Read the Full Video Transcript

Neal Shore: Pleasure to give this presentation. So here are some of the questions. I abbreviated the bottom four bullets. But for the majority of patients receiving enza- or bicalutamide, do you recommend a primary prophylaxis for gynecomastia? Likewise, going forward—and if you develop gynecomastia, what further recommendations? What's your preferred treatment for bothersome symptoms? Majority of patients—what about mastodynia, nipple pain, nipple tenderness? And is it appropriate to extrapolate to other ARPIs? I sort of took this and wanted to think about really focusing on a lot of the breast-related issues, but I'll touch on others as well.

So what's the clinical relevance for ARPI monotherapy? I'm going to present three trials that I've been in—well, two of the three that I've been involved with. And so, are patients who are undergoing ARPI without T suppression predisposed to any unique adverse events? What are the strategies to mitigate this? Because things have changed in the last two years, right? So we now have an upgrade in the enzalutamide guidelines and the product information from FDA as of November 2023 for the use of either enza mono or enza in combo based upon the EMBARK study. And I'll show you that in a second. And what are some of the things you think about to mitigate these strategies? You see them listed here. And then, ultimately, what am I doing?

So here are the high-risk features. But, of course, EMBARK, these are folks going on—they're embarking on a journey. And so for the residents and fellows and early investigators, this was almost a nine-year study to accomplish. But it's why we do clinical trials, so we can change clinical practice. And here was the definition of the M0, or what we call nonmetastatic HSPC.

Here was the trial design. Now, it's really interesting to know the journey of this in that we had the top line readout—it took eight-plus years from first patient until we got the top line readout in March, did an AUA plenary presentation in April 28 of last year. And then we had two New England papers—one in Evidence, one in regular New England.

In October, we presented more PRO and sexual dysfunction at ESMO. And then, in November, FDA expanded the product information label, so really a testimony to a lot of hard work and sponsor support.

So what you can see here, just going back quickly to this is—whoop, this is all going back on me here. There we go. Sorry. The trial, just very quickly, three-arm—I'm not going to go into details. What was particularly unique about it was a holiday or an interruption if your PSA at 36 weeks, you got to below 0.2. And that was a treatment holiday, something unique about that particular study.

Open-label enzalutamide—here's the KM that was presented for the combination arm, besting monotherapy LHRH, a hazard ratio of 0.42. And then, very provocatively, the enza mono beats LHRH alone with placebo, with a hazard ratio of 0.63. Additional PSA progression data, time to first antineoplastic, all in favor of enza monotherapy—so relatively, one could say, to use a hackneyed expression, truly game-changing.

So what about gynecomastia? Gynecomastia occurs essentially—here's the definition, but there's this imbalance between estrogen activity and a decrease in androgen activity. You can see the list of multiple other differentials as to why you could develop gynecomastia—not good news for those who like their alcohol and marijuana, but nonetheless, this is the list.

So what I did is I looked at three trials. Now, we have 536 patients who have had monotherapy enzalutamide. Bertrand Tombal led this All Comers population, 67 patients. The ENACT was a phase II study looking at an enriched population of active surveillance. That was another 114 patients. And the 355 from EMBARK, that gives us the 536 patients to really different endpoints and outcomes. I'm not going to focus on that.

But ultimately, what about the safety profile? Well, it's pretty comparable across the board—nothing really new. But one thing that really pops out is that in all three of these trials, there was no prophylactic strategy for treatment for gynecomastia, nipple pain, breast tenderness, whatsoever. And I think that's really important to recognize. So that's where we are moving towards now.

Common TEAEs—really nothing new, but, again, really focusing on the breast enlargement, nipple pain, breast tenderness. One sees that this is clearly an issue. So if you put a summary together from the Tombal—and they published three papers on this—ENACT paper, the EMBARK paper, one sees the differences, and they're fairly comparable. But this is now a real issue if you're going to entertain enzalutamide monotherapy or perhaps any other ARPI. Our colleagues in Europe and Nordic countries have had very good experience with 150-milligram bicalutamide, not approved in North America.

Let me just quickly go through a series of papers that have looked at this. They're relatively small studies, but they're prospective. Some of them are double-blinded, some of them are not. Ultimately, at the end of the day, prophylaxis here with androgen-related—for radiation, I'll first start with that. Then I'll go to the endocrine. There's a benefit, but the benefit is only there if you do that at the very beginning.

And so ultimately, Tyrel, Ozen, if you do prophylactic versus not, one sees the decline in gynecomastia—both studies highly statistically significant, whether it was 10 gray or 12 gray, and generally well tolerated. Now we look at endocrine studies, and there was a debate between aromatase inhibitors versus selective estrogen receptor modulators, that being tamoxifen and anastrozole, respectively.

Busy slide, but at the end of the day, the Saltzstein, the Boccardo, the Fradet paper is essentially demonstrating to you that prophylaxis with tamoxifen beats anastrozole and certainly beats placebo. Similarly, this is for gynecomastia and breast pain with Bedognetti and Serretta. It's really interesting that they looked at specifically here daily versus weekly, and then also switching over. And still, at the end of the day, the summary of all these trials is that tamoxifen is superior to anastrozole.

Now, interestingly, probably most oncologists who are treating this don't have any experience with this. And I think this is a gap that needs to be met. Tamoxifen is clearly superior to anastrozole and then also confirmed by these other studies. Now, what about combining prophylactic radiation and tamoxifen? Di Lorenzo, the Perdona study, are all very consistent with, again, a combination that this is the most effective strategy.

But one of the things that's never really been answered and looked at, even though the overall tolerability and side effect profiles are good, what is the accessibility, and what will be the cost? Here's a summary, a very nice meta-analysis by Johnson and others. It summarizes most of these papers if you want to get to that at your leisure.

But at the end of the day, tamoxifen was the most effective combination radiation over 1 to 2 to 3 days, with tamoxifen also particularly helpful—the radiation only beneficial if done initially and not later on. So tamoxifen is probably the least costly, most accessible—of course, drug-drug interactions, compliance, and other side effect issues.

If there is gynecomastia—and I think you're going to hear more about this later from Dr. Horvath—but this particular study is essentially that if the gynecomastia is there, starting radiation afterwards is essentially fraught with some complications. Surgery is clearly more invasive, but it can be performed on an outpatient basis, a subareolar incision and removal of the breast tissue. And it really is the gold standard for symptomatic gynecomastia once it has developed.

Now, of course, the systemic issues regarding enza monotherapy—haven't had time to go into importance of exercise and nutrition. We're going to hear more about this in other talks. So ultimately, my conclusions are for these questions. And I think we'll have probably some debate as to who I would recommend to give monotherapy ENZA 2 versus the combination.

There are different side effect profiles. That's important to recognize—more hot flush with ADT, possibly more sarcopenic obesity. And so that's going to be an issue to discuss—improved sexual function, which we published in Evidence earlier, and more data forthcoming.

Here are my conclusions. Do you recommend primary prophylaxis for gyne—yes. Knowing the options, it's all about shared decision-making. That was brought up by our patient advocate earlier—extremely important.

What further investigations? For me, it's been almost overwhelmingly just a good physical exam. I consider mammogram, haven't really used much of MR. Long-term potential for benign—or malignancies has to be considered.

Bothersome mastodynia, nipple tenderness, nipple pain—tamoxifen, enlargement, simple mastectomy. And then, ultimately, can we interpolate other drugs, the other ARPIs? The mechanisms of action are relatively comparable. I would say yes. Ideally, I'd like to see prospective studies. Thank you very much.