on their first visit and they’re taking more or less or, yeah. So that’s important.

I think we have talked about some of the specifics on enza, abi, daro and apa. So we’ll move to — the other things that I would do as a clinician, I would get baseline lipid panel, check calcium and vitamin D and start that education. If they’re hypertensive, especially if we’re putting them on that specific medication, you’re going to make sure that’s controlled, so in some parts that’s working with the PCP or the cardiologist. If that’s going to be you, and you’re monitoring, then make sure it’s controlled before you start.

We talk exercise, exercise all day. So I like to start it on day 1, let’s talk about what kind of activity level you have and what makes you happy.

Nutrition counseling I think is hugely important for patients and their families. It adds a lot of nice evidence-based interventions that patients can take back some control.

We’ve talked about a few case studies, so I don’t know if I need to go through this one in particular, but this is a 55-year-old man presented to an outside clinic. He came to us for another opinion. Elevated PSA on screening, biopsy, PSMA PET showed both soft tissue and bone mets. He was started on leuprolide, bicalutamide in an outside clinic, saw a medical oncologist. They were opting to put him on triplet therapy. He didn’t like the idea of chemotherapy so he came to us for another opinion. We tried to sign him on to one of our clinical trials which is talazoparib, which is a PARP inhibitor, ADT and abiraterone but his insurance didn’t agree with us, so he went on a doublet, right? So leuprolide, abiraterone with prednisone and radiation to the prostate. By the end of the year, his PSMA PET showed resolution of disease, PSA has been undetectable all this time.

But I think he's a good example of — so this is a 55-year-old guy, single, self-employed. When I looked up his work in our computer it said pop-up caterer, which I think in LA just means you own a lot of food carts, right? So think about someone who’s kind of — he was fairly disconnected with other people, he needed a little extra support. The insurance was a little iffy at times, so we watched him closely. He did develop some hypocalcemia from his bone-targeting agent. He developed some transaminitis from the abi. That’s generally an asymptomatic problem. We see it on labs when they come in but we need to hold that abiraterone, check weekly labs, make sure it reduces, which it did in 4 weeks, and we were able to continue him on a half dose. But in terms of him personally, he didn’t have a PCP. So that’s where, do we step up and kind of take care of the colonoscopy, the DEXA scans, the cardiology monitoring, exercise, urology referrals? There’s a lot that goes on, and all are very, very important.

Triplet therapy we’ve talked about already. I think the piece that I try to remember when someone’s going onto triplet is for a lot of these men, this is going to be the first time there is an outward change in their appearance. So I like to talk about hair loss, I like to talk about the skin changes from the steroids and some fluid retention. If guys have not shared their diagnosis with their family sometimes or their employer, this is the time to kind of talk them through that as well.

This is a little bit of a startling picture. I actually got it from an article that Dr Oh published a long, long time ago. Well, I don’t know, I wouldn’t say a long time.

DR OH: It’s 20 years ago.

MS BURNS: Okay. Thanks for getting me out of the hole. But when we talk about breast enlargement and nipple and breast sensitivity, so ignore the sternal incision, but look at the breast tissue on the left, which is before, and the breast tissue on the right, which is post bilateral mastectomy. We had a patient, gentleman, retired, extended family lives in Palm Springs where it gets to be 120 and they spend a lot of time with his family around the pool. And this gentleman came in and described a day at the pool when everyone was around and his little grandson said, Grandpa, why do you have boobs? He was stunned, heartbroken, didn’t know how to respond in front of — it was in such a public place for him. He came back so upset. When we talked about a mastectomy, which I generally think is a fairly radical thing, for him it was just do it, I need it. And he was so happy, so happy. So listen to our patients at all times, right? Alright, that’s me.

DR LOVE: So William, any comments? I’ve actually heard double mastectomy in a man is not anywhere near as complicated as a woman, and also that tamoxifen can prevent the gynecomastia.

DR OH: Yeah. I don’t use tamoxifen, partly because I don’t know what it’s going to do to the cancer because there are cross talk between AR and ER. That patient actually did not — it’s the same thing that happens with enza. He got bicalutamide. We had tried bicalutamide monotherapy many, many decades ago and I remember a few things. One is, it’s often not covered by insurance, so you really have to push for it because it is a true medical complication. The second is, we usually radiate the breast before we start monotherapy with a drug like enzalutamide and so I have now a series of patients. They have to be driven to do it. They tell me that it’s very painful. It’s less complicated but it’s very painful but they’re very happy afterwards because it’s a small percentage of patients who really have a story like the one you told, which is very emotional and very compelling.

DR LOVE: So we’re going to go on in a second and talk about PARP inhibitors. But first, Rahul, Kathy mentioned using radiation to the prostate in patients with metastatic — her patient got radiation even though he had metastatic disease. What’s the rationale? And typically, we don’t treat the local cancer when you have metastatic disease. What’s the rationale for doing this?

