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Aurelius Omlin: We did vote on the RP switch question. We didn't show it today. We'll see it in the publication. But we have some interesting results. After some of the complex discussions this afternoon. These are going to be very basic and clinically oriented. Again, I'm sorry, but that's also the reality.

And so question one is whether or not the panel recommends somatic genetic testing for DDR genes before recommending a PARP-RP combination in first-line mCRPC. And you see a lot of green, like we wished this morning, for the cardiovascular assessment. So I think a very strong consensus with 95% voting yes for testing first before recommending a combination.

Silke Gillessen: Anyone want to comment? Elena?

Elena Castro: Fine. No comment. I think it's very clear and very evident that this is something we should be doing.

Silke Gillessen: Perfect. So we go fast because afterwards we have some more radiotherapy questions. So maybe Barbara and Jason, if you can slowly walk up, thank you very much. So here is the question that we discussed about the ideal sequencing. So this is patients’ mCRPC first line when they had received ADT plus/minus docetaxel. And one time when somatic genetic testing is not available but is, in reality, in the real world, very often the case.

And you see here, really clear consensus for ARPI. Then some people in blue, 11% would give an ARPI plus the PARP inhibitor, and then some other options. If you have done the testing but there was no DDR alteration, in reality there is not much of a change.Karim, you want to, maybe, comment?

Karim Fizazi: Well, I mean, I may be biased. But I'm actually glad we are answering this question this way. Similar to what Johann said, I think the trials testing an AR pathway inhibitor together with PARP inhibitors show clear benefit for BRCA patients, some benefits for other alterations. We may argue about CDK12. I think PALB2, even if the numbers are small, we are mostly convinced. But I think also that most of us agree that the benefit is not strong enough to justify use in patients without DDR alterations. And I think it's very reasonable.

Silke Gillessen: Thanks.

Aurelius Omlin: We go to your topic, Ian—the sequence. I know it's not an ideal sequence, but here are the options for patients who have received ADT plus an AR pathway inhibitor in mHSPC and now are progressing to mCRPC. And again, we split it between no testing available, no testing done, or testing done and no DDR alteration identified.

85% and 88% respectively voted for option three, docetaxel, very few for the alternate ARPI (so the RP switch), very few also for option two (light blue PARP plus RP combination), radium, I think one, and lutetium also, surprisingly small numbers of 7% and 5% only. Do you want to comment, Ian?

Ian Davis: Well, I'm gratified to see this. It's what I was hoping to see. And I wondered whether some on the panel might be more inclined to move towards lutetium PSMA early, or be advocates for early PARP inhibition. I'm glad to see that did not turn out to be the case. Docetaxel still works?

Silke Gillessen: Is anyone from nuclear medicine here who wants to comment on the low use of lutetium? Because I think it's quite interesting. So PSMAfore—I don't know, Oliver, if you want to comment on the result.

Louise Emmett: Louise Emmett.

Silke Gillessen: We save it all for tomorrow. So you have to come back tomorrow morning, which is good.OK, we'll discuss it later. But I think it was—

Speaker: The availability issue as well. I think we're still biased by this issue.

Silke Gillessen: Yeah. Of course, we have said it's an ideal world, where you have everything available. But because it was quite surprising.

And now comes the triplet. Here, again, same thing—testing not available or you have no DDR alteration found. And again, it's quite similar. So after the triplet, as you see here, almost a consensus—or consensus—is lutetium after the triplet.

So that's very different from what we've seen before. I think that's quite interesting. So again, Anthony, if you see here, very, very few people for the alternate ARPI, then adding a PARP inhibitor, very, very few, and 19% would go for taxane.

Aurelius Omlin: Now, maybe now a nuclear medicine physician may want to come up because the results look different.Michael?

Silke Gillessen: Michael, finally—

Aurelius Omlin: You've been so quiet before.

Audience Member: Look, I think this may change, but for the moment, we don't have the evidence. I mean, there's been a lot of abstract presentations, but PSMAfore is still not published. So I think it's good that people wait for the publications and don't change practice by either press release or abstract. And let's review the evidence. And maybe in two years' time, when these are published, the practice may change.

Silke Gillessen: Absolutely. Anyone from the panel who wants to comment? Maybe, Karim, after your talk, are you happy with that result?

Karim Fizazi: Yes. I think, really, people are following the evidence, which is again reassuring. We have level one evidence for overall survival with lutetium PSMA, as we have for cabazitaxel. Again, not necessarily after triplet use altogether, but typically after sequential use, but it probably doesn't really make a big difference. So I think this is very sound.

