Julie N. Graff, MD

 That discussion got us into the nonmetastatic castration-resistant space, which is a whole other animal to talk about.

 Yes. With nonmetastatic castration-resistant disease, I remember we used to try bicalutamide, then we would try bicalutamide withdrawal, then we would try high-dose bicalutamide, and then we would use ketoconazole, estrogen patches, and all this voodoo. And then came the SPARTAN trial, which was the first trial I was aware of using apalutamide in patients who didn’t have metastatic prostate cancer, but their PSA [prostate-specific antigen] was rising despite castration.

The primary end point for that study was metastasis-free survival, so the FDA approved an end point that we hadn’t seen before in prostate cancer: the delay to time of spread. I and many others were very dubious about that end point because the first metastasis is not often a painful, devastating metastasis, like breaking your hip. We’d normally do imaging studies until we saw something and then put people on AR [androgen receptor] antagonists. When the overall survival benefit came to light and people were living longer because we were starting these drugs in the nonmetastatic castration-resistant setting, then I was much more of a believer. Because before, we were wondering if we were impacting someone’s quality of life without a very meaningful end point. But now the data are clear that these medications are very useful.

I’d like to add something. With these additions, first we use these drugs after chemotherapy in metastatic castration-resistant prostate cancer, but now the indications are you do it right away if it’s metastatic or as soon as it becomes nonmetastatic castration-resistant. People are going to be on these drugs a lot longer. If you look at SPARTAN, people were on these drugs for almost 3 years. Everything we know about the harms of castration are probably going to be amplified in terms of bone loss, muscle loss, weight gain, and fatigue. We also have to factor that in when we’re talking with our patients.

 That’s a great point. At this point, starting the medication is the easy part. It’s the discussion around not just the adverse events—we’ll talk a little about some of the quality of life stuff—it’s the long-term questions to other systems, whether it be metabolic syndrome, cardiac, or even just pain and, as you said, atrophy of muscles and the like. It’s a challenge that we’re not doing our patients justice if we’re just thinking in terms of their PSA effect and latest scan. That’s the wonderful thing about having agents that keep patients alive longer. It’s also the really intimidating thing about taking care of these patients long term.

Videos

Julie N. Graff, MD, highlights the efficacy associated with the use of androgen receptor inhibitors for nonmetastatic castration-resistant prostate cancer.

AR-targeted therapies for nmCRPC

 That’s really helpful in setting the table here. Today, we’re going to talk mainly about 2 of the indications, both metastatic castration-sensitive prostate cancer [mCSPC]—the patient who presents with metastases, either de novo or after recurrence—and then nonmetastatic castration-resistant prostate cancer in just a bit. When you talk about androgen receptor [AR] inhibitors for the patient with mCSPC, this is a critical area in regard to recognizing when to hand it off if you’re not going to do this. We’re seeing so much benefit for these patients with earlier recognition and earlier institution of therapy, so it’s really important to be aware of these things. But you have both apalutamide and enzalutamide that have an indication for the patient with metastatic castration-sensitive disease.

These indications arrived in 2019 for the most part, and we’ve now seen a couple years of follow-up data and final analyses. I don’t know that we have to spend a whole lot of time on all of the individual trials. To be a little provocative here, we’re always discouraged from comparing differences between trials, like a couple of tenths of a hazard ratio, or if they were collecting data differently. But when we think about the TITAN and the ARCHES trials, which for apalutamide and enzalutamide respectively, were the big trials that led to approval in this space, I’m curious if you see any differences or anything that guides you in your therapy.

One of the things that I always found interesting was from the get-go, you had the signal for overall survival from apalutamide in the first analysis. Why was it so clear with one and not the other? I’m curious, do you distinguish much between these agents? How do you choose between those two? Even in other discussions with other drugs, how do you factor some of these differences in trials into your thoughts?

