Alicia Morgans:  Hi, this is Alicia Morgans, GU Medical Oncologist, and Associate Professor of Medicine at Northwestern University. I am so excited to have a conversation with Dr. Felix Feng, who is a Professor of Radiation, Oncology, Urology, and Medicine at UCSF, who is talking to us about the use of ADT in intermediate-risk prostate cancer. Here of course, with my co-moderator Dr. Michael Cookson, who is the Professor of Urology and the Chairman of The Department of Urology at the University of Oklahoma. So, Mike, I'm going to pass to you for the first question of Dr. Feng.

Michael Cookson:  Thank you very much. Excellent talk. And we are continuing our discussion on the contemporary treatment of strategies for androgen deprivation therapy and focusing this one on radiation. Felix, your talk brought up a lot of moving parts, if you will. And I think that the studies that are to come will help give guidance on a lot of this, but even within that unfavorable intermediate-risk, there us a lot of heterogeneity, right? And I would just like to ask you because I think some people would think that... I know when we do prostatectomies, for example, we often find a four, three turns out to really be a Gleason 8 or a 9. So what strategies do you have for patients who are really on the high end of that unfavorable intermediate-risk? And do you ever treat them with longer than six months' duration?

Felix Feng:  You know, Mike, that's an outstanding question. I rely in my own personal practice, on genomics potentially a little bit more than, well maybe widespread in terms of use, and I tend to be an earlier adopter of technology. And so in my practice, we get some kind of genomic classifier, usually decipher on the majority of our patients. And if I have a patient with a super high decipher score, what I will do is I will have a conversation with that patient about what that high genomic classifier score means in terms of the risk of metastatic disease and so forth. And as you know, we treat high-risk prostate cancer, traditionally with 18 to 24 months of androgen deprivation therapy when we give radiation.  We treat unfavorable, intermediate-risk disease with six months. It's likely that there is no magic threshold between six months versus 18 to 24 months. And just like there's a continuum of disease, there is probably going to be a continuum of the duration of androgen deprivation therapy that is needed. And so for patients with relatively more aggressive disease based on clinical parameters and genomic classifiers, sometimes I will actually increase the duration of androgen deprivation therapy up to a year.

Michael Cookson:  Yeah. Well, another thing that you made me think about, and certainly this is common practice in our active surveillance population. We use biomarkers, but we also use MRI and repeat biopsies. Are there any good studies looking at the role of really re-staging the patients with imaging and biopsy prior to the radiation treatment to really make sure, in addition to the genomic classifier, that we are really categorizing them correctly?

Felix Feng:  There are a number of good studies based on MRI, and MRI is obviously much better at detecting things like extracapsular extension and seminal vesicle co-invasion, which actually would upstage the patient by certain risk categorization strategies to a higher risk profile. And so sometimes an MRI can be used and if I see extracapsular extension or seminal vesicle co-invasion, I start treating those patients a little bit more like they are high risk versus intermediate risk.

Michael Cookson:  Yes. And sometimes the biopsies can be obtained differently and targeted in those settings too, which again, could change your strategy.

Felix Feng:  Absolutely.

Michael Cookson:  Shifting a little bit more to the androgen deprivation impact now. I'm wondering how many studies we will have to redo if we start using say, relugolix, an antagonist, and we know that it has a more rapid on and off switch, and all the old studies that you showed, had that lingering side effect and lingering androgen deprivation. What do you think is going to have to happen in the world of radiation oncology now that we have better dosing and hypofractionation coupled with these antagonists?

Felix Feng:  That's a very good question. And so I was talking with a number of colleagues recently about that exact issue in the sense that we do know these oral GnRH antagonists result in a shorter period of testosterone suppression than six months of a GnRH agonist. There have been studies looking at patients who receive six months of a GnRH agonist and on average, it takes them about seven months to recover their testosterone levels after the completion of androgen deprivation therapy.  So I routinely tell my patients that six months of lupron probably equals one year of having low testosterone levels and so forth. And at the same time, maybe that additional period of testosterone suppression is what leads to the efficacy that we see in these trials as well. And so when I pool my colleagues about, can we just shift in relugolix and these agents that result in faster testosterone recovery, if they become FDA approved and so forth. It is a mixed bag of answers.

