EMBARK Trial: Enzalutamide Monotherapy and Combination Therapy for High-Risk Biochemical Recurrence - Neal Shore

May 28, 2024

Alicia Morgans speaks with Neal Shore about managing biochemical recurrence (BCR) in high-risk patients, particularly following radiotherapy (RT) and radical prostatectomy (RP). Discussing findings from the EMBARK trial, Dr. Shore emphasizes that combining enzalutamide with LHRH, or using enzalutamide alone, significantly improves metastasis-free survival compared to leuprolide monotherapy. He focuses on managing side effects like gynecomastia, recommending prophylactic measures such as radiation therapy and tamoxifen, a well-tolerated and cost-effective selective estrogen receptor modulator. Dr. Shore underscores the importance of shared decision-making, considering patients' preferences and individual risk profiles. He highlights the benefits of enzalutamide monotherapy, especially for maintaining sexual function, and stresses the need for vigilance in addressing adverse events to ensure patients' well-being during treatment.


Neal Shore, MD, FACS, Director, CPI (Certified Principal Investigator by the Association of Clinical Research Professionals), Medical Director for the Carolina Urologic Research Center and practices with Atlantic Urology Clinics in Myrtle Beach, SC

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

Read the Full Video Transcript

Alicia Morgans: Hi. I'm so excited today to be joined by Dr. Neal Shore, who's joining me from the Carolina Urologic Research Center, and who also joined me recently in Lugano, Switzerland for the APCCC 2024. Thank you so much for being here with me today, Neal.

Neal Shore: Thanks very much, Alicia.

Alicia Morgans: Wonderful. So Neal, you really helped us think through biochemical recurrence and how we treat that. And of course, this is an evolving landscape. You've been very involved with that. Can you share a few of your thoughts with us today? And then we'll have a conversation after you do.

Neal Shore: Sure. Absolutely. Happy to do so. It was great to see you and all of our wonderful colleagues at APCCC and, of course, kudos to Silke Gillessen and Aurelius Omlin. I loved this meeting. I was asked to talk about: are some patients with biochemical relapse, after RT and/or RP, candidates for androgen receptor pathway inhibitor or antagonist, as the title says, monotherapy? And how to manage the systemic therapy. Really, I chose to talk about the side effect profile. And this is all based on the EMBARK trial that looked at over 1,000 patients, an 8+ year study, high-risk BCR patients who ultimately went on to demonstrate, in three different cohorts, that monotherapy LHRH was inferior to combining enzalutamide and LHRH. Even monotherapy enzalutamide was superior in terms of metastasis-free survival, our primary endpoint, compared to leuprolide alone monotherapy.

But what we saw was that there really were not only clinical relevance benefits to androgen receptor pathway inhibitor using enzalutamide, but there are some unique adverse events of interest. I'm going to address those right now in our short time that we're talking. And how can we mitigate some of these particularly unique adverse events that we see with monotherapy androgen receptor pathway drugs, such as enzalutamide? FDA expanded the label in the US and it's now been expanded by the EMA, as of a couple of weeks ago. So for your high-risk BCR patients, you can offer them enza and LHRH, as well as just enza monotherapy. And so how do we mitigate some of these adverse reaction profiles? I'll talk to you about what I'm doing now.

Here's just a quick recapitulation of the EMBARK trial. As I already said, it was a three-arm trial. The combination enza LHRH versus placebo LHRH was blinded. The enza monotherapy, of course, was not blinded, and some would say that could give you some skewing of your interpretation of the adverse events. We had a treatment holiday built in. I'm not going to talk about that today. I think that's a nice feature of it. If they nadir to less than 0.2 at 36 weeks. The primary endpoint you see is metastasis-free survival. A key secondary endpoint will be OS. We plan to report that out sometime in 2025.

Quick, the KMs, here's the combination besting leuprolide at landmark analysis at three years and five years. A hazard ratio of 0.42. And then similarly, when you look at the monotherapy enzalutamide arm, a hazard ratio of 0.63 besting leuprolide alone monotherapy. So these are really now, to my conclusion, the new standards of care for patients with high-risk BCR. Either combination LHRH and enzalutamide or enzalutamide monotherapy. And there are differences, of course, in the hazard ratios. But I think as importantly, there are differences in the adverse event profile. I'm going to really focus, primarily now, on three trials. There was an early trial that was led by Bertrand Tombal and Matthew Smith, where they took 67 patients and they received just enzalutamide monotherapy. I led the ENACT trial, which was a large phase two study in active surveillance, an enriched population of grade group ones and grade group twos, 112 for a year received enza-mono, and the other group received active surveillance.