DR AGGARWAL: Yeah. This is a real paradigm shift. In patients with low-volume metastatic prostate cancer, so 4 or fewer bone metastases, nothing outside the spine and pelvis, no visceral organ metastases. It’s actually randomized Phase III data from what’s called the STAMPEDE trial out of the UK where they took men that were all on hormone therapy and then randomized to radiation of the prostate versus not. Surprisingly, there’s a long-term survival benefit, not just improvement in local disease control, but long-term overall survival benefit with giving radiation to the prostate. So this has really become a standard of care. But patient selection is important. For those patients with high-volume disease, the patient William presented with a liver metastasis, that’s not the type of patient we’d recommend radiation to the prostate for.

Current Role of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

DR LOVE: So talk a little bit about PARP inhibitors in prostate cancer, and another scenario where you see multiple agents within the same class, multiple PARP inhibitors, also multiple tumors where the strategy is being used. Tomorrow at lunch we’re going to talk about ovarian cancer, and they probably have the greatest experience with PARP inhibitors. It’s an integral part of therapy and we learned a lot about tolerability issues and keeping people on longer-term therapy.

So William, this is a situation typically we do testing for germline and in some cases somatic testing looking for particularly BRCA mutations. And for some reason, what you typically see, if you do see BRCAs, is usually BRCA2. And so we talked about a patient who has metastatic disease, a BRCA2 mutation. Can you talk a little bit about sort of what we know about the use of PARP inhibitors, who gets them in prostate cancer and then what kind of outcomes you see?

DR OH: Well, many of the clinicians in this audience use this in ovarian and breast cancer. We’re actually relatively later to this because people don’t tend to think of prostate cancer as necessarily being inherited through a family history of a gene named after breast cancer, right? It’s confusing to some of the men.

So here’s an example. This is a 74-year-old man who presents with metastatic prostate cancer and his mother had this very important history, which she had breast cancer at the age of 37. He had bone mets, you can see it’s an older case, he had a bone scan, and he had leuprolide and abiraterone as his first treatment. But when he started to get castration-resistant, that is, his cancer started to progress, he got chemo but he progressed again, and we’ll go back to him in a minute.

So just the first thing to remember is, there’s 2 ways to look for genetic abnormalities or mutations in a cancer patient, the first is germline and the second is somatic. And germline means, what did you inherit from your mother and father? And somatic means, what happened during your lifetime to alter the cancer, because we know that cancer can be a genetic disease, not always, but obviously if you inherit 1 abnormal mutated gene, like a BRCA2 gene, you have a much greater chance of developing cancers that are associated with it.

But unlike in the breast cancer story, I can tell you that at least 60% of mCRPC patients do not ever get tested. And you can see that it seemed like it was rising and then the pandemic happened. But even post-pandemic, we’re still not testing the majority of these men. So this is really important to do in your own practice, to remind the doc that you might work with and to order it yourself, really, I think. I love partnering with my nurses and nurse practitioners to kind of have a protocol where we don’t forget this. And even in the best practices, I only do prostate and GU cancers, this sometimes falls through the cracks. And as you pointed out, Neil, the majority of what we call DNA damage repair mutations are actually BRCA2. So there’s a whole bunch of them. We don’t have to talk about all of these. But unlike in breast cancer, which I think has a predominance of BRCA1, in prostate cancer it tends to have a predominance of BRCA2. And you can see there are other important ones like CHEK2 and ATM, which we can talk more about.

I should point out, if you can go back, that half of these are germline. That means half of them are inherited from your mother or father. And the other half are actually somatic, meaning they inherited perfectly normal genes in this field but then they somehow damaged it during their lifetimes. Remember, cancer is a disease of accumulated mutations over time, especially prostate cancer, and that is why prostate cancer is more prevalent as you get older. It’s a disease of aging and that is, as we get older, we accumulate some of these mutations. Luckily, they don’t all turn into cancer or else we’d all have cancer, but in some patients it escapes through.

So the last few years we’ve really learned about how you should be using PARP inhibitors. And this is — M1 means metastatic castration-resistant prostate cancer. One of the things that was realized is that, remember the ARPIs that we’ve all talked about today, if you combine an ARPI with a PARP, I know that sounds very confusing, but an ARPI plus a PARP inhibitor actually probably synergizes. And so, that is, we should be using these maybe up front rather than waiting for the patient to progress on a drug like abiraterone or enzalutamide. So the PROpel study looked at this in mCRPC, first-line, patients who have a BRCA mutation and were randomized to receive abi plus placebo versus abi plus olaparib. So everyone’s getting the abi but if you had a BRCA mutation, you can see how dramatic the effect is. This is overall survival. Huge benefit if you carry a BRCA mutation.

So it just reminds you why it’s so important to test. And by the way, people don’t always know their family histories. They don’t always — their family histories may be inaccurate, or they may never have talked about it so it’s really important not just to ask the family history, but also to test for these mutations.