And so some of my colleagues say, "Yes. ADT is ADT." And others of my colleagues say, "Well, no, because those trials were done with presumably a longer duration of actual testosterone suppression," and so forth. And so I think it would be nice to see some studies looking at the efficacy of these agents, but at the same time, as you and I both know the moment we start a randomized phase three study, that is 2000 patients and 10 years later. And so I think we would probably be trying to look for some surrogate endpoints based on PSA metrics and so forth.

Michael Cookson:  Yeah. Well, I love your example of the personalized approach to it. And I think that is a common theme throughout the whole spectrum of care.  So I applaud you for that. Alicia, do you want to weigh in on this?

Alicia Morgans:  Sure. I do think, and I look forward to us sorting through what effective testosterone suppression versus actual duration of medication administration ultimately does to these radiation trials, and I think that it is definitely something that we are eager to sort out, and hopefully, we can use surrogate endpoints, because as you said, that is going to take a while. But one thing that I know patients are really excited about is the opportunity to have their testosterone recover. I'm just curious, in the radiation population, particularly the intermediate risk, where we are thinking about a shorter duration of systemic therapy in combination, is this something that you find is important to your patients? And it was interesting, the quality of life data, do you find that data to ring true, that it does take the patients a while to recover when they don't have that fast off switch?

Felix Feng:  Absolutely. I do. And oftentimes it depends on the characteristics of the patient, such as age, right? And so my older patients, boy, it takes them long sometimes to recover their testosterone, sometimes much longer than an additional seven months after the completion of six months of androgen deprivation therapy. But sometimes, I'll have a 40-year-old patient who literally will have normal testosterone back within three months of completion of his course of androgen deprivation therapy. And it's not just an age-based thing, sometimes it is actually harder to predict in these patients. And so I think that is one of the areas of uncertainty. When I have a patient come to me for treatment and I say, "Hey, I would recommend short-course androgen deprivation therapy." I counsel them and I warn them that the effects are going to last beyond the duration of the therapy itself.

When they say, "Well, what's the average?" I explain that to them as well. When they say, "How do I know whether I'm going to be above average or below average in terms of when my testosterone comes back?" I tell them, "We can take a guess based on age and so forth, but that in truth, there is no crystal ball here." And some patients where I thought that it was going to take them a lot longer to recover their testosterone, it doesn't take them long at all. And some patients where I think, "Oh, they should come back very quickly," it takes them longer than what we expect. And so I think that patients have to realize that there is a bit of uncertainty there and they have to be okay with that to proceed with that therapeutic strategy.

Alicia Morgans:  Yeah. I can imagine that if there is a little more predictability in something that turns off more quickly, like a GnRH antagonist, that might be helpful for a patient's peace of mind and certainly, we can see. The other thing I think helps my patients' peace of mind is trying to reduce the risk of complications, things like cardiovascular disease, which we didn't really talk about in this particular talk. But those risks apply certainly to men who are receiving radiation therapy as well. When I think about prostate cancer, all-comers populations, it's a fair number and who are going to at least have risk factors. Does this strike you as something that is going to be important for the radiation population in addition to the more advanced disease populations where we think it will have a significant meaning?

Felix Feng:  Absolutely. It does. And so Anthony D'Amico and others have shown that for patients who have had a recent heart attack, or who are in congestive heart failure, or have poor ejection fractions and so forth, that those patients actually do not benefit from the six months of androgen deprivation therapy, that they actually do worse probably because of the cardiovascular factors and the other cause mortality. And so when I see a patient, I also take a look at their cardiac history and if they have a pretty significant cardiac history, I will at least have a discussion with them about the potential for cardiac events with androgen deprivation therapy. Again, the majority of studies looking at cardiovascular events with androgen deprivation therapy have been in the context of years of androgen deprivation therapy, so for six months, I don't think it is as big of a deal in patients without major cardiac risk factors.  But in patients with these cardiac risk factors, we at least need to counsel them.

Michael Cookson: Well, Dr. Feng, we've really appreciated your insight into the management, especially of these intermediate-risk patients and the unfavorable versus the favorable, your personalized approach, and the role of ADT, and the management of them. So thank you very much for your expertise and your time on this.

Felix Feng:  And thank you for inviting me to present and to talk with you today.

Alicia Morgans:  Thank you.