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Sam Chang: Hi, my name is Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee, and we are quite honored to have an international speaker today, Professor Ursula Vogl, who is the head of the Prostate Center, as well as the head of [inaudible 00:00:19] at the Oncology Institute of Southern Switzerland. She is here to discuss actually ESMO highlights focusing on prostate cancer. She is the one who actually gave the highlight session during the ESMO meeting, and she's been kind enough to spend some time with us. So thanks so much in advance, and Dr. Vogl, we're looking forward to your presentation.

Ursula Vogl: Thanks, Sam. Thanks for having me today. And I am honored to briefly summarize my presentation that I gave at ESMO, which is a great privilege. And then we will have time to, yeah, go through the highlights and talk through it.

So I started actually my highlights session on the Tuesday, the last day of ESMO, and I was worried that there were not enough people, but in the end, the room was full. And I think also online people were very much interested in prostate cancer at this year's ESMO. And we had a lot of highlights. This is my outline that I presented. So I went through from stage to stage. So I chose one highlight in high-risk locally advanced disease, one in mHSPC, and one in mCRPC. And I tried also to select mostly academic trials because I think this should be also the focus in highlights at the ESMO meeting.

So I start with one study, which was actually a combined study from one STAMPEDE arm and the trial PATCH. It was a phase III trial looking into transdermal oestradiol versus classical LHRH analogs in non-metastatic prostate cancer. And just to give you some background, I mean transdermal oestradiol is known; it's in use especially in postmenopausal females that are symptomatic. But going through the rationale for using it instead of an LHRH analog is actually because we know that the transdermal oestradiol maintains actually the oestradiol in the system but suppresses also the testosterone, which is the goal of treatment for prostate cancer, and has less, let's say, adverse events that are actually not a part of the goal of treating the cancer. So it's known that suppression of endogenous oestradiol, which is spared by the transdermal, actually leads to more osteoporosis, increased fracture rates, lipid changes, all the metabolic things that we would like to avoid, but also memory loss. And it's mostly responsible also for hot flashes, which is mostly annoying for our patients with prostate cancer when we talk about testosterone suppression.

And the group that actually presented, Professor Langley at ESMO, the trial has already published studies on transdermal oestradiol, and they showed that it's equivalent for castration rates to LHRH analogs without the excess cardiovascular morbidity or mortality, which is reported with the oral estrogens. And there's also potential benefit on improved bone mineral density, more favorable metabolic profiles. But not to forget that, of course, there's an increased likelihood of gynecomastia, which is something to be seen in the future in clinics, how to deal with it. So this is a little bit the story of the PATCH trial, and you see that the idea was raised already in 2006, going from a Stage 1, Stage 2, into a Phase II, Phase III trial. And actually they reported data from the M0 patients from STAMPEDE.

STAMPEDE is a big platform, huge, that enrolls patients in parallel, adapted to standard of cares. And so that it was actually useful to open the trial also for STAMPEDE patients, and that were then added to the patients that have already enrolled in the PATCH study. You see an impressive number for an academic trial. They presented over 1,000 patients at this year's ESMO meeting from 75 UK sites, the M0 population that were randomized into standard treatment with an LHRH analog or the transdermal oestradiol. Just to know practically how it works, the patients had to actually change twice weekly four patches, and when testosterone was suppressed, actually three patches were changed twice weekly, just to know how it's done in practice. Primary endpoint was MFS, so metastasis-free survival, in a non-inferiority design. And as you can see in the curves, it's clear that the endpoint was reached.

So the three-year MFS was 87% in the LHRH analog arm and in the transdermal oestradiol arm almost the same. So non-inferiority has been proven in terms of MFS, and it was also not inferior in terms of OS. Castration rates were similar. Hot flashes of any grade were less; you see almost half than with standard treatment. But as I mentioned earlier, we have to deal with about 43% more gynecomastia when we use the transdermal oestradiol approach. And I think to put it into context, what we used so far for testosterone suppression, going over surgical castration in the 1940s, then we had the agonists, the antagonists, and now also an oral antagonist, relugolix, that is approved since about two years now.

Professor Langley actually summarized her presentation that transdermal oestradiol patches should be a standard of care additional option in M0 disease. But I discussed some open questions as I already mentioned, let's say the M1 cohort has not yet reported. So it would be also a question for patients with metastatic disease hormone-sensitive to be useful, gynecomastia compliance of adding a lot of patches twice weekly. Then also has it a benefit of testosterone recovery? So I discussed it with Professor Langley afterwards, and she said they have the data, but it's not yet reported. So we will have the results maybe in future meetings. And also on the metabolic and bone health issues and cognitive impairment. It will be nice to see in the future what the transdermal oestradiol patches can add actually.