I guess people recognize also that lutetium PSMA is probably safer in many patients as compared to cabazitaxel, or at least this is the subjective perception of it and from patients' perspective as well. So those two first options—lutetium PSMA first, taxane second—I think are very reasonable.

Silke Gillessen: Johann?

Johann de Bono: Can I just comment that not all prostate cancers are the same? So if you're at the end of the bed and going through the patient's results and it's a strange tumor, like a low PSA, maybe liver mets, do worry that you may have a PSA-low tumor, maybe a mismatch repair-defective tumor, or CDK12 loss, or even a BRCA tumor that has, I guess, different sensitivity.So I think the key thing is just think about the patient before you—particularly that low PSA patient that has low ER signaling and maybe low PSA.

Silke Gillessen: Yeah. Good point.

Ian Davis: I wasn't surprised to see this result. But just to remind the audience, this is not the population of VISION and TheraP. In VISION and TheraP, they received ARPI and/or docetaxel in the CRPC setting. And that's not what we're asking in this question. So as Michael very correctly pointed out, this is moving beyond the evidence. And we cannot assume that it will be the same outcome.

Silke Gillessen: Of course. Michael?

Michael Morris: Just one more word on the PSMAfore issue. And Michael's right. The data is not published. It's only the hazard ratio for survival that is just out by press release. But you do know from the relatively mature RPFS data that, relative to a second ARPI, it delays disease progression, patients have less toxicity than a second ARPI, and they feel better for longer than an ARPI.

So when we think about all of these options here for first-line therapy, what I would say is that, one, we're at a point where we have a selection of therapies. They don't have to all beat each other in terms of OS.

What is important is that you feel the best with the least amount of therapy. That ultimately, from a patient standpoint—even if all of the options make you live just as long as each other. The whole idea of treating cancer is to keep it under control while feeling the best and getting the least amount of treatment. And in that light, I would say that we should start evaluating those first-line treatments.

We're going to lose OS as an endpoint, with enough treatment options up front. And we have to start thinking about it from a patient-centric standpoint in terms of what's easiest to get, even if you don't live longer in one choice versus another. We're going to have hazard ratios of one for a lot of future trials. And then that's going to beg the question of what's best for the patient.

Silke Gillessen: Thanks. Michael, I think that's an important comment. And I think we also go and look much more for symptomatic progression. But it's obviously also important.

Aurelius Omlin: Now we move on to patients with a pathogenic BRCA2 alteration. They are progressing to first-line mCRPC. They may have received, or they have received, ADT plus/minus docetaxel. We voted on the question: what would be your next choice of treatment and ARPI, as we did in patients that have no known alteration or have not been tested, 8%.

But again, a strong consensus—92%—vote for ARPI and PARP inhibition combination. And nobody voted for any of the other options. Joaquin, that's what you've been advocating?

Joaquin Mateo: Yeah. As I discussed before, I think it's a reasonable option. But it should not distract us from acknowledging that there are still bits of data that we don't have completely, and we have to work towards completing them. But in the meantime, I think that we want BRCA patients to get access to PARP inhibitors at some point during their disease. And if the combination has been shown to be safe up front, I think it's reasonable in order to secure that they will eventually get exposed to the drug.

Aurelius Omlin: And we assume now that the testing has been done properly, it's not a liquid biopsy with a low allele frequency and low ctDNA content, et cetera. So I think this is what we assumed in this question.

Joaquin Mateo: Which is what happens for the majority of patients. I think that we know that testing is difficult. Interpretation of testing is difficult. But it is true that most of the time when you see a pathogenic BRCA mutation, this is straightforward clinical significance.

Aurelius Omlin: So the next question goes along that line. Again, BRCA2—we selected BRCA2 specifically because we asked separately about the other alterations. Again, first-line mCRPC, but now the patient had ADT plus an AR pathway inhibitor already for metastatic hormone-sensitive disease. Nobody voted for a switch in these patients.

44% voted to add the PARP inhibitor to the concurrent treatment or change the AR pathway inhibitor, plus add the PARP inhibitor. 49% voted for the PARP inhibitor monotherapy, and 7% for other options. And if they have received the triplet, the picture is almost identical. 41% would add the PARP inhibitor, but 55% now would go for monotherapy in these patients. Elena, can we get a comment from you?

