Anwar Padhani: Pleasure.

Phillip Koo: Great. So this flare phenomenon is something that we've known about for a long time thus far. And we've created these workarounds, ways to sort of get around it. Why is it of utmost importance today to address this problem?

Anwar Padhani: Okay, so there are multiple ... The flare phenomena is about the bone scan and the value the clinicians are placing on the use of the bone scans for precision oncology trials. And in fact, it's been quite successful with the workarounds, but there are multiple consequences of the workarounds. And one of those is the inability of bone scans to detect the volume of metastatic disease, the actual volume rather than the depicted volume.

Number two is the readout, the readout of progression on a bone scan using the workaround, particularly the two plus two rule of the prostate cancer working group means there's a delay in starting the next treatment. And if you want to participate in precision oncology trials, you want a rapid readout, much like serum markers for example. And that's why the flare phenomenon is and a workaround for that is becoming important in today's world.

Phillip Koo: Okay. Could you explain the two plus two rule to the viewers out there who aren't familiar?

Anwar Padhani: Okay. So essentially, the flare phenomenon is the presence of two new lesions on the first post-treatment scan. So, interesting. Two, not one. So, there's an issue there. Number two, it has to be on the first one in what's called the flare period, which is usually between eight to 13 weeks, that sort of area. Now, if you see two lesions, that could be due to progression or something called pseudoprogression. Pseudoprogression is where the tumor gains a bit of momentum before a treatment starts to work. So, you may see a slight worsening of the disease before it gets better. Or it could be an osteoblastic response.

There's an issue there. So, it could be real, it might not be real. So, to deal with that, you have to do another scan at least six weeks later, at which point you have to document another two. Okay. So, you're saying, "I need two to start with and I need two afterwards." Now, let's say you had one and then you had another one. That wouldn't count. Issue. Secondly, there are whole bunch of patients, probably about 30% who have super scans. If you have a super scan, you can't develop a new focal lesion. The only issue is let's say you have a lesion that does that and just gets bigger. It's not new, it's just got bigger. Well, that doesn't count. This crazy phenomenon has actually a number of limitations, which doesn't bode well for its use in precision oncology. It just doesn't.

Phillip Koo: I completely agree, and it's kind of mind-boggling, the fact that we've used this for so long.

Anwar Padhani: Yes.

Phillip Koo: Because today, if we introduced this type of test into trials today, people would laugh you out of the room.

Anwar Padhani: Exactly. But on the other hand, its use has been validated.

Phillip Koo: Yes.

Anwar Padhani: Now, that's the interesting thing. So we know it's not that great, but in fact, for the development enzalutamide, for abiraterone, it works. So, there's no doubt it works. But we've found out that there are multiple limitations.

Phillip Koo: Great. So today, clearly we have a lot more tools that we could employ.

Anwar Padhani: Yes, exactly.

Phillip Koo: MRI, PET/CT, or whatnot.

Anwar Padhani: Exactly.

Phillip Koo: Tell me your thoughts on how these new imaging agents could be used.

Anwar Padhani: Yes. The essential thing is that we need to monitor the tumor, not the matrix response to the presence of tumor. And that's how functional energy comes in. You can use something like choline or PSMA, which directly looks at the health of the cells. So, that's why they make sense. Similarly, you can use MRI, particularly diffusion MRI. And diffusion MRI looks at the cellularity of the bone marrow, because that's what we're talking about, and the cellularity of the tumor cells within the bone marrow. So, you can see how by looking at the tumor cells themselves rather than the matrix response, you actually get a better readout. And that's why we are advocating these next-generation technologies for next-generation imaging trials or clinical trials.

Phillip Koo: How about thoughts on PSMA PET/CT in some of these trials?

Anwar Padhani: Correct. So, I think there's a role for all of these technologies Now, the PET technology is no doubt, they are highly sensitive. So, they tend to be quite useful for the detection part of the disease. And their high sensitivity makes them very useful for that purpose. So, if you have clinical trials in the early space, the development of metastatic disease, when you want to detect early metastatic disease, then those technologies make sense. Whole-body MRI has a role for the later part of the disease because you'll be repeating scans every six to eight to 12 weeks.

I mean, we do eight of these a day looking at patients on treatments. For that, it's unreasonable to do PSMA because in the UK for example, there's a huge shortage of PSMA. In my center, I can only get four doses every two weeks. So, if I've got patients on clinical trials or patients being treated, I need a technology that I can use on a daily basis that I can just do whenever I need to. So, we prefer to do whole-body MRI for that purpose. There are different roles for PET technologies and for MRI.

Phillip Koo: Any closing thoughts on how to incorporate these types of ... tools into clinical trials?

Anwar Padhani: Correct. There's no doubt that these tools need to be incorporated into clinical trials so that they can become more validated. One of the biggest hurdles to their incorporation previously was the lack of SOPs essentially, standards, quality standards. And we've spent the last two to four years developing consensus criteria on how to do the scans, how to analyze the scans, how to assess the scans for response assessment, et cetera.

So, there are now SOPs or publications that now say, "Well, this is how you should do it." And I think we're now ready to incorporate ourselves into the clinical trial space. That's some of the data that I'll be sharing later on today. The important thing to remember is that imaging tools are expensive to do, and that raises barriers. But we can see the costs are already beginning to come down, particularly in the rest of the world, not in the US. And that will enable us to more easily incorporate ourselves into that.

Phillip Koo: Great. Well, thank you very much for your time.

Anwar Padhani: Oh, yeah.

Phillip Koo: We look forward to hearing your lecture later today. And also congratulations on another amazing APCCC conference.

Anwar Padhani: That's a great meeting. Thank you.

Phillip Koo: Great. Thanks.