So then going to the next stage of disease, which is metastatic hormone-sensitive prostate cancer, I think everybody was waiting for the ARANOTE trial, which is a phase III trial, adding on information on another AR pathway inhibitor, another ARPI darolutamide in the doublet. As you know, in the last years, we were more intensifying also to triplet therapies, adding on docetaxel and an ARPI to ADT. And this was actually one of the last ARPIs that we know that data were missing in the doublet combination.

So the primary endpoint was rPFS compared to other trials done in that setting, phase III. Almost all had OS, or at least as co-primary endpoint, despite the ARCHES trial. And there was a lot of discussion about the study because you know, ADT monotherapy was no more standard of care since a long time when they started enrolling in 2021. Actually, they opened the trials in countries where actually maybe the ARPI was not accessible, mostly also in Asian countries, in South America and Russia, the trial was done. But there was some criticism about that. But I think it has been done ethically in those zones where it was not standard of care. And I have to say worldwide, there are still countries where the doublet is not a standard of care because of problems with reimbursement or accessibility.

So I think the ARANOTE trial actually represented also from the characteristics what we see in the other doublet trials of phase III. We had high-volume patients, low-volume patients, de novo and recurrent patients included, and the rPFS primary endpoint has been reached with a hazard ratio of 0.5. What we will wait for is still overall survival, which is immature. You see here a trend from the forest plot being effective, let's say, in all subgroups mentioned, even better hazard ratios in low volume. But this is only a subgroup analysis. And as you can see, the hazard ratio looks good already for OS, but it's still immature. And look at the median treatment duration and follow-up; it's quite short, so we have to wait for further follow-ups, also not yet approved darolutamide in this setting. But which was very impressive was that we know that darolutamide is one of the best-tolerated ARPIs.

So you see any treatment-related adverse events were almost similar to the placebo plus ADT, and especially... actually no drug discontinuation or less drug discontinuation with darolutamide, which I would like to highlight not to underestimate. Also, for whatever combination that we use in metastatic hormone-sensitive prostate cancer, that bone fractures were higher when adding on darolutamide or even any ARPI. So we should look for bone health in our patients already in mHSPC. And we published this already in a review, a meta-analysis that actually darolutamide has an excellent side effect profile, but bone fractures were also higher. So Fred Saad actually was discussing this as a new standard of care for mHSPC, darolutamide and ADT. And of course, the last points here with OS immature and regulatory approvals, they have to be awaited.

So another trial that I've chosen was the STAMPEDE RMK, presented by Professor Gillessen in the oral session. And that metformin, a long story of phase II and III trials, a lot of them were negative or some were contradictory of the antitumoral effect of metformin when used in prostate cancer. And the STAMPEDE platform also questioned the benefit of metformin to standard of care in one of their arms against standard of care. So also a big really recruitment, compliments to the investigators, 1,874 patients randomized, primary endpoint overall survival. So really ambitious also to show a benefit of the experimental drug metformin added to standard of care for overall survival benefit. And you see that this is actually the standard of care in these times of enrollment was mostly ADT plus docetaxel. So only 3% of patients had an ARPI in that sense or being one of the other STAMPEDE arms. And actually the overall survival as primary endpoint was not reached by the hazard ratio.

But if you look at the pre-specified, but not pre-powered subgroups, and this was also Professor Gillessen was underlining not pre-powered. You see a trend of a benefit in the high-volume patients, but this is only something, let's say, hypothesis-generating that merits maybe another future investigation. But what we know, and I'm very much into research also with physical activity and metabolic adverse events from hormonal treatments, you see that there's a big change from baseline over months 6, 12, and 24 on metabolic parameters. So patients had less weight gain, cholesterol, glucose, and also all those factors were improved when adding metformin. It was very well tolerated. We know metformin has GI toxicity, but in the end, I think this study shows that metformin unfortunately did not see the benefit on OS, but there is a trend and future investigation merits for the high-volume disease. Metabolic parameters were significantly improved.

Going into the last chapter, mCRPC, the PEACE-3 trial was in the presidential session, so of course I had to choose it for my highlights. And you see in mCRPC developments are ongoing. And the two drugs that were actually investigated in the EORTC-1333 trial were already in use and approved in mCRPC. So they combined here the two standards, Radium-223 plus enzalutamide versus enzalutamide in this phase III trial.