Elena Castro: Well, I think Joaquin already discussed this in his presentation. We don't really know what the ARPI is adding here after the patient has already progressed to one ARPI. But if they wait to give this patient a PARP inhibitor, it's in combination because it's the only approval, or it's the only thing we have access to. I think I will also use it in combination.

The patient needs to receive a PARP inhibitor. I believe so. Perhaps we don't know yet what the ARPI is adding. But if it's the only way that—

Aurelius Omlin: Does it depend for you on whether or not the patient had ARPI for mHSPC or enza?

Elena Castro: I don't think we have that data yet.

Silke Gillessen: Yes, Johann, what is your—so I think, Joaquin, we have understood very well you would go for monotherapy. From your talk I understood—

Joaquin Mateo: I think that with the evidence that we have right now, we should consider the monotherapy still as the standard option. But I do see the point of questioning ourselves, what is the role of keeping pressing the same pathway when patients progress from hormone-naive to castration-resistant? And what is the right backbone that we are going to keep on these patients in the long term?

But I think these are questions that we have to address from science and clinical trials. In my talk, what I was referring to is if we look at the labels and what has been shown in randomized trials, it's still a patient that has progressed on one of these drugs and has access to the PARP inhibitor monotherapy. I'm yet to see the data that giving them together is better than just giving the PARP inhibitor, if they have already received the other one.

Silke Gillessen: Yes, Johann.

Johann de Bono: I just don't think it makes a lot of biological sense, thinking about disease biology, giving the second ARPI with the PARP inhibitor. So personally, I would give the single agent because it doesn't make biological sense, because a lot of these tumors are getting spliced variants. You have—you know, enza, it's not going to work, anyway.

And in fact, Charles Sawyers and Karen Knudsen, many years ago, showed that AR blockade blocks Non-Homologous End Joining, NHEJ—beautiful paper. And many groups have shown that if you inhibit NHEJ, you may actually decrease PARP inhibitor sensitivity. So I don't think it makes biological sense to give the combination, in my opinion.

Silke Gillessen: That's good. Thanks, Johann. So now, I think it's an important question for all the countries where you don't have access to a PARP inhibitor or where you do have access, but patients have to pay out of pocket. So if you have no access and you would like to give—so your indication is a PARP inhibitor—do you recommend treatment with a platinum-based therapy instead of the PARP inhibitor?

And I think it was quite clear. So most people would say yes. Only 3% would say no. But half would say yes before even a taxane chemotherapy. And the other half would say yes, but only after a taxane chemotherapy. Yes, Johann.

Johann de Bono: I think this is a really important question. Having worked in Africa myself, I would argue that maybe we should also consider the platinum and the taxane together based on what we know for ovarian cancer. And platinum AUC5 is very well tolerated. And in docetaxel, you can give it in good tolerability. And I know of one patient who had a 13-year response to that combination after getting liver mets and BRCA2 setting. So this is a really key question.

Silke Gillessen: Anyone else who wants to comment on the combination? So Johann, he's here, who has done a beautiful phase II study with combining cabazitaxel with a platinum. I think it's doable. It's manageable. So I don't know, Ian, Karim, someone who wants to comment?

Ian Davis: I found this question very difficult to answer. Yes, it is not difficult to deliver the combination. It's a general principle in solid tumor oncology for treatment—palliative treatment—of an incurable cancer. Monotherapy is the way to go. So the only justification for combining it is if there is a molecular basis to that. And there may be in this sort of situation. So I would tend more towards the combination in this setting. I actually can't remember what I voted for now.

But today that's what I'm thinking.

Silke Gillessen: It's almost a 50/50 chance. You've been in green or blue.

Ian Davis: It's probably changed. It's changed.

Karim Fizazi: I actually typically go for combination therapy when there is an emergency—when you really believe that if you don't, you're not making the right choice immediately, basically, the patients will die or will rapidly deteriorate and you won't have a second shot. So this is really how I'm trying to make my decision. Otherwise, I mostly go for single-agent treatment to try to be on the safe side with regard to toxicity.

Ian Davis: That is the "window of opportunity" issue. Again, he might not have the chance, as you say, to come back with another cytotoxic.

Silke Gillessen: Thanks. Conventional.

Aurelius Omlin: So we are going to show very briefly. We selected all the genes that were included in the TALAPRO-2 trial and asked them individually: if you had a patient with mCRPC, would you recommend—or do you recommend—a PARP inhibitor or monotherapy or combination sometime in the disease course if there was evidence of a BRCA1 alteration, ATM (we heard all the limitations from Johann's talk), and RAD51C? And you see for BRCA2, it's clear—it's 89% in the same indication—

Silke Gillessen: BRCA1.

