Michael Morris: Thank you, Oliver. It's such a privilege, always, to be here at UroToday, and also to talk to you.
Oliver Sartor: Well, thank you. This is a very provocative time, particularly in the imaging realm, and it turns out we're going to focus on imaging over the next 6 to 10 minutes. I'd love you to tell me about Prostate Cancer Working Group 4 imaging changes, particularly about PSMA PET, which I think is on everybody's mind. So Mike, take it away.
Michael Morris: Sure thing. So I agree with you. PSMA PET is on everyone's mind because it's become our reference scan for so many different contexts. Those contexts that we feel most comfortable with are in staging for those who are higher risk with localized disease, and also for documenting where the disease distribution is for those who have relapsed. The big question, and I think major challenge for us, is how to use PSMA PET as a clinical trial's endpoint for either documenting response or documenting progression. We understand that PSMA PET is very different from the imaging assessments we did in Prostate Cancer Working Group 2 and 3. It's a much more accurate study, both in terms of establishing where a disease is, and it's a study that I think, in the end, we all feel very comfortable with using now in those contexts, but we really don't know what changes a PSMA PET reflects, whether that's reflecting anti-cancer activity or failure of anti-cancer activity. And so we needed a way to take this imaging study that all of our patients are getting and that we are ordering clinically to get the daata to move from simply describing distribution of disease to response and progression.
Oliver Sartor: Mike, one of the things has been so problematic is we've used the PSMA PET as baseline, whether it be VISION, PSMAfore, as you know extremely well, but the repetition of PET after beginning therapy in the prospective setting has been largely absent. ENZA-p trial's done a little bit, but it's not even published. So I wonder how do we move from thinking about a novel imaging agent in the context of trials, which are predominantly non-prospective, non-phase III without the endpoints we really want. So how do you move from point A to point B? That's a very difficult question. I'm kind of putting you on the spot a little bit.
Michael Morris: I think that that's what Working Group 4 serves to meet as an unmet need. Working Group 4 recognizes that we need to transition from an era of bone scintigraphy to an era of molecular imaging in order to collect the data to bridge the knowledge gap. So in Working Group 4, we are highly recommending that in clinical trials, not only is the baseline scanned with cross-sectional imaging, bone scintigraphy, and PSMA PET, but we then longitudinally repeat those serially on study to document the various phases of response and progression. We recognize that that represents both a financial burden to sponsors and a time burden to patients, and so we have focused those serial assessments in the pre-treatment realm, the early-treatment realm where you're most likely to see a response, and then as the patient begins to progress at the end in order to try to minimize the burden of what is basically triple imaging. But hopefully we can do this now, collect the data so when it comes time to do Working Group 5, we no longer need the bone scintigraphy.
Oliver Sartor: Mike, I could not agree more. And of course I was part of the imaging subcommittee and we had many discussions, I'll simply say the integration of the imaging, the therapy, the health-related quality of life, and the outcomes, to be able to create a whole that is larger than the sum of the parts is exactly what we need. I was so pleased to have Working Group 4 endorse that concept. That's going to take us where we need to go.
Michael Morris: I think so. And I think, as you are a key component of that committee, we worked really hard with international experts in trial design, imaging, and that included radiology and nuclear medicine and clinicians to come together with both a schema of scheduling and as well a proposed set of endpoints for PSMA PET, which really harmonized pretty well with the endpoints that we had for Working Groups 2 and 3 in terms of bone imaging, that we could superimpose both the goals of those endpoints of progression and the means by which we implemented those definitions to meet those goals. But maybe we should talk a little bit about that, what the definition of progression is, because that's changed since Working Group 3 for both bone scintigraphy and for PSMA. We used to have, and we still do, a 2+2 rule to basically mitigate the influence of pseudoprogression or flare. And that was, you had to have at least two new lesions on the first on-treatment scan and then another minimum of two lesions on the next one in order to qualify as truly demonstrating for progression.
And we still need to do that for bone scintigraphy. But after that period of flare, we had this rule in which all patients needed a confirmatory scan in order to meet a definition of two new lesions, at a minimum, defining progression. And that, I think, many folks had a problem with in terms of keeping patients on a potentially ineffective therapy to get that confirmatory scan, even in the context of really rapid disease progression. Those patients could develop a significant increase in disease burden simply to meet that regulatory endpoint. And the date of progression was backdated from that confirmatory scan back to the original progression scan. So it did seem like, "Okay, we are holding the patient on ineffective therapy and then backdating it to the original date of progression anyway." So in Working Group 4, what we've said is that if you have six or more new lesions, whether that is on the bone scan or the PSMA PET, there is no confirmatory scan. The date of progression is that date that six or more new lesions were documented. For bone scintigraphy, obviously that's bone specific.
For PSMA PET, then that applies to anywhere in the distribution of the disease. And we additionally made a rule in terms of patient safety that if, on the PSMA PET, you saw any non-pulmonary visceral metastasis, specifically we're thinking of liver, any single lesion, even if it's only evident on a PSMA PET but you have high confidence that it represents disease, that documents progression. And that way we are both retaining our original dates for rPFS that we established in Working Groups 2 and 3, but we're also trying to minimize the likelihood of keeping patients on for longer than they need to or should clinically in order to meet a regulatory endpoint.
Oliver Sartor: Well, certainly I agree. I mean, a new liver metastasis has important prognostic information. We don't necessarily need to get another confirmatory scan. One last question, because this sort of "six or more" is an interesting definition, and there's a lot of debate, a lot of debate on this point, and oligoprogressive was sort of distinguished from polymetastatic progression.
Michael Morris: Yes.
Oliver Sartor: And I wonder if you might touch on that briefly, this sort of "five or less" and "more than six" in that sort of discussion, because I think people would be interested in hearing more.
Michael Morris: First of all, I love that it encourages debate because debate will stimulate people to collect data, and all of these candidate endpoints need to be supported or refuted by data. I mean, we have equipoise on these. We're happy to develop better endpoints if it turns out that that lesion number should be three or nine, or it should not be lesion number at all, but rather SUV or volume of disease. So we welcome the debate. It's not something that puts us into a corner in any respect. It actually serves the purpose, which is get everyone around the world to collect their data and let's, by all means, improve the endpoint. But the reason that we chose five was because our thinking was, when you do have oligoprogressive disease, clinically we feel relatively comfortable about directing focal therapy on just a lesion or a handful of lesions that can easily be irradiated and maintain the patient on their therapy.
And we did that in all the ARPI registration trials. You were permitted to irradiate a single resistant lesion that was emerging on treatment and continue the patient on otherwise life-prolonging therapy. That was the only cutoff that we were basically using with the five, is most people felt comfortable treating up to five or five or fewer lesions with focal therapies as opposed to, if you have six or more lesions, you're thinking, "Maybe I should be switching systemic therapies," at that point. So right now that definition is based strictly on clinical consensus, if you will, even though we didn't do any formal consensus Delphi process around that. But I would say that it's a candidate and we are already beginning to assess the data from large clinical trials as to whether six is the right endpoint or the right cutoff, and also whether six by PSMA PET is the same as six by bone scintigraphy. That all needs to be explored. But it was the clinical judgment of when you would ordinarily be changing systemic therapy that really drove that number.
Oliver Sartor: Mike, I really appreciate you being here on UroToday, helping to explain this important new publication just out in JCO. So congratulations.
Michael Morris: Thank you. And thank you for all your help in formulating the criteria as well.
Oliver Sartor: Very small role on my part, but a big role on yours. Thank you, Mike.
Michael Morris: Thank you, Oliver.