And there have been several other studies, this is MAGNITUDE with an alternative PARP inhibitor called niraparib. And a third one, this is the MAGNITUDE study in the BRCA group, and you can see a very significant benefit in progression. And then TALAPRO-2. Now TALAPRO-2 used talazoparib plus enzalutamide, not abiraterone, but a similar design, all first-line mCRPC. And again, you see in not just BRCA patients but all HR-deficient patients you can see the difference.

But at ASCO this year, GU ASCO, we actually saw that when they looked at all-comers there was still a survival benefit. Now that means that the implication might be that patients might respond to talazoparib plus enzalutamide independent of whether they carry a BRCA mutation or not. I think that’s still very controversial, we can talk about it. I’m not using this in all my patients. It’s not FDA-approved to use in all patients, but it suggests that maybe we’re missing some mutations that may matter.

Now, the way we first started using PARP inhibitors was of course in the third-line setting, that’s monotherapy, and many of you remember this from about 5, 6, 7 years ago, the PROfound study. And this was in BRCA1, BRCA2 or ATM patients and they were randomly assigned, if they had one of these mutations, to olaparib versus placebo. And you can see, there was a significant benefit in survival. I think Monica is going to talk about the adverse events, but just a reminder, anemia and fatigue are the most common and we’ve learned about managing this.

So in this patient, he did have this very strong family history. He has genomic testing on the tumor that showed a BRCA mutation. And in fact, he started on olaparib because he was detected in this second-line setting and his PSA declined by 90% and his pain improved, so I’ll pause there.

DR LOVE: So a couple of questions from the audience, Rahul, before we get more into PARP inhibitors. There’s actually a person here in the audience who has a brother with metastatic prostate cancer, age 60. And the question here is, what’s the typical survival of a patient presenting with metastatic prostate cancer? Her brother was told “maximum of 10 years but likely 3 to 5 years.” Do you agree with that? And of course, we can never predict an individual, but is that generally what you see?

DR AGGARWAL: The wide range of it really does reflect reality, where it can be as short as a couple of years all the way out to 10 years would be on the long end. The medians really depend on that volume of disease status as well as whether patients present up front with de novo metastatic disease. But those factors, along with the nadir PSA after about 6 months of therapy actually is a very strong prognostic factor. So we get this question a lot from patients. I like to tell patients, let’s look at these factors and really try to make it a little bit more of a precise kind of estimate, obviously a super important question.

DR LOVE: So William, another person in the audience who I guess works with men in a prostate cancer support group and says this is a very common question in this group, which is, why do some men recover their testosterone levels after you stop therapy and others don’t? And is there anything you can do to sort of move things up, get things moving?

DR OH: Yeah. There’s 2 strong predictors of testosterone recovery, the first is how long are you on the testosterone suppressing therapy? So the longer you’re on ADT, the less likely you are to recover. And the second is your age. So the older you are, the less likely you are to recover. So you have to think of the testicles, they’re like a Ford factory. They make testosterone and when you shut them down, and if you shut them down for 2 or 3 years, they’re much less likely to make testosterone. So this is why this concept of intermittent is so important and you have to balance what you’re trying to do with the cancer with what you’re trying to do for the quality of life, because men do feel better when their testosterones recover.

DR LOVE: And of course, there’s always patient involvement in difficult decisions, it always is helpful for patients who want to be involved.

Rahul, we’ll hear a little bit more in a second from Monica on some of the nursing and side effect issues. But again, very common situation in oncology to have multiple agents even approved within the same class, hard to compare them. We heard about 3 different PARP inhibitors that are being utilized right now in prostate. How do you decide between them?

DR AGGARWAL: Yeah. It’s a great question. Again, same situation, we don’t have really any head-to-head trial data, so you really have to kind of look at the differences. They seem to be pretty slight, the toxicity profile, in terms of rates of higher-grade anemia, GI-related side effects like nausea, decreased appetite and fatigue. Those are the big classes of side effects with the PARP inhibitors. Seems to be pretty similar. I think what it comes down to a lot of is just familiarity and I think, for that reason, I tend to use a lot of abiraterone/olaparib or olaparib alone, but I think the other PARP inhibitor is also very reasonable.

DR LOVE: Alright, well, let’s get into a little more granularity about what patients go through who get PARP inhibitors. Monica.

MS AVERIA: So whenever I see a patient in clinic and they have known germline BRCA mutation or other HRR abnormalities, I talk to them about the benefits of genetic testing. Genetic testing helps identify at-risk family members. Once a cancer-predisposing germline mutation is identified, testing at-risk family members is important so we can find out who else is carrying the familial variant. Genetic testing also leads to early detection and prevention. It allows for earlier and more targeted screening and preventive measures. It also offers personalized treatment, because knowing about a BRCA mutation or other HRR abnormality can help with the treatment decision of some therapies, because some patients would be most likely to respond to these treatments with their history of genetic changes. It also helps with the patient’s and family members’ informed decision-making skills, because providing them the knowledge and the support they need will help them make their own decisions about their health and family planning. It also helps reduce anxiety and uncertainty.

