Eric Small: Thank you very much. Thank you very much. Also, I need to add my thanks of course to Silke and Aurelius. You have a room full of fans, you guys. So thank you for putting on a spectacular meeting. So we're changing gears here a little bit. I just want people to be aware of this, that the active word here is CRPC. So thus far the focus has largely been on hormonally sensitive disease. And this is now disease where it has already been established to be castrate-resistant. These are my disclosures, none pertinent to this talk.

So these are the definitions that have been set out there already. And it was great to follow these wonderful speakers because I don't need to go through this again. But if you think of the definitions, we could I think agree that oligometastatic CRPC is a patient with limited number of metastases who has ADT-refractory prostate cancer. Fairly straightforward.

The question is what is oligoprogressive CRPC? And that is a little bit, maybe a little bit different than oligoprogressive hormone-sensitive disease. So you could hold that this is CRPC disease progression, which is manifested as new oligometastases. Some people and this is where it gets confusing, would hold that this happens in patients that have preexisting metastases. So I asked you to bear that in mind that we're dealing both with prior mets, no-mets, but also hormonal status. Because the identification of preexisting metastases is so dependent on imaging as we've heard all morning long, and the timing of the imaging, and the frequency of the imaging, I would hold that the term oligoprogressive CRPC might be replaced and I would submit for your consideration these terms. And they're different than in the context of hormonally sensitive disease. So I think of synchronous oligometastatic CRPC as metastases that are synchronous with the emergence of ADT resistance. Meaning the very first time you see ADT resistance, you know it because there's oligomets. As opposed to metachronous oligometastatic CRPC, in which there are new metastases that develop following the clinical emergence of ADT resistance.

So there are many unanswered questions in oligomet CRPC. There's a number of questions that are shared. And Piet has just outlined them beautifully with hormone naïve prostate cancer. What is the cut point between oligomet and polymet, is it just five because I have five fingers? Optimal imaging technology, optimal timing. And does the modality of oligomet ablation matter? We've mostly heard about radiation therapy but there are some unique considerations with a CRPC disease state. Does it matter if the oligomets are synchronous or metachronous? And importantly, what is the role of changing or adding systemic therapy? And again, the question of endpoints. So does it matter if oligomets are synchronous or metachronous?

I will tell you that this is a data-poor area. But I would hold that it's likely to be the case. You can imagine that oligomets, synchronous mets, certainly have more systemic therapeutic options. There has been no therapy yet for CRPC. Maybe more radiosensitive than patients with later disease that have had recurrent therapy. And there's been the opportunity for clonal evolution. And you could argue as well that ablation of early CRPC clones that have developed metastatic potential may, in fact, delay the progression to more subclonal cancer down the line, which would not be the case in a metachronous disease.

What is the role of systemic therapy in these patients? So let me give you a quick example. This is a fairly standard patient, 73-year-old man gets treated with radical prostatectomy and adjunctive radiotherapy. He has a PSA recurrence. He gets treated with ADT. And a year ago his PSA starts to climb. His PSA climbs to 4.6. He's got a PSA doubling time of around six months. He gets negative conventional imaging. So what's the diagnosis here? I'd asked you to vote, but we don't have the time. The diagnosis is quote-unquote, "non-metastatic CRPC." What is the treatment for this disease? Well, the treatment for this disease is what I call the SPA treatment. SPA refers to SPARTAN, PROSPER, and ARAMIS. So you can all remember that. Now you don't have to remember the trials at all. So SPA treatment is good for you. There's level one evidence, metastasis-free survival shown here. We'll hear more about this later, is prolonged by the utilization of these drugs in these patients. However, in this particular patient, we did a PSMA PET. And low and behold, the diagnosis changes from non-metastatic CRPC to PSMA PET detected oligometastatic disease. So what do you do with this man?