 Thank you, Ben. The truth is you get used to one of the AR antagonists and you use it because it’s the one you’re used to and know a lot about. I think of apalutamide and enzalutamide as being very similar. The end points on these trials were a little different. One of them was rPFS, or radiographic progression-free survival. The other had more of an overall survival end point. I think of them as pretty much interchangeable. I don’t think one is better than the other. People who use these medications should remember that apalutamide can decrease the thyroid function and cause rash. Those are different from enzalutamide. Both drugs can cause profound fatigue. We should also remember that in the metastatic hormone-sensitive or hormone-naїve setting, there are options of chemotherapy with docetaxel and abiraterone therapy.

It’s a tight field. I don’t know if you’re ready to hear it, but there are all these new data coming out looking at docetaxel followed by androgen receptor antagonists or abiraterone, and saying that it’s better to use both chemotherapy and hormonal therapy. It’s funny in oncology how excited we were to drop docetaxel in 2010 when we got newer treatments, and now we picked it up again for CHAARTED, which focused on newly diagnosed metastatic high-volume disease. Now we’re picking it up again and are probably going to give all the therapies up front.

 Yes, it’s interesting. The ENZAMET trial didn’t really suggest it. We weren’t sure if it was going to be proven that sequential or combination was going to be better. That wasn’t really what it was looking at. It did show the effectiveness of enzalutamide to some extent, but it was a bit of a question. But I agree, the emerging data that are starting to come out on some of these other trials are really exciting for where we can be. It makes sense to me. The strategy for most cancers is to try to address it from multiple different mechanisms, and early if possible, to try to get it knocked down as much as possible. We’re not talking about cure for many of these patients, but anything we can do to prolong survival is really meaningful.

Various factors that medical oncologists consider when selecting to treat metastatic castration-sensitive prostate cancer with either apalutamide or enzalutamide.

AR-targeted therapies for mCSPC

 Today, we’re mainly talking about all the androgen receptor [AR] inhibitors that have come out in the last 10 years. Do you want to give a quick review about these, and what we’ll be talking about the rest of the day?

 Yes. I had the pleasure of starting my training in medical oncology in 2006 and completing it in 2009, and things have been changing rapidly ever since. I got to start in the low of, “Do we start this patient on chemotherapy or not? Or do we radiate it?” For 6 years, all we had was chemotherapy for metastatic castration-resistant prostate cancer. When I and probably a lot of people watching started, we used to call it hormone-insensitive, right? The thought was that castration doesn’t work anymore, so it’s not sensitive to hormones. Thanks to people who do great laboratory work, we figured out that the androgen receptor is still very active and the cancer cells still express PSA [prostate-specific antigen]. There’s all this evidence that hormones are still important.

We began to focus more on contributions of hormones outside the testicles, such as the adrenal glands and even the cancer itself. And then these androgen receptors came to light. Ben, I know you’re familiar with bicalutamide, nilutamide, and flutamide, which were around in the 1990s, that were targeting the androgen receptor but didn’t do a great job of it. Now that we have these newer drugs, specifically enzalutamide, apalutamide, and darolutamide, which are next-generation—second- and third-generation androgen receptor antagonists—the game has really changed. When we were working with bicalutamide, we had a study that showed bicalutamide plus hormone deprivation therapy, by that I mean castration, was better than hormone castration alone. Then another study showed the opposite, or that it at least wasn’t as good.

But with these newer studies, we have convincing data in multiple stages of the disease from newly diagnosed to metastatic castration-resistant that we’re helping men live longer. Some say these newer androgen receptor therapies bind 1000 times tighter to the androgen receptor than bicalutamide would. They inhibit its translocation into the nucleus and its binding to the DNA. These are very powerful drugs. I tell my patients that they also have more serious adverse effects than bicalutamide does. Enzalutamide and apalutamide in particular can cause seizures, so it’s crucial to ask your patient if he has a history of seizure. Certainly, I sometimes see patients who are on a seizure medication, and I say that we can’t use those two2. I know we’re going to get into the trials more. Darolutamide didn’t make that distinction.

In the field, when I see someone with metastatic castration-resistant prostate cancer, my first line is usually to continue the castration and then add either abiraterone or a next-generation androgen receptor antagonist. You asked about AR inhibitors, and I immediately think of enzalutamide and these kinds of drugs, but there’s also abiraterone that came on the scene earlier than the other ones by a year or two. What it does is it blocks the adrenal contribution to hormones. I like to use that drug pretty early on, too. It’s the only one that’s generic and much less expensive than the others.