Helping individuals and families understand the implications of the genetic testing results can potentially help them have increased knowledge, therefore reducing their anxiety. And last but not the least, genetic testing for children and grandchildren of our patients helps connect them to resources, support groups and networks and other relevant organizations.

So when we talk to our patients about PARP inhibitors, I tell them that PARP inhibitors target DNA repair mechanisms. By blocking PARP, PARP inhibitors can cause cancer cells to die, especially the ones that have DNA cell repair defects. This slide is a brief explanation of what Dr Oh already discussed in detail about PARP inhibitors for patients with metastatic castrate-resistant prostate cancer.

So in terms of dosing and side effects, just a brief discussion. Olaparib, abi and prednisone is dosed at olaparib 300 mg po BID with abiraterone 1,000 mg po QD and prednisone. Side effects include fatigue, nausea, vomiting, diarrhea, decreased appetite, cough, anemia, lymphopenia. Niraparib, abiraterone and prednisone is dosed at niraparib 200 mg po QD, plus abiraterone 1000 mg po QD and prednisone. Side effects include fatigue, nausea, vomiting, diarrhea, decreased appetite. It also comes with anemia, neutropenia and thrombocytopenia. Talazoparib with enzalutamide is dosed at talazoparib 0.5 mg plus enzalutamide160 mg po QD. Side effects include fatigue, nausea, vomiting, diarrhea, anemia, neutropenia and thrombocytopenia. And finally, rucaparib is dosed at 600 mg po twice a day. Side effects include fatigue, nausea, vomiting, diarrhea, constipation, elevated ALT and AST, anemia, thrombocytopenia and rashes.

PARP inhibitors is again also not without side effects. For fatigue, we encourage our patients to engage in exercise routine. Massage and cognitive behavior therapy can often work as well. We also assess in clinic about the potential other reasons that they may have fatigue. Anemia, thyroid dysfunction and vitamin deficiencies are other potential causes.

For nausea on PARP inhibitors, we educate our patients to take prophylactic antiemetics 30 to 60 minutes prior to taking their PARP inhibitor medication. Olaparib interacts with CYP3A4, so we counsel patients not to take aprepitant and we also recommend our patients to take PARPI after their meals to reduce nausea. If patients are having significant vomiting or vomiting, we encourage them to identify food triggers. Food diaries often help. We also counsel the patient that if they do vomit, not to take the second dose and just wait for the next dosing. For diarrhea and constipation, we encourage them to take loperamide and laxatives respectively.

For anemia, thrombocytopenia and neutropenia, we see the patients in clinic regularly with complete labs including CBC with differential. For anemia, again, we evaluate for other causes of anemia. We hold PARP inhibitors for anemia more than or equal Grade 3. We transfuse pRBC if needed, and once hemoglobin returns to baseline and the patient experiences resolution of their symptoms, PARP inhibitors can be restarted at reduced dose. Thrombocytopenia does occur on PARP inhibitor treatment although transfusion is rare. With all the side effects that I mentioned, I need to emphasize that the biggest side effect is fatigue, gastrointestinal symptoms as well as cytopenia.

So when looking after patients in clinic on PARP inhibitors I talk to them that we treat until the patient develops disease progression or if they develop unacceptable toxicity. We manage their PARP inhibitor treatment and toxicity by holding the dose, treatment dose modification as well as supporting them with their side effects. PARP inhibitors is given with concomitant GnRH unless the patient had history of bilateral orchiectomy. So with that, we need to also monitor for ADT side effects as mentioned earlier.

Other less common side effects of PARP inhibitors are headaches, insomnia, sexual dysfunction, body changes, depression, emotional lability. We assess treatment burden on the patient continuously, because increased burden clearly leads to decreased quality of life and decreased well-being and we also consistently assess for other barriers such as financial implications and compliance issues.

DR LOVE: I want to ask you about this case, Monica. I know it’s a little bit complicated, this 74-year-old man. But without getting into all the details in terms of the clinical history, I’m curious what happened, I guess last October, when this man got put on olaparib, abiraterone and prednisone, one of the combinations that William talked about. How was he feeling when he started the therapy and what happened at that point, Monica?

MS AVERIA: So this patient developed increasing PSA and had a scan, which showed left proximal femur lesion. His PSA increased to 1.72. Coincidentally, he also developed left lower leg discomfort with and without activity, though no pain med was required. So in October when the restaging showed disease progression, he underwent tumor profiling and the patient was found to have an ATM mutation and after discussion the patient elected to start olaparib, abiraterone and prednisone. His PSA after, it increased from 1.72 by December, since he started in October, decreased to 0.17 and he underwent SBRT to the left femur from December 13 to December 30. And we saw him last week and his PSA decreased to less than 0.02. This patient is tolerating olaparib, abiraterone and prednisone combination. He is asymptomatic, he feels well. He likes to run so that didn’t interfere with that activity. His biggest side effect is Grade 1 fatigue, as he would describe it, and Grade 1 nausea. He takes antiemetics once or twice a week. He also has 1 daughter who underwent genetic testing with no actionable mutation.