Aurelius Omlin: —as in BRCA2. 8% would use it at a later stage compared to BRCA2. And for ATM and RAD51C, it's a bit all over the place. We obviously don't know. We have also PALB2, CDK12, CHEK2. We don't want to go into too much detail here. And of course, there's a lot of other factors that need to be considered—technical factors, testing factors. But, Johann, you want to comment.

Johann de Bono: I didn't talk about CHEK2 today, but please, can I tell everybody? CHEK2 does not sensitize to PARP inhibition, CHEK2 alterations. In fact, it probably causes resistance to PARP inhibition. So that gene should not be in the list, really.

Karim Fizazi: And I guess this is supported by evidence. I mean, every trial reported negative findings for CHEK2 patients, unfortunately. I think CDK12 is a more interesting thing. This is quite frequent. It's aggressive. And I think the recent meta-analysis that was done by the FDA suggests that indeed there is some efficacy of PARP inhibitors for CDK12 patients. So it's true. I mean, this is obviously good news for those.

Silke Gillessen: I guess we have to very critically write that section. Joaquin?

Joaquin Mateo: I just wanted to say that I was happy to see these results. Also, some surprise. But I wanted to congratulate you for including these options, because I think that when we run all these trials for PARP inhibitors (but other drugs also), we are testing drug A versus drug B at the moment of the disease. But actually, when it comes to centering the decisions on the patient, unfortunately, we know that the patient is going to need several therapies.

So we need to interpret this evidence also in the context of when to use drugs. And clinical trials do not always give us the option because, as I was saying, with all the options we have now, it's impossible to run each of them against each other. So it's important to understand that a drug may work not as well as another in a certain indication and may be an option that you keep as a backup after the ones that you think may work best.

Aurelius Omlin: Johann. Sure.

Johann de Bono: I think patient choice is key. And what we haven't mentioned here is: discuss with the patient the options, see what the patient wants. But if I was the patient and I had PALB2, don't give me anything else but olaparib—or PARP inhibitors, sorry. Not olaparib—PARP inhibitor, one of them.

Silke Gillessen: Yeah, like the BRCA3. That would be much easier if we could call them that way.

Aurelius Omlin: But just one point. Yes, it's good to include patients in the discussion, but how do we do that? You can do it and the people on the panel can do it. But all of us outside have little experience, have not had a chance to participate in the trials. So it's probably quite challenging.

Johann de Bono: Understood.

Silke Gillessen: So now, a bit of radiotherapy. So thanks again, Jason and Barbara.

So we now speak about oligometastatic first-line mCRPC—again about these five lesions. And we wanted to ask, what are people doing in oligometastatic first-line mCRPC? And you see here, 40% would add or switch to systemic therapy, 45% would add/switch systemic therapy and perform MDT of all lesions, and 14% would only give radiotherapy to the lesions. So maybe, Jason, can you comment on that?

Jason Efstathiou: Yeah. I think we are informed in oligometastatic disease by a number of Phase II trials in the non-metastatic castrate-resistant setting. But the ARTO trial from Italy that was in the metastatic castrate-resistant setting— it included up to three lesions treated, and the randomization was Abi +/– SBRT.

The addition of SBRT led to very significant gains in terms of biochemical response—impressive—complete biochemical response, and progression-free survival advantage. And so I think based on that trial, in this setting, the addition of MDT makes a lot of sense. And I think Option 2 makes a lot of sense.

Silke Gillessen: Thanks. So in the sake of time, we go to the next one. Now we speak about oligoprogressive disease, and we have discussed that this morning also a bit in the hormone-sensitive setting. So it's oligoprogressive, not oligometastatic.

And here, you see it's a bit different. So 30% would switch systemic therapy, 20% would switch therapy and give MDT, and almost 50% would not change the systemic therapy but perform MDT on all progressing lesions. So Barbara, maybe you want to comment on that.

Barbara Alicja Jereczek-Fossa: I'm quite glad to see MDT in many options, in many answers. And indeed, I think it's an option. We can consider it as a line of the treatment, so it is not yet—we have some ongoing trials. But I think that it's an option. It's another line to be considered.

I have some preliminary data from the ARTO trial. I just discussed it with Dr. Francolini. It will be presented in Glasgow ESTRO next week. And also, in this kind of patients, there is a benefit of adding MDT.