Also, lots of patients enrolled, and as you can imagine, bone-dominant disease, but also lymph nodes were allowed but no visceral metastasis. And the primary endpoint was rPFS. We already heard results from this study because actually it was Dr. Gillessen at ASCO '21 presented data from actually the mandatory add-on of bone-protecting agents in patients from the amendment onwards because they'd seen, and this was already reported in combination with abiraterone with radium, that the bone fracture rates were higher when actually abi and radium was used. And they made it mandatory, and you see there was a big difference in reduction of bone fractures when bone-protecting agents were made obligatory in this trial. And actually it's a standard of care, and every patient with bone metastasis mCRPC should receive bone-protecting agents, denosumab or zoledronic acid.

So you see patients were mostly also one-third were pre-treated with docetaxel in mHSPC, and the tolerance, and let's say the compliance was good because radium was administered for the maximum of six cycles in almost 90% of patients. The primary endpoint was reached with an rPFS benefit with a significant hazard ratio. So excellent data, the overall survival at interim analysis is favoring the combination, but actually the statistical boundary was not yet reached because there needs a longer follow-up because of the crossing of the curves in the beginning. Very well tolerated, the combination, of course you see more side effects from anemia and also neutropenia when adding on the radium, but actually the treatment discontinuation due to toxicity was very low in both arms.

So Professor Gillessen actually postulated of course this as a new potential standard of care in first-line mCRPC patients with predominant bone metastasis. And also Professor Fizazi as a discussant actually underlined this. Of course, we have to see long-term OS and also seeing what actually the add-on of the bone-protecting agent added also on side effects of osteonecrosis. And of course, nowadays, when we use mostly ARPIs in mHSPC, the question is on what patient in mCRPC these new data are actually applicable. But last but not least, radioligand therapy lutetium very en vogue. The SPLASH phase III trial presented by Professor Sartor was also a topic at the ESMO meeting.

So we know that Lutetium-PSMA, and especially 617, has an important role. So the drug has been approved by FDA, EMA, in patients mCRPC pre-treated with ARPI and the taxane. So this is basis from the VISION trial. And we also have data from the phase II TheraP trial. So it's one of the standard of cares already. We've seen data in the taxane-naive patients post-ARPI from PSMAfore, which was actually timely, published also the full paper during this year's ESMO meeting.

And here the primary endpoint was reached rPFS, and OS are still immature. And the SPLASH trial, which you see has a similar concept of patient enrollment and also characteristics, uses a second radioligand for lutetium PSMA, which is not the 617, which is approved, the Pluvicto from Novartis, but the PNT2002, which is better known as lutetium PSMA-I&T. And you see SPLASH and PSMAfore have different characteristics, especially concerning the sequence.

So the distance of the cycles, eight weeks, six weeks, and also the radiation dose is different and also the number of total cycles. So they chose in SPLASH and PSMAfore not only a different radioligand, which is, when you ask nuclear medicine physicians, actually a similar drug, but you see that the radiation dose and the cycles are different. And Professor Sartor presented this trial, and you see that actually the study has reached its primary endpoint with rPFS. And remember that the control arm was a second ARPI, which continues to be of course a lot criticized because in standard practice we should not use two ARPIs in a sequence because it has not very high success rates in terms of oncological outcome. And you see that a lot of patients crossed over, also similar to the PSMAfore trial. The OS of course is immature but will be difficult also to be reached positive because we have that high rates of crossover.

It's very well tolerated. Also, as known from the 617, we mostly see dry mouth and fatigue, but the rest is really almost negligible or even better than the alternative ARPI. So the conclusion of SPLASH was of course that we are confronted with a positive trial. Lutetium I&T reduced the risk of rPFS or death by 29% versus the second ARPI. OS is immature, and it has a good profile. So a nuclear physician colleague of mine from Switzerland, Irene Burger, discussed the SPLASH trial. And of course there's a lot of open questions, especially about optimal dosing and timing of lutetium PSMA therapies since we have two different products actually available. Thank you very much for the attention.

Sam Chang: Dr. Vogl, what a tremendous summary of some of the key highlights focused on prostate cancer. I'm going to take each disease process and don't want to put you in a difficult situation, but going to ask you hypothetical questions. So let's take the locally advanced patient now that has the options of what we've done for centuries, LHRH analog therapy, what we've done more recently with the antagonists, both injection as well as oral, and now we possibly not yet, but have transdermal oestradiol as an option. If you have a new patient, say all these medications are available, at this point, what would you end up giving this patient who has locally advanced disease?