DR LOVE: Kathy, I’m kind of curious if you see, in ovarian cancer sometimes they’ll switch PARP inhibitors in a patient who’s having tolerability problems. Do you ever, in a patient who’s having a lot of symptoms from 1 PARP, switch to another? Is that ever successful?

MS BURNS: Not in my experience.

DR LOVE: So a couple of other questions coming back to you, Rahul. William was saying it looks like the earlier you treat maybe the greater the benefit. Right now, the trials that were done were patients who were so-called castrate resistant combined with hormonal therapy, which were not necessarily that many patients. A lot of people think the ideal point to treat was where William was talking about, as first systemic therapy in hormone-sensitive disease. Do you ever treat a patient right now? You have a patient with a BRCA2 mutation who presents with metastatic disease, can you include a PARP inhibitor in that situation?

DR AGGARWAL: Yeah. It’s a great question. In the metastatic hormone-sensitive setting we don’t yet have clinical trial data available or FDA approval to give a PARP inhibitor in that setting. So I personally would want to first wait and see what the data show, because still the risk/benefit. These patients are going to be on treatment for many years potentially before they progress so you’re being exposed to a PARP inhibitor for a long time. The bar rises in terms of seeing that magnitude of benefit, so I think we’ll start to see some of the Phase III data coming out soon in the hormone-sensitive setting.

DR LOVE: So William, another issue is testing here. You talked about genetic testing, looking for germline mutations that are in all the cells versus somatic testing. NGS is a typical test where we look for that same thing in ovarian cancer. Do you do both tests? Do you do the genetic tests first, and when do you do it? Do you do it just in a patient who’s first getting metastatic disease, or when?

DR OH: Yeah. Well, if you look at the NCCN guidelines, they’re very complicated. And so my suggestion is every metastatic patient with hormone-sensitive prostate cancer, once they develop metastasis, they should both get germline and somatic testing at that time. It just makes it easier. Germline testing will come back in a week or two. Now you do have to get preauthorization, but generally these patients will be covered if they have reasonable insurance. Somatic testing takes longer, and so I like to do it as soon as they have metastatic disease.

Now, there are indications earlier. Let’s say a young man who presents with that family history I told you about, even if we don’t give the PARP inhibitor in the setting of metastatic disease, it does influence my decision-making around that person. So let’s say he presents with high-risk localized prostate cancer and he’s getting surgery. If he has a family history where his mother died of breast cancer in her 30s, I want to know, not only for the reasons that were mentioned earlier about the cascade testing in the rest of his family, but it will make me follow him in a slightly different way because I do think that these patients, unfortunately, the ones who carry these mutations, have a more aggressive course.

DR LOVE: And just remember, there’re 2 reasons to test. One is for the patient’s benefit, to see whether they might benefit from a PARP inhibitor or a different type of therapy, but the other is from the family implications and the possibility of preventing cancer. We’ve heard many stories — actually PARP inhibitors are used in pancreatic cancer. We had a patient who ended up dying but he had a daughter who was found to be BRCA-positive who had prevention through surgery and was able to avoid at least breast cancer. And also I was kind of flashing on — we were mentioning we were coming here to ONS for 17 years, how much more challenging, like 10 years ago there wasn’t that much to talk about. Now we’re like barely able to get through this in an hour and a half.

Current and Future Role of Radiopharmaceuticals in mCRPC

DR LOVE: So we’re about to go to a completely other type of therapy that really didn’t exist in the past and now is a critical part of treatment, radionucleotide therapy. You have 2 different types of therapy. We put out the scenario of a patient who initially gets treated. We talked about the triplet that’s given in some patients, particularly if they’re younger or they have aggressive disease but then progression after that. And in this situation bone-only metastatic disease. So just keep that scenario in mind, and Rahul is going to go through what a radiopharmaceutical agent is, which ones we have, when we use them and how patients tolerate it.

DR AGGARWAL: Yeah. Thanks so much, Neil. And yeah, it’s become complex in a good way, and we have a lot more options for our patients than we used to. And so I’m going to talk about radiopharmaceuticals and start like I did last time with a patient of mine.

This is a different patient, 74-year-old gentleman presented again with de novo disease, had back pain, obstructive symptoms, PSA was 124, high-grade prostate cancer. Did get right up front germline and somatic testing, nothing hereditary. Somatic testing pretty typical, TMPRSS2-ERG fusions we see in about 60% of patients. PTEN, P53, this is what we call a double-hit, so 2 tumor suppressor genes lost, high risk. We kind of already knew that. PSMA PET scan with multifocal osseous and nodal metastases. Here’s just an example of his PSMA PET. On the left is what we call the whole-body MIP image. This gives you a good kind of gestalt of the overall disease volume. And then I always like to look at the sagittal views of the spine to get a sense of the disease burden there. Patient’s having symptoms, I’m going to have a low threshold to get an MRI to further look at the spine.