This really is the treatment of non-metastatic CRPC that isn't non-metastatic. Higher sensitivity imaging modalities will certainly further reduce the proportion of patients that have quote-unquote, "Non-metastatic CRPC." And so a good question that has been asked is, how likely is PSMA PET to reveal metastases in these non-metastatic patients? And Dr. Fendler and colleagues have done a very interesting study. We participated in this study, patients who would have been eligible for one of the SPA treatments. Meaning a PSA above to a PSA doubling time of less than 10 months. We went back and looked at their PSMA PETs. And low and behold, PSMA PETs detected disease in 98% of those patients. And of those, around 30% had oligometastatic disease. That's really compelling and interesting data.

So how do we approach these patients? Well, I think level one evidence supports the use of a next-generation androgen receptor inhibitor. And there'll be a debate later on about the utility of it, but I think the data supports it. Even in men who are likely to have oligometastatic disease on functional imaging. And in fact, the role of ablative radiotherapy of oligomets without systemic therapy, there's very limited data. And I'll show you what we got, but it's not a lot. Certainly, the combination of the two of targeted therapy plus a SPA regimen is reasonable. But also not yet studied in a critical question.

So what is the utility of local ablative radiotherapy without systemic therapy to control oligomet CRPC? And I will warn you that the studies that are out there are limited and they're retrospective. We do not have prospective randomized studies. Here's one study from the Dresden group in which local ablative radiotherapy was used. The patients all had prior definitive local therapy, had CRPC, had a positive PSMA PET, and got treated. The point of PSA progression was determined for each patient. And the individual time to the PSA progression without the targeted radiotherapy was estimated. So each patient served as their own internal control. And these are the differences. This is not a standard approach, and it's only provocative. It suggests that potentially this approach could delay the time to PSA progression.

Here's another large study published just recently. This is a retrospective study. 11 centers, 86 patients with 117 lesions. This disease was termed oligoprogressive during ADT. So I would argue this as synchronous. Either Choline PET CT or a CT and bone scan were done. It required a controlled primary tumor. And these are the data, fairly limited. The median metastasis-free survival is 12 months. The one-year next metastasis-free survival rate was 50%. Systemic treatment-free survival rate was 71%. But without knowing why people get put on the next systemic therapy, I think this is pretty challenging data to interpret. But this is the type of data that we have.

One more article I'm going to show you, this is from a Japanese group in which again, retrospective study. 23 patients with CRPC. They all developed subsequent metachronous oligomets. And this is what we see with radiation. 70% of patients had a PSA decline. More so if it was intra-pelvic than extra-pelvic. And you can see the time to PSA progression. But pretty scant data pretty difficult to interpret. Certainly no data on which we can garner a consensus in my estimation.

So certainly ablative radiotherapy of both synchronous and metachronous oligometastatic CRPC is feasible and safe. The data are provocative but very premature. There are no prospective comparative data to suggest that this ablative radiotherapy is in fact beneficial. There are no prospective data to compare this ablative radiotherapy or surgery in synchronous versus metachronous metastases. And certainly, no prospective data to define the role of adding targeted radiotherapy to a systemic therapy that we know works.

So here's this patient again. He now gets treated with apalutamide. He gets a SPA treatment, okay? I'm just about done. His PSA declines but then starts to climb. And now he has new lesions. So this is oligo-recurrent CRPC while on appropriate therapy. And Silke specifically asked me to comment on these patients. And the bottom line is there is no data.

So a patient has progressed on apalutamide. We have no data to suggest that the biology is different from poly-metastatic disease. The utility of a secondary ASI is probably limited. So adding abiraterone, it seems unlikely. Established systemic therapy options are limited. And I would argue that the risk-benefit ratio of chemotherapy would favor this targeted radiotherapy. But there are no data. And I hate to leave you with no data. I know people have a lot of questions. So does it matter if oligomets are synchronous or metachronous? Probably but unproven. What is the role of changing therapy? Other than the SPA therapy, unknown. And what are appropriate endpoints? I've listed them here.