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Anthony Joshua: I'm here to tell you about hot flushes. They were first documented in 1896, in the medical literature. And because we're in Switzerland, I'm the only presenter who has got two title slides. I'm being neutral about whether they're a hot flush or a hot flash. So I'm going to have two title slides, and I'll leave it to the audience. And in fact, probably we should vote on this as to whether we call them hot flushes or hot flashes. And I look forward to the answers to that question.

Nevertheless, here are my disclosures, and none of which are relevant. This is what we're going to be talking about—the pathophysiology, which is fascinating, the prevalence and impact of hot flushes in men with prostate cancer, the evidence of treatment to date, challenges, and conclusions. So what's the pathophysiology?

The pathophysiology is illustrated here. When you castrate a man with an LHRH agonist or orchidectomy, you suppress the testosterone. You also suppress the endogenous estradiol. So interestingly, men have more circulating estradiol than are postmenopausal women, but it's the lack of endogenous estradiol that causes the hot flushes. And why?

So this is new since I was in medical school. They identified a neuron called a candy or candy or KNDy neuron, which stands for Kisspeptin, Neurokinin B, and Dynorphin. So these neurons are tonically apposed between estrogen and neurokinin 3 receptor to lead to their activity. So you can imagine the absence of estrogen or in the presence of tamoxifen, the estrogen is going to be depleted. They're going to get a tonic positive signal from the neurokinin 3 receptor, which leads them to then project to the median preoptic nucleus to these thermal neurons, which then cause vasomotor symptoms and lead to an increased activation of heat dissipation mechanisms, contributing to the experience of hot flashes and night sweats.

So this is important pathophysiology that is fascinating because, in one study, they gave men high-dose testosterone with an aromatase inhibitor, and they were unable to prevent the hot flashes even with high-dose testosterone. So you actually need the estrogen. Now, what happens to men with prostate cancer?

So the incidence of hot flashes generally is thought to be between 44% to 80% of men undergoing ADT. They tend to peak at four months after initiation with LHRH agonist. Sometimes quicker after orchidectomy. There are actually no useful predictors for men that are going to get hot flashes. It is said that sometimes younger men with a lower BMI may have more severe hot flashes.

After 12 months of ADT and cessation thereafter, the median time to the cessation of the hot flashes is 7.6 months, with a testosterone of median 5.7. And after five to eight years of therapy, 70% of men have hot flashes at five years—this is continuous ADT—reducing to 40% at eight years. So the hot flashes don't really go away. And your body doesn't necessarily get used to the lack of estrogen.

So what is the impact? So this is an important topic in my clinic. The literature tells me that 30% of men report hot flashes as the most troublesome effect of therapy. They're associated with sleep disturbance, diminished cognition, and a lower quality of life. And up to 55% of patients report distress and 11% severe distress just from the hot flashes. And as we all know in this room, it can lead to treatment discontinuation and abbreviation.

So what are people doing? So this is a practice survey of 64 UK uro-oncologists. And you can see here the interventions that were used. And then you can see, in black, the satisfaction with those interventions. So lifestyle change, cyproterone acetate, acupuncture. And you read down the list. So none of which are particularly effective, but we'll go through them.

So in terms of non-evidence-based lifestyle interventions, they're listed here. And they're often found in guidelines because they're cheap and easy. And obviously things—don't eat spicy food, don't have hot coffee, have a fan when you're in bed, take a cold shower, wear layered clothing, don't smoke, exercise either aerobically or anaerobically, and don't drink alcohol. So they're in guidelines. They're cheap and easy to do. They're good for general health, but they're not necessarily evidence-based.

However, in terms of alternative lifestyle recommendations, which are not pharmaceutical, there's a few interesting ones. So firstly, cognitive behavioral therapy. So there is increasing evidence this does have a short-term effect. And there was a study called the MANCAN2 study out of the UK, demonstrating a 40% reduction in the problem rating of hot flashes. And at ASCO this year, we'll hear about MANCAN2, which is a guided self-help cognitive behavioral therapy intervention versus treatment as usual in men. It's a 200-man randomized study—that's going to be quite exciting.

There are acupuncture studies showing that there is potentially quite effective 40% reduction, which can, in fact, be sustainable. And there is this new thing called an Embr Wave heat pump watch. In a small study of women who had a crossover intervention, it did, in fact, influence hot flashes, in particular, and they're troublesome when they're asleep. Now, in terms of pharmaceutical interventions, I've broken this up into various categories.