This patient did get triplet therapy, ADT plus darolutamide plus docetaxel for 6 cycles given that he was high-volume de novo metastatic. We give doce for 6 cycles, we stop, we continue the combo. He did get an optimal nadir of 0.02 at 12 months but had a pretty short time to castration-resistance. You can see the PSA trend there, all the way up to 12. We couldn’t get another PSMA PET scan due to insurance auth at that point, so he did get conventional imaging with a CT and a bone scan, and that did show or confirmed what we saw initially, it was also true now, there was pretty widespread osseous metastases. It’s important to get the cross-sectional imaging as well to make sure we’re not seeing any visceral organ such as lung or liver or bulky nodal metastases.

This patient was symptomatic. He had more pain multifocally in the lumbar spine and pelvis. So we talked about various options. We could go back to docetaxel. We could do cabazitaxel, which is a second-line chemo. We could do radium-223. And so I’ll talk a little bit about that. This was the first radiopharmaceutical that was shown to improve survival in patients with metastatic CRPC. And radium, if we kind of think back to our chemistry days, is in the same column of table of elements as calcium. So it behaves like calcium in the body. It gets deposited in the bone and then emits alpha particle radiation to try to kill the adjacent cancer cells, so kind of a neat drug. It’s given IV once every 4 weeks for up to 6 doses. The ALSYMPCA trial was the first trial to show the benefit with this agent. These are symptomatic, bone pain present patients, most had had prior docetaxel, given radium plus best supportive care versus best standard of care alone plus placebo and it showed a prolongation of survival and led to FDA approval of that agent.

More recently, actually just presented at ESMO last year, was somewhat surprisingly, this was actually taking radium and moving it all the way early. This was first-line mCRPC giving it in combination with enzalutamide, which was the first ARPI given to these patients. Patients got the combo versus enzalutamide alone looking at progression-free survival as the primary endpoint. And in fact, they did show an improvement in progression-free survival, hazard ratio of 0.69. You see a pretty nice separation in the curves, and about a 10% improvement in PFS at 24 months.

Somewhat even more surprising, this was just an interim first look at overall survival, but it showed a nearly identical hazard ratio, so 0.69. Based on the statistics of the trial, this didn’t quite yet meet the prespecified threshold to say for sure this improves survival, so follow-up is ongoing, but encouraging to see this data come out with a front-line combination.

Let’s go back to our patient. He did in fact choose radium-223 because he was bone-predominant. He did not have bulky soft tissue disease in his visceral organs. We tend to give 3 cycles and then we restage patients to make sure no new soft tissue disease has developed. You can follow improvements in bone pain, deep reduction in alkaline phosphatase tend to be good ways to monitor a positive response. PSA responses can be a little bit more variable with radium-223. He showed a good response, got the full 6 cycles, tolerated quite well. A little bit of flare in bone pain after the first dose. Anemia was pretty mild. He had a little bit of fatigue and diarrhea. These are typical side effects we can see with radium. Got through all 6 cycles and then he was asking me, well, what should we do now? He really wanted to travel, wanted to spend time with his grandchildren, was not progressing, so we gave him a little bit of break from his treatment.

But then the question comes, well, what should we do next? And this is where we’re really excited to have PSMA-directed radioligand therapy as another FDA-approved agent. PSMA we can use diagnostically, we’ve shown you a lot of PET images, but we can also use it therapeutically. And we select patients for Lutetium-PSMA, which gives the therapeutic radiation based on the PET scan. So you have to have at least 1 positive lesion, no soft tissue lesions that are PSMA PET-negative. So when we look at those criteria, it’s about 85% of prostate cancer patients with mCRPC, so pretty high percentage of patients.

Two randomized Phase III trials have established Lutetium-617 as a standard of care. The VISION trial was post-chemotherapy. PSMAfore was a prechemotherapy study. Both met the primary endpoint of PFS. VISION showed improvement in overall survival. PSMAfore is showing a trend towards improved survival, especially when you adjust for crossover. And actually, just a couple of weeks ago we got FDA approval for Lutetium-617 in the pre-taxane mCRPC setting. And this just shows you the survival curves for these 2 studies showing the improvement in survival on the left with VISION, a trend towards improvement with PSMAfore. And this just shows you the FDA press release, literally just came out a couple of weeks ago.

So our patient did get that treatment break followed by PSAs and scans, was able to travel, eventually did, of course, progress. PSMA PET was positive. We treated him with Lutetium-617. We’ll talk about the toxicities, which generally are pretty manageable. We like to get post treatment SPECT imaging. You can see a nice reduction in his disease burden, even after 2 doses of treatment. He had a nadir PSA of 6, got through all 6 doses of treatment, and is currently on a treatment break. Does have some mild to moderate cytopenias, and we can kind of talk about the management there in our discussion.

