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Christopher Sweeney: So we now have 10 minutes for questions, taking us to the 12:30 mark. Professor Smith.

Audience Member: My question is for Dr. Horvath. So monotherapy with enzalutamide and most other antiandrogens approximately doubles serum levels of both estrogen and testosterone. And unopposed estrogen receptor signaling results in harms like breast symptoms and probably contributes to the benefits of enzalutamide monotherapy, including bone protection and maintenance of sexual function and interest.

So you commented on the benefits of tamoxifen at reducing breast symptoms. Can you speculate or comment on the potential detriments of tamoxifen on the putative benefits of enzalutamide monotherapy?

Lisa Horvath: I would have to say no because none of that was looked at in any of these trials. There is— I mean, there is better bone health, I understand from my ancient memory of breast cancer treatment with tamoxifen rather than aromatase inhibitors.

But I do think that, as you've alluded to, with all of these side effects and the treatments for them, there's a seesaw of risk versus benefit, and that's going to need to be considered. And I don't think we can just simply say, well, this looked good when we gave high-dose bicalutamide, and therefore it will work and be effective and not impact these things in enzalutamide. I think it needs clinical trials.

Audience Member: I agree. Thank you.

Christopher Sweeney: Anders, a Danish perspective.

Audience Member: OK. Anders, urologist from Sweden. There are other studies on antagonist and agonist shown. I mean, the PROfound study, prospective randomized trial, patient optimized for cardiovascular risk factors, did not show any benefit for the antagonist. I would like to get more comments from you on what we really know about the antagonist and agonist today, because the meta-analysis did not really show an advantage for agonists.

Charles Ryan: Great question. So the issue is, if you optimize patients for cardiovascular health, is there really a difference between the antagonist and agonist? And I think it's a fair point. And I would also counter that there are analyses on typical patients coming into, I believe this was US clinics, where 96% had some cardiovascular risk factor when hypertension is included in that or hyperlipidemia.

So the cardiac risk factors are extremely prevalent. And I would say that for patients who have no CV risk factors, either an agonist or an antagonist is perfectly appropriate. The key is that we need to assess the patients and their risks as they walk in the door.

Audience Member: Thank you.

Moderator: Alicia.

Alicia Morgans: Yes. Thank you. Just a wonderful session. So thank you, everyone. And I wonder, as I'm considering the risks that were outlined first by Professor Suter—thank you for acknowledging and really reinforcing to us that we are actually taking patients, even if they don't have cardiovascular risk factors, and potentially causing those cardiovascular risk factors and actually exacerbating those who have cardiovascular risk factors.

And I wonder, in that context, as we think about Professor Blanchard's talk about this delayed recovery of testosterone, and some patients never do, should we be more aggressive in our studies of giving back testosterone, potentially in situations where we have no evidence of disease? And I appreciate that we may actually unmask microscopic disease that we're not aware of, but I don't think we would be causing prostate cancer, just to put that out there. And so I wonder if there is this risk-benefit ratio where we should be more aggressive with some of our studies, and just curious to your thoughts.

Christopher Sweeney: Who?

Alicia Morgans: You can all comment. No, just kidding.

Maybe we could start with Professor Blanchard, and then you can respond as a rebuttal or agreement, Dr. Ryan.

Pierre Blanchard: Well, I think it's an excellent question. And I don't know, honestly. I think in patients treated with short-course ADT, it's reasonable. For patients treated with longer-course ADT—so locally advanced disease—it's really a trade-off between risk and benefit.

And I really don't know. I think it would make sense in terms of reduction of the side effects of long-term ADT. But there's always this question about the increased risk of recurrence of microrecurrent disease. I don't know. I mean, I'm interested in the rest of the panel's opinion.

Charles Ryan: I would say, we have a lot of evidence now emerging from the group at Hopkins and others showing that you can administer testosterone even to people with CRPC. And so I think that the issue of whether we're inducing more aggressive prostate cancer to emerge is a little less of a concern than it perhaps was a decade ago.

And so as you point out, the quality of life and actually the cardiac and other morbidity benefits may exceed any risk of prostate cancer “recurring” or “surging.” And as it was mentioned in the last setting, when we talk about treatment interruption, usually when we restart treatment, it's sensitive to treatment, ADT. So I'm a proponent that it should be done. It would be great for us to have more studies and have more granular data around the impacts.

Alicia Morgans: Thank you.

Christopher Sweeney: Move on to the next question.

Audience Member: Just for testosterone replacement therapy, just a word of caution. Actually, this is all— the cardiovascular story started by showing that in elderly patients, if you inject testosterone, you have a high risk of cardiovascular event. It ended up in a warning by the FDA. So if you supplement patient, it has to be cream. You can't use these kinds.

My question is to Pierre. Pierre, one of the limitations of the study of testosterone recovery is that they mix one-month, three-month, six-month depot injection. And when you say that actually, there is a more rapid recovery with antagonist, this is true, with the caveat that it's only available in a one-month depot injection.

So do you think that if you go for six months—radiation oncologists, they like to say, OK, I give a shot of six months leuprolide, so I'm happy. But if your target is to get a rapid testosterone restoration, should we go back to Michele Bholat and recommend monthly depot?

Pierre Blanchard: Yes, that makes sense.

I mean, so I don't use six months. I use usually three months. But I think your point is well taken. Six-monthly injection is not a big deal. And if that can improve testosterone recovery, I think it's a fair point.

Christopher Sweeney: Two last questions. Anna.

Audience Member: So Dr. Ryan, just two questions. One is, do you think that the potential cardiovascular benefits of the antagonists might be negated when you use them in combination with some of the secondary hormone agents? That's one. And the second question is, if in the animal study that you showed, it seemed like the increase in FSH was really short-lived. So would a strategy of starting with an antagonist and then just moving on to the cheaper alternative work?

Charles Ryan: So that latter point is, I think, a really important one that I've actually done. When you want to have a faster castration, you want to get the disease under control, et cetera, it makes sense. We don't have, I don't think, long-term data on that switch. And if anybody does, I'd love to hear about it.

But the issue about the mitigation about whether or not the benefits of an antagonist may be mitigated by giving abiraterone, for example, is a good one. And I think that with some careful modeling, we might be able to look at that with some existing datasets, because we do have a lot of outcome data now on patients in those settings.

Another just quick point on that. I was really struck by the cardiovascular morbidity data in CRPC being much worse than in CSPC. And I think there's something that we need to tease out from that interaction as well.

Audience Member: Thank you.

Christopher Sweeney: Last question, Chuck.

Audience Member: So Dr. Ryan, just along those lines, I think that the agonist versus antagonist is still fairly controversial. There was a large database analysis from Clarivate that was recently published in the Journal of Neurology by Crawford, actually. And it really showed absolutely no difference. So saying that the pronounce was due to having good cardiologists managing the patients—I mean, this is a real-world evidence database. So honestly, if you look at it all together, the HERO feels more like an outlier than the other ones. I mean, I don't know what you think, but—

Charles Ryan: A fair point. I think it all gets to what's the background of the patients coming in? And I think that's how well are we addressing those issues and what are the populations that enter these trials?

Audience Member: Thank you.

Christopher Sweeney: Cardiologist, this last one.

Thomas Suter: Yeah. Well, let me say this. I think I really appreciate that you think about the heart. In the end, my philosophy is always that you treat the patient with the best evidence for what you want to treat. And we deal with the consequences, honestly.

Christopher Sweeney: Thank you. Thank you.

Thomas Suter: I think if you can do that, we're all happy, and our patients are happy.