The first one is castrating oestrogenic treatments. So this is subject to the ongoing STAMPEDE arm that I understand we'll hear about sometime in the near future, where men get high-dose transdermal estrogen. So the hot flashes are certainly reduced compared to LHRH, in the data that's been presented to date—86% versus 35% with grade 3 hot flashes, 0% versus 3% in what could only be described as a statistical quirk in the fabric of space-time. The rates of gynecomastia are exactly the same, but in the opposite direction.

So 86% of men get gynecomastia with high-dose castrating estrogen versus 38% with LHRH and similar data. So that's going to be an interesting story to follow as to whether high-dose estrogen becomes a standard of care. What about non-castrating estrogenic treatments?

So there are three studies that have looked at this. And the data is reasonably promising. Estradiol gel so useful for men that don't want to take more pills for six months. Reduces hot flashes by about 1.6 to 2 per day. Didn't really have an effect on the weekly hot flash score, but certainly some effect associated with gynecomastia, associated with nipple tenderness, as you can see there—double the rates.

Estetrol, which is a fetal estrogen, also reduced the rates of hot flashes. You can see there, 60% versus 14. Again, gynecomastia and nipple tenderness—fairly prominent. And another study demonstrating that only one month of topical estrogen also has a reasonably good effect. So what about hormonal non-estrogenic treatments?

So there was a study by Irani et al., that some of you may be aware of. Medroxyprogesterone, cyproterone acetate, and venlafaxine—they all worked. But certainly, the cyproterone and the medroxyprogesterone, as you can see there in red, worked better than the venlafaxine. And so the conclusion of this paper was that either of those should be preferred. The venlafaxine doesn't work as well.

Other studies have suggested the venlafaxine dose—it may be effective in the short term, and it may also be dose-dependent. May be a problem with polypharmacy, men getting serotonin syndrome. There are studies about the utility of gabapentin, but relatively high doses are the only ones which are effective, up to 900 milligrams a day.

And there is a case report in The New England Journal of a single man getting oxybutynin, which is probably the lowest bar of a paper in The New England Journal that I've ever seen, demonstrating that that did work for hot flashes. But we have the randomized study being presented at ASCO this year of men being randomized to oxybutynin placebo, which is an alliance study, which will be fascinating to hear the results of. So we'll get some hard data about that.

Now, one of the new options is this drug called fezolinetant. So this is a neurokinin 3 receptor antagonist approved in the US and approved in Australia. I understand in Europe. Obviously, never been tested in actually anyone with cancer. So here are the pivotal studies of fezolinetant in postmenopausal women.

You can see there's a cascade of studies all ending in the word "LIGHT," some of which in Anglo-Saxon women, some of which in the Asian populations. And so it's now approved fairly broadly. It's fairly cheap compared to the cancer drugs we deal with. All of the studies had roughly this trial design where randomized versus placebo at various doses. The approved dose is 45 milligrams.

And if you take the meta-analysis—I won't bore you with the details—it does reduce hot flash severity, it does reduce hot flash frequency, and it does increase quality of life in postmenopausal scales of quality of life. So it does seem like theoretically a very good intervention that may be applicable, but we have no studies, let alone women with breast cancer, certainly none with men with prostate cancer. And we're certainly trying to address that.

So the challenge is, obviously, the side effects. I won't need to read through all of these side effects for you. Fezolinetant has fairly rare side effects—hepatotoxicities and headache, GI symptoms. Oxybutynin—the side effects, at least in my practice, are not that bad. I don't use the high doses that can cause those anticholinergic side effects, and you're well aware of the side effects of some of the other drugs.

So briefly, the trial designs in hot flashes are problematic. The scales we use both for the hot flashes and the quantification of the effect of quality of life are imprecise. There is a very large placebo effect, and it's hard to fund off-label treatments.

But the conclusions I think that we can draw here is that the current management of hot flashes is, in fact, suboptimal. It's definitely an area of need. There's no single solution. You may have to rotate through interventions and use them in combination. Side effects do need vigilance. Looking forward to upcoming data about what we can do about this, and we certainly need further comparison and combination studies. Thank you very much for your time.