And just very quickly, there are lots of room for improvement with these radiopharmaceuticals. What’s the right dosing scheduling? Should we give Lutetium earlier? A lot of new isotopes coming along, all have had different properties. And then of course, multiple combinations being tested as well.

DR LOVE: It’s interesting. I notice the patient had a PTEN deletion.

DR AGGARWAL: Yeah.

DR LOVE: We’re waiting to see this capi study. In breast cancer these agents really had more than a 50% reduction in progression. We don’t know what we’re going to see there, but it just shows you how quickly things are changing.

So William, I’m curious first of all about the — I think everybody was kind of surprised. I always thought radium was a really cool drug and I wasn’t sure exactly where it was going to fit in. I love that radiopharmaceuticals are so well tolerated and effective. What do you think about this radium plus enzalutamide? Do you think people are going to start doing that, adding it in the first-line setting?

DR OH: Yeah. One of the issues is, you remember I said that now we’re not giving people just ADT for mHSPC. So in the United States, it’s actually pretty rare to see a patient who walks in the door with CRPC and who has not already received one of these ARPIs. So I don’t think we’re going to see a lot of them, but I was surprised. I saw that abstract and I said, wow, that’s a better drug than I thought it was going to be. And I think what it says is, if a patient has only bone mets, you really should think about a way to bring radium into their story.

DR LOVE: So also curious, Rahul, in terms of, you mentioned the fact that now we can use Lutetium before chemotherapy and of course, again, much better tolerated than chemotherapy. Right now, what’s the typical scenario where you’re bringing in Lutetium, and where do you think this is heading? Also, I think you mentioned in your write-up that this patient had dry mouth. How much of a problem was it?

DR AGGARWAL: Yeah, all great questions. I think right now, I mean this FDA approval just came into play, so I’d say the majority of our patients are still getting Lutetium post-docetaxel or post-taxane. I do expect that to shift, because head-to-head there’s better quality of life and better toxicity profile with Lutetium, so I think we will see it shift prechemotherapy. The dry mouth tends to be Grade 1 for the most part, usually manageable. We do have to counsel our patients on using mouth rinses, Biotene, drinking lots of fluids. Where I worry about it a little bit more is with actinium and some of the other isotopes that might have more of a xerostomia-type side effect. We’ll have to see.

DR LOVE: I’m getting a little bit of dry mouth here in Denver. I’m not sure if it’s the altitude or what.

Anyhow, Kathy, let’s talk a little bit about life with radiopharmaceuticals. I’ve got to say, your campus is beautiful. I’ve never seen these pictures.

MS BURNS: Come on out.

DR LOVE: I’ve got to check it out.

MS BURNS: Thanks very much, it is beautiful.

So this is what we’re talking about, some radium and Lutetium. Radium in general, we’ve already said, is bone marrow suppression, nausea, vomiting, diarrhea, peripheral edema occasionally. But just kind of good nursing care, anticipating what people have at home and educating. So this is an area that nurses are really becoming more involved in is radiation safety. So if you work in a place like nuclear medicine, radiation oncology, specific patient education has to be very clear because it gets interpreted in different ways.

So with radium, you don’t have restrictions on personal contact. So it’s not like you have to be far apart from a person. Most of the radioactivity is removed through the stool. So the education surrounds bathroom hygiene. What do you do if you’re incontinent, if you get it on your clothing, if it gets on the floor? So that’s a really big point for nurses. And those precautions are for about a week after the dose, and we talked about that.

I think I’ll skip the radium case study because we did that before. When you prepare patients for Lutetium, it’s given in radiation oncology or nuclear medicine. So if you work in those areas you’re going to be very involved with that. But if you work in medical oncology or ambulatory care, you’re going to be involved in it as well and you may be involved with people that you’ve never seen, met or ever will meet during the time. It’s very important to get all on the same page. Family caregiver can be an incredibly important part of this because patients do need to be isolated with this drug, so separated by 6 feet. We usually recommend you can drive home with your partner if you sit in the back seat on the right-hand side. But once you’re home, you should be in your own room with your own bathroom. It doesn’t always work for everyone so walking through the different scenarios can be helpful.

If someone travels. We have people that travel from out of state. If they’re going to get on a plane, they need a radiation safety card and documentation as to why they’re radioactive. Give them a little explanation on time, distance and shielding to really reduce the radioactivity exposure for other people in the family, including young children, pregnant women and pets.

Let’s see. I think we covered most of these, that not everyone qualifies. Not everyone will get 6 treatments in a row. There’s a lot of kind of this imaging, decision-making. If someone has a great response and their PSMA targets are gone, there’s no reason to continue to treat. So we’re learning a lot about how to treat, when to treat.

The other thing that’s come up, I work in a combo GU/med onc/urology practice, and a lot of our patients have urinary devices. So it might be some individualized information and discussion around nephrostomy tubes, Foley catheters, urine sitting in those bags and tubes, how often they should be drained, should there be any shielding between the urine, et cetera.

