Phillip Koo: Hi, my name is Phillip Koo, and welcome to UroToday, where we are very fortunate to have with us Dr. Gafita and Dr. Fendler. Dr. Gafita is a post-doc scholar at UCLA's Ahmanson Translational Theranostics Division, and Dr. Wolfgang Fendler is the vice chair of Nuclear Medicine at the University of Essen. Thank you, guys, both for joining us today.

Wolfgang Fendler: Thank you for the invitation.

Andrei Gafita: Thank you for having us.

Phillip Koo: First off, congratulations on your paper that was recently published in the Journal of Nuclear Medicine, which really has taken PSMA PET imaging into a new dimension. Obviously, to this point, we focus a lot on PSMA PET to detect disease at initial diagnosis, whether there's a metastatic disease or not, and then we focus a lot on biochemical recurrence. What you guys have done is really shown the ability for PSMA PET to be used, to give us more insight into prognosis, use PSMA as a biomarker and also use PSMA to assess treatment response. Dr. Gafita, could you give us a little overview of what you were able to accomplish in your study.

Andrei Gafita: Phillip, so as you mentioned, we've seen with a lot of excitement the recent AVA approvals of PSMA PET, not one but two tracers. As many of us thought, this is the beginning of the end. We actually thought is the end of the beginning. We have a lot of work to do to move forward the PSMA PET and shifting this focus from diagnosis purposes to assess drug efficiency or treatment response assessment. In order to do that, we thought we have to develop a first standardized framework on how to evaluate the response to treatment and also to show that actually, PSMA PET has prognostic value and can be used as a response biomarker.

Phillip Koo: Wonderful. So Dr. Fendler, can you talk to us more about RECIP. RECIP stands for Response Criteria and Prostate Cancer and how that was developed and applied in this study.

Wolfgang Fendler: Basically, we had a large data set of more than a hundred patients from three institutions who underwent Lutetium PSMA Therapy.,These patients had a PSMA PET scan at baseline and after two cycles of therapy. These patients also had to mature outcome data, so high number of survival events. In this dataset, we were able to assess and define how to analyze the PSMA PET on baseline as compared to follow-up in a way that it would be prognostic. It would predict the overall survival in these patients. The central metric was the volume. We assessed changes on these total disease volume on our PSMA scan from baseline to follow-up, and we assessed whether there are new lesions from baseline to follow-up, all based on the PSMA scan. Those two criteria change in volume of the total tumor and new lesions. They would be combined to define and create the criteria which are prognostic of overall survival under Lutetium PSMA Therapy in this patient cohort.

Phillip Koo: That's very interesting. The ability to use volume and new lesions, similar to what we've had in other response criteria, but use really focusing on PSMA. What were you able to establish established in this study using RECIP in this patient population?

Andrei Gafita: We demonstrated that we can use entering PET, the so-called entering, so PSMA PET of the two cycles of mutation PSMA to predict survival in this patient and so that PSM impact is prognostic. On top of that, actually, what we see in the clinical practice is the so-called heterogeneous response. Sometimes we do see a very good response in total tumor burden. However, we do see one or two new lesions, and it is very confusing for us and also for the clinicians because from one side, you can consider the patient as being as progressing because of new lesion. On the other side, you can consider as being a responder because of the decrease in total tumor burden. RECIP clarifies this heterogeneous response, which in our cohort accounted for about 10% of the patients, and we classify those as having stable disease. This would be a major accomplishment for the clinical evaluation of these patients.

Phillip Koo: Where do you foresee this playing out in the future? In this study, every patient completed all the cycles. I imagine in the future, we might be able to say, hey, if you're not responding at this point, we could dose modulate, dose adapt or whatnot, or, but what are your thoughts on how it could be applied clinically?

Wolfgang Fendler: I think the field has changed quite significantly over the last years with the introduction of the new PSMA PET scan. There's a new imaging modality available now that is being increasingly used, especially in biochemical recurrence but also now being used before Lutetium PSMA Therapy to make an indication. On the other end, we also have more and more approved applications but also new experimental applications on PSMA-directed therapy. In this setting, for us made totally sense to evaluate the new PSMA PET scan and its prognostic value for future assessment and future application. I think there are two scenarios where this can be used. One is as a biomarker as a surrogate endpoint in clinical trials in the future to get clinical trials focused on PSMA-directed therapy. You really can image change of your tumor burden and your target undertreatment and the other hand, and the other application could be the clinical application of Lutetium PSMA Therapy and outcome assessment under Lutetium PSMA Therapy.

We have now a new biomarker that was established in this patient cohort and that is associated with overall survival and can help to make a decision. Whether patient should continue under Lutetium PSMA Therapy or whether he would be eligible possibly for other options and should be evaluated for other options.

Phillip Koo: In your opinion, do you feel like this is ready for prime time? Is this something that should be now part of our practice, especially in patients with advanced disease.

Andrei Gafita: I'm glad, Phillip, that you asked this question. We have now in preparation a follow-up manuscript where we looked at RECIP from a visual point of view. As Dr. Fendler mentioned for this study, we use a segmentation software to assess that the changes in total tumor volume, which is not widely available. In a follow-up paper to enable RECIP to be used in clinical practice, we actually assess the change in total tumor burden by visual assessment. We found that actually, you are on the safe side if you use just the visual assessment to look at changes into tumor burden and new lesions. RECIP could be used in clinical practice already. However, we do need clinical trials to navigate our findings on an independent cohort.

Phillip Koo: That's great. I think a way to simplify with a visual assessment, as opposed to segmenting these lesions, does make it a little more practical. The final question I have is when you looked at RECIP, and you looked at PSA responses, any signal, any data that you got that you could share with us regarding that.

Wolfgang Fendler: We've combined both, also in really in a combined assessment because PSA responses are very important. They are standard assessment under almost all prostate cancer treatments, and they are very, very useful and very valid also. Usually, PSA [inaudible 7:38:00] and tumor volume assessment on PSMA PET go along, so the volume goes down. Also, the PSA level goes down. For those cases where it might be discordant, we have also made suggestion on how to combine both assessments. Change in PSA level and change in RECIP how to make a combined conclusion on whether the patient would be a responder or a non-responder under Lutetium PSMA Therapy. That's being defined by increase and decrease of both values and also presented as a table in the RECIP publication.

Andrei Gafita: Maybe I can add here. We actually, we, like Dr. Fendler mentioned, we looked in the discrepancies between PSA and PSMA respond by RECIP. We actually have seen on about 10% of patients who actually, according to PSA, were progressing but were responder according to PSMA by RECIP and the other way around. That's why we, as a next step, we look at the prognostic value for PSA as a prognostic value market and then for PSMA by RECIP, and then when we combine those, we actually, we've seen a significantly higher prognostic value for PSA plus PSMA by RECIP. This just suggested that we might be able to use in the future the PSA plus PSMA PET or 12 weeks after treatment initiation as a composite endpoint to assess drug efficacy. If that's the case, this might reduce the number of patients that we require to enroll in a trial to show drug efficacy.

Phillip Koo: I think that's great. It makes a lot of sense to be able to combine the multiple pieces of information biomarkers into a composite tool, as you mentioned, and I think that's probably where there's a lot of power. Very exciting. I encourage all the viewers to go and read this article, published in the Journal of Nuclear Medicine. We'll try to have a link on the site. Very much appreciate the time and look forward to seeing more work showing PSMA as that type of biomarker response to therapy tools. Thank you, guys.

Andrei Gafita: Thank you very much for your interest. Thanks.

Wolfgang Fendler: Thanks so much.