Silke Gillessen: OK. That's interesting. So we are waiting for the results at ESTRO. Thank you very much.

So last one, maybe not least one—what are you doing with the majority of asymptomatic patients with mCRPC who have disease progression in the spine with an epidural soft tissue component? Do you recommend prophylactic radiation therapy to try to avoid problems like the risk of symptomatic spinal cord compression—which we know is really terrible for our patients?

And you see here, 65% said yes in the majority of patients, 33% said yes but only in selected patients, and very few of the panelists said no. So I would maybe first ask one of the clinicians, maybe Karim or Ian, to comment. Would you send your patients to a radiotherapist in that setting?

Karim Fizazi: I do, and typically, we will discuss all these patients at the multidisciplinary meeting. So I would vote green, I guess. So yes, for the majority of patients—understanding, of course, that there are specific cases where it's more difficult, et cetera. But I'm also glad that most of us recognize that this is a very serious option to do.

I mean, spinal cord compression is really a terrible thing. It still happens in almost 10% of all the patients before they die from prostate cancer. So if we can prevent this from happening, it's very, very important. And we mostly can.

Silke Gillessen: Can I ask Nina to come to the microphone? Because this question has been partly inspired by also long weekends working with you, looking at spine MRIs. But we can, in the meantime, also get the radiation therapists' opinion.Barbara?

Barbara Alicja Jereczek-Fossa: I'm worried by this: 2% of not sending patients for radiotherapy. It's really worrying because we discussed really a lot today and yesterday, and I'm sure also tomorrow, the quality of life. And these patients live longer and longer, and we are happy to see this OS benefit. And it means that if we don't treat them in this moment, it means that they will live a couple of years, maybe even more—as you said, sometimes even 10 years on a wheelchair. And it's really worrisome.

So please remember that this is an indication to treat. It's a short treatment, no problem with combination with ongoing treatment.

Aurelius Omlin: This was probably a mistake or a tired panelist.

Barbara Alicja Jereczek-Fossa: Late night, doing the questionnaire.

Silke Gillessen: And don't forget David Donnelly's paper, who spoke a bit against this. I think we are all doing it, but there is some data out, even if it's not perfect, that speaks against it. So I think this is maybe those—how many—two people who have read the paper and believe the paper. So Nina?

Nina Tunariu: Thank you. Very briefly, I think the only weakness, with all the respect and love I have for David Donnelly, is that in that paper they looked at the MRI spines routinely in a system. What we did with Aurelius—and I think it's a very useful exercise we did—you can see epidural disease on CT. So now, in our routine reporting of CT scans in prostate cancer, we report epidural disease or not. And I think that's a very useful technique and it's a very useful biomarker. You don't need to wait for an MRI spine or for the patient to have symptoms.

Silke Gillessen: Can you say the factors to watch out for?

Nina Tunariu: The factors we are looking for is what I teach my residents and oncologists. It's the epidural disease—it's a soft tissue component of the metastatic bone disease. So you need to educate your radiologists to look on a soft tissue window rather than bone windows because on bone windows you will miss the cord compression.

Secondly, the disease extends into the paravertebral space in a lot of patients at the beginning, before it goes into the canal. So if you look there, you may be able to see it even better. So those were the two most important factors. Thank you.

Silke Gillessen: And it should also go to 2025 because I think a lot of your radiologists are not reporting that on a CT scan. So I think we can all learn from that experience. Anna, last comment.

Audience Member: Can we be careful about that, though? Because systemic therapy may be needed for other sites of disease. And if we now make it mandatory that we have to radiate for an asymptomatic epidural component prior to systemic therapy or even clinical trial participation, we might get ourselves into some trouble. I think we have to be a little bit cautious with the recommendation.

Jason Efstathiou: I would just say, though, we want to prevent badness. And a very quick course of radiation, which is incredibly well tolerated, may really help do that and not necessarily limit the systemic therapy management.

Silke Gillessen: And that's the majority of asymptomatic patients. That is not the patient that Johann mentioned before with the squamous cell, low PSA, and all that. So it's your usual patient where you see something with mCRPC first line, and it's quite short. And if you give an AR antagonist, I think Jason or Barbara wouldn't say you couldn't start a systemic therapy.

Audience Member: Yeah. I just think it has to be cautioned with. Weigh the options and patient dependence.

Aurelius Omlin: Well, many trials mandate in a two to four weeks window, not from starting.

Audience Member: Exactly.

Aurelius Omlin: Your point is well taken.