PSMA PET Academy PSMA PET Imaging: At Least One Line of Novel Antiandrogen, and One Line of Chemotherapy - Ken Herrmann & Johannes Czernin

March 17, 2023

In this educational initiative, focusing on the knowledge of PSMA PET imaging and PSMA theranostics, Drs Ken Herrmann and Johannes Czernin discuss a case of a 61 year old patient diagnosed with prostate cancer in 2010. An initial TNM classification was cT2, cN1, M1c and lymphadenectomy and prostatectomy were performed. The patient resurfaced to the urologist in February 2019 when there was a PSA increase. There were multiple lung lymph node and bone metastasis and the patient was started on ARDT first line after six months and then continued a PSA increase, it was switched to second line ARDT. The patient perfectly meets the VISION trial criteria for inclusion into our standard treatment. Drs Herrmann, Czernin, Gillessen, and Fanti review this patient case and provide insight into the management of this case.

Independent Medical Education Initiative Supported by Novartis/Adacap and Point Biopharma


Ken Herrmann, MD, MBA, Professor and Chair of the Department of Nuclear Medicine, Universitatsklinikum Essen, Essen, Germany

Johannes Czernin, MD, Nuclear Medicine Physician, Chief of the Ahmanson Translational Imaging Division, UCLA, Ronald Reagan UCLA Medical Center, Santa Monica, CA

Read the Full Video Transcript

Ken Herrmann: Hello, my name is Ken Herrmann. I'm a nuclear medicine physician from Essen, Germany. It's my great pleasure to introduce you to my co-host today, Professor Johannes Czernin.

Johannes Czernin: My name is Johannes Czernin, I'm working at UCLA, I'm also a nuclear medicine physician, and it's a pleasure to do this together with Ken Herrmann.

Ken Herrmann: Johannes and me, together with Silke Gillessen and Stefano Fanti created the PSMA-PET Academy a couple of months, almost years ago, with a goal to introduce the majority of people first to pacemaker imaging, but also to discuss about potential applications of radioligand therapy. In addition to the initial set of videos of introductory classes, we have a total of five cases. And this is actually case number five and I have to admit that in contrast to all our other friends who present cases, we are going to present more question and answers. And Johannes, how our good friend Shakespeare said, "To die or not to die," we have modified the topic and you can quickly read through the title if you want to.

Johannes Czernin: Yeah, so to stop or not to stop that is the question here. So Ken, why don't you take the patient history slide first and guide us through this case.

Ken Herrmann: Obviously it's a very fictional case. It's a patient who was actually treated in Europe. The patient was born in 1949, had the private diagnosis of prostate cancer in 2010, so he was 61 years old. Back then the initial TNM classification was cT2, cN1, M1c. And because of the lymphadenectomy and prostatectomy were performed in addition to this, the patient has also it because of the metastasis had adjuvant radiation. The patient started ADT then as you can see there was a long gap in between and indeed the patient resurfaced to the urologist in February, 2019 when there was a PSA increase. There were multiple lung lymph node and bone metastasis and the patient was started on ARDT first line after six months and then continued a PSA increase, it was switched to second line ARDT.

Also the patient did not show any response to it. So then finally in October 2019 the patient was started on chemotherapy at the end of it, six cycles of docetaxel. Roughly 10 months after the patient still progressed and the patient was switched down to cabazitaxel. So second line chemotherapy, he had also additional external beam radiation to T12 and L2 because of bone mets and pain there. And unfortunately, the patient had asked to stop the intake of cabazitaxel due to toxicity. And this is pretty much when the patient presented to the medicine department.

And in summary, we have a patient who had a total of four lines of therapy, two lines of ARDT and two lines of chemotherapy. So Johannes, is this a patient who you would consider to treat with PSMA related therapy?

Johannes Czernin: Yes, the patient actually perfectly meets the VISION trial criteria for inclusion into our standard treatment and that would also be covered by all the insurances Now in the United States. There's of course a question whether one could have treated already before cabazitaxel treatment that would also qualify, that would be eligible for lutetium PSMA treatment in the US and specifically given the tear up as they call it, data that came out that showed superiority for lutetium PSMA over cabazitaxel treatment. So that would've been an option to go in earlier whereby the outcome data are not really known whether that is just providing a progression-free survival benefit or an overall survival benefit.