So yes, side effects, nausea, generally well managed, just plan ahead, make sure they have something at home. It generally happens in the first 2 to 5 days. Kidney injury we watch very closely. Marrow suppression is real. Some people will need blood transfusions, and some people afterwards can become transfusion-dependent so that’s a big teaching point for nurses. Dry mouth, I used to work in a radiation practice and I’m a big dry mouth fan. There needs to be so much more research in this area as we try to take evidence and information that we know from radiation into this area. So we want to learn more about prevention, supportive care, dental input as well. Without saliva the teeth are at risk. So if we’re going to move that Lutetium earlier in the treatment, we need to be much more proactive about quality-of-life care in that way. Fluoride trays would be important. So if you work in research or if you have an interest in this type of area, go for it.

I’m not going to talk about this Lutetium patient. We’re going to end on a happy note and no, City of Hope doesn’t have a cruise line, but that would be awesome.

This patient of ours is a 61-year-old. He had triplet therapy to start. He had persistent PSMA prostate cancer with bone mets. He received 4 cycles, dry mouth we’re talking, with a great response. So 4 cycles of Lutetium with a great response, both in PSA and radiographically. He started to think, gosh, this is a really good treatment for me, I’m going to start and plan ahead. So he started to plan a cruise every time he’d have the few weeks off in between this drug. So he’d have Lutetium, go on a cruise, he’d bring his friends, his family, it was awesome. By the time he was close to 6 he said, I really want to continue this, it’s working great. We were able to get him into a UCLA clinical trial where they’re giving more than 6. He’s had 8 and he’s so happy, so you never know.

But I do want to make one point at the end that there’s a huge opportunity for us to collaborate. So again, these are teams that may not have worked before. Nurses can be the glue. I want to make sure that if you have an interest, you get a seat at the table in planning how we’re going to give these drugs, improving the patient experience, coordination, supportive care. It’s so important, and I wish you well. Thanks.

Oh, it’s not the end. Neil’s in charge.

DR LOVE: Yeah, we got a couple — yeah actually one thing I’ve wanted to ask and we haven’t had too much of a chance to talk about this, and we can go back to the patient. Just kind of curious what it’s been like taking care of this man, and how is it different taking care of him than other patients? What makes him different? Can we just go — trying to go forward to the case she just talked about. Yeah, I think it’s the next slide.

MS BURNS: The one with the ship.

DR LOVE: Yeah, the 61-year-old man. Pretty young man to be dealing with this. What’s his life situation, and what’s it been like to take care of him?

MS BURNS: Yeah. He’s a great guy. He lives in the Sierras of northern California, about a 6-hour drive from us, so kind of in the boonies, not a lot of healthcare up there. And he is very independent, and like I said, he sort of plans ahead and thinks ahead and looks ahead and, I don’t want to say he drives his care but he definitely is part of it, and a big part of it. So his symptoms have been relatively minimal. A little bit of dry mouth, no nausea at all, some fatigue. He feels a little tired the few days after treatment and that’s about it. He’s able to work and he’s been a pleasure to work with.

DR LOVE: So one of the things that we talked about over the years here at ONS is we know there are a bunch of people that come to our programs who are new to oncology. And of course, they start getting asked, why are you in oncology, isn’t it depressing? And I’m just kind of curious, I’d like to ask both of you just as kind of a final note here, what do you find rewarding about taking care of patients? I’ll start with you, Kathy.

MS BURNS: I’ll go. Everything. I’ve done it for 30 years. The patient connections that you get, and not just patients but with families as well, is so strong and deep. And we have bad days and good days, but most every day I’ve practiced I’ve been able to come home and say, I’ve helped at least 1 person. So it’s a great career and I wish you all the best if you’re new and getting started with it. You’re in the right place.

DR LOVE: Monica, any thoughts? What kind of rewards do you get out of practice? Any advice to people just coming into oncology in terms of avoiding burnout and maintaining your own quality of life?

MS AVERIA: So I had an attending who once told me, everyone has their own cross to bear. He said that at 7:15 in the morning, I think about 19 years ago. But every day I think about that. We each have our own cross to bear. For me, people ask if it’s depressing but you do make an impact every day, unknowingly and knowingly. Some people will tell you straight up in your face, write you a card, tell you every day. But for us, we have the privilege of dropping everything, all our issues before you go through that hospital door and when you knock through that clinic room, you do drop everything and you realize, yeah, we each have our own cross to bear. But it's not about you now. To make that difference, it’s huge.

DR LOVE: So for a couple of years, we used to start these programs by showing pictures of what people do to get away from the job, and that’s the advice we usually give to people, get a little break away from things and sort of regroup.

We’re going to come back this evening, talk about chronic lymphocytic leukemia, really a rapidly evolving area. We’re going to talk about that everything changed for CLL in December. So there’s some new stuff going on that we’re going to talk about tonight, really an interesting change to first-line therapy of CLL.

Thanks so much to the faculty. Have a great day.