Julie N. Graff, MD, of OHSU Knight Cancer Institute, comments on the impact of the availability of newer-generation androgen receptor inhibitors on treatment outcomes for patients with advanced prostate cancer.

AR-targeted therapies for advanced prostate cancer

™ video series titled, “The Role of Androgen Receptor Inhibitors in the Management of Advanced Prostate Cancer.” I’m Ben Lowentritt, director of the comprehensive prostate cancer program at Chesapeake Urology Associates in Towson, Maryland. Joining me is my colleague, Dr Julie Graff, an associate professor of medicine at Knight Cancer Institute at Oregon Health & Science University in Portland, Oregon.

In today’s discussion, we’ll discuss the treatment of advanced prostate cancer and the role of androgen receptor inhibitors as a treatment option for metastatic castration-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer.

Let’s get started. Julie, it’s good to see you. How are you doing?

 One of the questions that always comes up is, what is the role of the urologist when a patient has advanced prostate cancer, both in the nonmetastatic CRPC [castration-resistant prostate cancer] space and the metastatic castration-sensitive prostate cancer space? As a urologist, if a urologist is interested enough, we have the expertise and experience with most of the agents that are hormone-mediated to diagnose these patients and then treat them through a lot of the stages of this disease. But more than anything, you must have the interest and take the effort to stay up with what is a quickly evolving and emerging science that’s coming out in this. So even if you’re not going to be treating it yourself, you’re at least recognizing when you need to refer a patient to someone who’s taking care of it.

What’s your practice like in your area? How do you get these patients? What do you see as the role of the urologist?

 Thanks for asking that, Ben. At my institution, urologists pretty much give their patients over to medical oncology if they have metastatic disease or they become castration-resistant with biochemical relapse. Sometimes we even get them earlier because they’ll be receiving hormonal therapy with their radiation or after surgery. In the academic setting, there’s a strong desire to get patients over to medical oncology, probably more so than in private practice where it matters that you have these patients because they can be billable, etc. In academic medicine, people are on a flat salary.

The medical oncologist plays an important role. Of course, I’m biased. But I did a 3-year internal medicine residency and I know about diabetes, heart disease—things that I’m sure surgeons know about but may not deal with from day to day. We’ll go through these agents, but some of them have potential adverse effects that need to be managed in real time.

 That’s a great point. Anyone who’s choosing to focus on this should be aware and in constant communication with the medical team and the patient themselves to make them aware of the potential risks. With all of cancer exploding, your institution is fortunate to have you specializing in this. We sometimes struggle in the community in finding medical oncologists who are as up to date and as engaged with our patients. There’s a lot of give and take there. There’s understanding when the appropriate time is to hand off, or maybe how to work more in concert. That’s always evolving in these types of care. Our practice pattern for years was that hormonal therapies were always given by the urologist. Even when I was training, I was trained in that. But as those treatments became more complex, you had to focus on it more to really stay up on it.

Is there anything out of the NCCN [National Comprehensive Cancer Network] guidelines that steers this discussion one way or the other?

 Focusing on the guidelines, it’s hard for me to say. When we use chemotherapy, it’s pretty obvious that the patients should come to medical oncology. Some urology practices were able to offer chemotherapy, but at that time, it was very medical oncology–focused. In terms of the guidelines, a urologist who’s well trained and up to date in all the medications could treat a patient until they need chemotherapy. It’s just a question of whether you want to. You also bring up an excellent point, which is that medical oncology is changing so rapidly that unless you focus in 1 area, it’s easy to miss out on developments. I don’t know how the general oncologist does it anymore.

 Yes. We hear that from our colleagues all the time. When you have a really good relationship, you can develop that more collaborative approach, and that’s always the best thing for the patient. That’s great. Thank you.

The role of urologists in working with medical oncologists to treat patients with advanced prostate cancer, with special considerations for early referral.

Julie N. Graff, MD

Articles

AR-targeted therapies for nmCRPC

AR-targeted therapies for mCSPC

AR-targeted therapies for advanced prostate cancer

Collaborative approaches to treating advanced prostate cancer