Ursula Vogl: Well, I think we have to be very honest that we have those excellent data, but it's still not something that is standard of care. It's not in the guidelines yet. It's not approved, let's say, and it's a small cohort. We're talking really about the locally advanced M0 patients. But I think it's something where we talk about side effects in our first meeting with the patients, and the patients are really concerned about hot flashes especially. We can actually say that this is something we know that significantly reduced when applying the patches.

But then of course you have to mention it's quite, let's say you have to think about changing the patches, but Professor Langley said the compliance in the trial was excellent, so of course you monitor the testosterone, so they had the proof that they actually applied it correctly. And then we have to approach the topic of the negative effect of the gynecomastia. And now already in prostate cancer, going from data from EMBARK where we use enzalutamide maybe already in some exceptional cases without testosterone suppression, we have to focus more on those older topics, let's say how to deal with gynecomastia, maybe breast irradiation, all this comes up.

Sam Chang: Yeah, no, really good points. And I think that at least within the US, the cardiac concerns also are obviously real. You mentioned the possible impact on bone health, but yet not known regarding if it translates to actual fracture risk. All those things I think are really important. The morbidity of just a few doses of radiation to prevent the gynecomastia is something that's been not done infrequently in the US, and so many trade-offs you can honestly see. And then cost will come into play as well, honestly. I think really, really good points.

Let's switch to metastatic HSPC. To me, in listening to the different presentations, to me determining the differences in terms of which ARPI should be used in combination. There's no direct comparison. So there'll be a lot of different issues that come into play. Metformin, if I'm a patient with metastatic hormone-sensitive disease, I've not been on metformin, I'm not heavy, I don't have any pre-diabetes or whatever. Based upon this data, would you start that individual on metformin?

Ursula Vogl: Well, I mean we of course direct a little bit on that subgroup analysis of the high-volume patients. And I just lately had a patient that really was concerned about the weight gain that you might undergo in the future. And we see it every day. So patients in the median, they gain four to five kilos in the course of disease. And I think it's a drug that is really well tolerated, and I think it doesn't do any harm. I think patients should be informed that we have those results. And it costs also not a lot. So I think in patients that are well-informed and sometimes questions come from them, what can I do to prevent weight gain? Besides, of course, the usual physical activity and diet consultations. I think in a very interested patient on that topic, I would consider giving metformin in addition to the standard of care treatment.

Sam Chang: Agree with you absolutely, regardless of overall survival benefit, etc. It's interesting. Large epidemiological studies have been done regarding incidence diagnosis, high-risk cancer, yes, no, in terms of metformin. And you're right, there's mixed data regarding is it beneficial, is it not? But the downside of metformin for most individuals, there's so little. I think it may become... I mean, there are individuals in the US who already are giving it prophylactically for other reasons, but its benefit continues to stay on. The medicine's been around for a long, long time, and those results I think were very, very, not only hypothesis-generating, but I'm going to tell you right now, it's going to be patient-driven as well. So really interested regarding your thoughts.

In terms of lutetium and PSMA-targeted therapy and radioligand therapy. I think it's definitely here to stay; it's only I think going to be used earlier and earlier and earlier. In talking with the nuclear medicine folks, the side effect profile is really pretty good. In your discussions with your colleagues, do they think the targeting can get even better? Do they think they can actually spread out? It's already spread out from six to eight weeks, which is a benefit. What do you think the holy grail will be when it comes to radioligand-based therapy?

Ursula Vogl: I think unfortunately, some non-academic things will be the holy grail because availability, reimbursement, and also the laws on the radioprotection differ from country to country. So in Europe, for example, we're confronted that in Switzerland, for example, we have to recover the patient on the ward for at least one night for the radioprotection law. They have the same in Germany; Italy actually resolved the problem. So it's more a logistic problem and also costs and accessibility. I think unfortunately this will be more discussion about radioligand therapy than actually the dosing and future applications of the drug. So we're still struggling with this topic a lot.

Sam Chang: No, those are incredibly salient and real-world thoughts. The logistics in the US in terms of the administration safety, all the legal and regulatory loopholes have limited its applicability. But I think that step-by-step, hopefully those regulation hurdles will decrease. I don't know if they will, but I think that point is actually very much on the spot.

So Dr. Vogl, thank you so much for spending some time with us on your busy schedule. This will be by far one of the most popular sessions I know with UroToday in terms of your essence of giving the highlights of the prostate cancer within the ESMO 2024. So thanks again.

Ursula Vogl: Thank you for the invitation. It was a pleasure.