And then the EMBARK trial, which you see here. You see some of the important aspects of the treatment-related adverse events, serious AEs, discontinuations, etc. Note at the very bottom where it says prophylactic treatment for adverse events was not part of any of these protocols. And I think that's a very important concept to realize because that's what I'm going to talk about today and how we can mitigate some of these specific monotherapy ARPI, in this case, EMBARK enzalutamide. How can we mitigate?

Here's a summary of the breast-related symptoms from those three trials. It was a little over 500 patients, so it's a pretty healthy number of patients receiving enzalutamide monotherapy. 67 in the Tombal trial. The ENACT is 112, and now another 355 patients in the EMBARK, which was led by my good friend and colleague Steve Freedland and myself.

So in breast enlargement, you see the numbers. Tenderness and pain are less so, but it's real, and it can be daunting to some patients. So let me just get to the bottom line of what I presented at APCCC without going into a deep dive into the data. A lot of this is now based on prophylactic radiation, one or two sittings, 10 to 12 Gray. This was for patients receiving high-dose bicalutamide, the earlier generation ARPI at 150 milligrams, typically not approved in North America. But when you did a single or two-day dose, 10 to 12 Gray, one sees a decrease in the breast enlargement, gynecomastia, benefiting those who received radiation versus those in the control group, respectively, 52 versus 85%, 15 versus 50.8%. No real differences in breast pain or tenderness, and generally well tolerated. The pain and tenderness become important as we talk now about endocrine therapies.

And there's a whole series of really nice studies. You see the authors listed here. They looked at an aromatase inhibitor versus a selective estrogen receptor modulator. Essentially, what you see here is that tamoxifen was superior to anastrozole. There's a typo in there, apologies. In multiple studies, you can give tamoxifen, which is well known for being used for breast cancer patients. I don't treat breast cancer, but this is now a generic medication. The daily did better than the weekly in one study. You really want to start these patients pretty soon, almost simultaneously or within a month. Clearly, another oral agent to potentially be adding, but it's inexpensive. It's generally very well tolerated. There's a small VTE incidence and a small incidence of some worsening hot flush, but overall very well tolerated. One would need to also look at DDIs.

These two papers by Di Lorenzo and Perdona were interesting because if you combine prophylactic radiation and tamoxifen, earlier studies showed tamoxifen bested anastrozole. This combination was actually most beneficial in reducing all breast-related symptoms. I thought that was very interesting. Now, I found this very compelling in that most urologists around the world, maybe there are some exceptions in our Nordic and Scandinavian colleagues and in parts of Europe, where there's just not a lot of experience with this. And maybe even arguably for our medical oncology and radiation oncology colleagues as well. This just lists a nice summary of numerous studies. This is a nice paper by Johnson et al, where they really summarize a lot of these different authors and trials, and you can see the numbers of patients. The anti-androgen is invariably bicalutamide. These were the interventions that were studied and the conclusions that ultimately they came up to.

If you have gynecomastia, and for prophylaxis, this again was a summary by the Johnson meta-analysis paper. Tamoxifen is the most effective, as it works as a selective estrogen receptor modulator versus an aromatase inhibitor, anastrozole. My conclusion was tamoxifen is least costly. It's very accessible. You want to think about drug-drug interactions, compliance, of course, and some additional side effect concerns. If indeed you have breast enlargement, you've already started that kind of horse is out of the barn. You want to go with the removal of the breast tissue. Radiating a gynecomastic breast is a bad option. It doesn't do well; you get a lot more complications. And tamoxifen as a SERM does not reduce the gynecomastia. We hear that word, a mastectomy, but this is really a sub-areolar incision below the nipple. You can remove the elevated amounts of the gynecomastic breast tissue. This can be done on an outpatient basis if indeed the breast enlargement is particularly psychologically debilitating.

So the questions, and this is my final slide for this, are that for the majority of patients, and these were questions that were posed by the scientific committee at the APCCC. Do you recommend primary prophylaxis for gynecomastia? I said yes. And now, knowing the options with shared decision-making, I'm really pushing more of my patients now towards the prophylactic RT, which can be done in one or two sittings, as well as tamoxifen. Of course, cost always has to be factored in and reimbursement for patients. For patients who receive enzalutamide and develop relevant gynecomastia, what further investigations? This was one of the questions. I think nine times out of 10, just a good physical exam is all that's really needed. If you're worried about a malignancy, one can get a mammogram. I don't think there's any relevance to getting an MRI for these patients unless you're concerned that there's really a significant mass and there may be invasion.

For the majority of patients who receive enzalutamide and develop gynecomastia, what's your preferred treatment? Well, if it's about pain and tenderness, then tamoxifen. If it's about enlargement, then simple mastectomy as I described. And for mastodynia, nipple tenderness, and pain, tamoxifen. This was the last question that APCCC was asking. Is it appropriate to extrapolate the data generated with bicalutamide 150 on prophylaxis of gynecomastia to the AR antagonists, apalutamide, darolutamide, enzalutamide? I think the answer for the prophylaxis, absolutely yes. These are very powerful ARPIs; that's kind of the acronym we settled on at APCCC, which I think is great. But I think, of course, in a purist trialist way, prospective trials are always preferable. And of course, one needs to evaluate for DDIs.

Alicia Morgans: Thank you so much, Neal. That was, I think, so important from a treatment perspective when it comes to biochemical recurrence and those high-risk BCR patients. But also so important as we try to think about how we keep patients feeling well. And gynecomastia for some patients may not be an issue. For others, it is certainly something that they want to think through. Now, do you see these patients with high-risk BCR in your clinic? I certainly am starting to see them in mine. And are you enacting more of the combination therapy or more of the enzalutamide single agent when you do see patients?

Neal Shore: I really appreciate the question. For years I was doing nothing really. I was just, oh, I kind of asked how are you doing? Hot flush, sexual dysfunction, libido, fatigue, definitely paying attention to bone health issues, bone demineralization, and starting bone health agents. I was always thinking about the cardiological effects. I've been sort of fairly blissfully avoiding questions around breast enlargement. And after I saw how high the percentage was, when you give an ARPI with unopposed testosterone suppression, you get a marked increase in your estrogen estradiol levels. And that's what causes the gynecomastia, the breast enlargement, the nipple tenderness, and breast pain concerns. Realizing how high it was, and so unique to the monotherapy in the research I did in preparing for APCCC, it became glaringly clear to me that tamoxifen as a SERM is very inexpensive, very well tolerated, and short of any DDI concerns, is a very good strategy.

And then, of course, we're fortunate in the US, as we have access to radiation therapy and can just send the patients over to my radiation oncology colleagues for one or two days of just getting a 10-12 Gray to the breast tissue, as well as considering adding on the tamoxifen. That's what I've pretty much started doing now. And I really started aggressively doing this since the approval by the FDA on November 16, 2023. So my experience is now I'm looking at somewhere around eight to ten patients. But I think this is going to be really important for our patients who want to go on enzalutamide monotherapy. There are side effects, undoubtedly, but what we've also demonstrated with that compared to the combination with an LHRH, is you then don't have as much hot flush. You don't have as much fatigue. Clearly, you have a betterment, and most importantly, for those who want to maintain some level of sexual function.

Alicia Morgans: Absolutely. So you do have patients who are really keen to use the single agent. And how do you kind of go about that decision-making as we kind of wrap things up?

Neal Shore: Yeah, it's this wonderful shared decision-making. And I say, look, we're really proud that we were able to do this study, which has now changed the paradigm. We overuse that word paradigm. But monotherapy LHRH, whether continuous or intermittent for a high-risk BCR patient in EMBARK, we used a pretty stringent less than or equal to nine months. I think EAU defines a high-risk BCR as less than or equal to 12 months. I think for my patients, north of 12 months, I'm watching those patients. I'm not starting them. I am not intensifying. If I can go with an intensification regimen and I really do a very full-throated discussion of the differences in risk profile. Most patients are not going to really ask me about the hazard ratio. The hazard ratio was better, was lower in the combo versus the mono, but the trial frankly wasn't powered to make that analysis. It was really powered to look at the version against LHRH monotherapy alone.

Alicia Morgans: Great. Well, thank you so much for sharing your expertise, for talking through how we keep patients well while they're getting their treatment. I always, always appreciate talking to you.

Neal Shore: Oh, my pleasure, Alicia. Thanks very much.