Ken Herrmann: You make very good points because technically this patient was obviously treated in times of when PSMA 617 was not yet approved for therapy. Obviously, the VISION label would be included, it could be fulfilled in this case because he had at least one line of novel antiandrogen, he had one line of chemotherapy.

Technically, when we look about PSMA-4, study currently enrolling, we could even consider if PSMA-4 is positive to actually treat the patient or in August, 2019. But this is something we want to discuss in the future, but I fully agree the patient was very well suitable. We performed the PSMA PET scan, which I'm not going to show, but the patient met the inclusion criteria and we are going to move on.

The patient had the PSMA PET progressive disease, the PSA was 260 nanogram per milliliter and as we discussed, the patient met the inclusion criteria in this case for the VISION dose between sub-study and he received a total of six cycles of PSMA radioligand therapy with a cumulative activity of almost 42 GBq lutetium 617. And here are the corresponding body scans post the first cycle of lutetium 617 after the third cycle and after the six cycle, and also the corresponding PSA values.

And what we can see very nicely is that already after one cycle, the PSA went down from 260 to 49, then after the third cycle it was down at 0.1 nanogram per milliliter. And that was actually after the fifth cycle with 0.08 nanogram per milliliter. And then at time of the sixth cycle it actually increased a little bit again to 0.45 nanogram per milliliter. Now this being said, the patient was on a study protocol. We know that the maximum of cycles were six cycles, but overall we want to discuss this a little bit outside of the study protocol. Johannes, what do you think? What is next in this patient? Would you continue the treatment if you would be allowed to or would you stop the treatment or how do you judge this case?

Johannes Czernin: So I do believe that there is already progression of disease between cycle five and cycle six. And that would suggest to me that continuing with lutetium PSMA is probably not very helpful. There's of course the alternative not available clinically in the US going with Actinium PSMA and switch over to alpha therapy, targeted alpha therapy. And then of course what also has not been done in this case yet is initiate some combination treatment between the alpha treatment and some pharmacological approach. But there's no question that this patient is now progressing between cycle five and cycle six.

Ken Herrmann: You raised a couple of very important topics and I agree absolutely with the assessment that the increase of PSA in this case despite we don't really see any uptake, relevant uptake, in the whole body scan is probably already a sign of progression. Also, the couple of topics that you mentioned: combination treatment or for example in this case the patient didn't undergo BRCA mutation testing, didn't undergo PARP inhibitor treatment. Obviously some things with the recent modification actually the patient could actually be also a candidate for the combination of an ARDT plus a PARP inhibitor. But I would like to translate the discussion in a more, let's say [inaudible 00:07:32] level.

And one big question is of course if patients respond very, very well to therapy, for example patients may we really see that the PSA is already below 0.1 after two cycles and you don't see any remaining uptake in the post therapy spec. Is this a patient Johannes, where you think it makes sense to stop the treatment because we don't have a correlate anymore, a drug holiday? What is your opinion there?

Johannes Czernin: Well, I think that there are no prospective studies telling us whether this is a successful strategy to do the drug holiday. At least I haven't seen the data. From a kind of cancer biology point of view, I would be concerned about the drug holiday because there's obviously, even if the PSA is less than 0.1 nanogram per milliliter, there's still disease. And also assuming that this patient underwent multiple lines of treatment already, the residual disease may be the most aggressive clones in this case, micro-metastasis. So I would think that you should not change a winning team after two cycles and you should continue treatment and get as much radiation into the patient as targeted radiation into the patient as possible. But that of course needs to be shown at one point in a prospective trial whether the drug quality makes sense or not.

Ken Herrmann: I fully agree and I just want to very quickly mention that Louise Emmett from Sydney is doing great work on this and trying to see how, and especially in the patients who have this kind of exceptional response, you might delay the additional treatment. But you're absolutely right, this has to be shown perspectively also in a randomized fashion to understand what is the cost of the drug holiday to the patient.

Then another question is obviously when we perform the six cycles and you have very good PSA responders, let's say for example after six cycles, the PSA is less than 0.1 and you have the option, and I know it's not in the label, but technically you might have the option to in clinical trials. Would this be a patient where you would continue treatment or as a patient where you would wait until the PSA relapses and perform a re-PSMA treatment?

Johannes Czernin: Well, I would probably monitor the PSA very frequently and wait 'til I have the initial rise again and then I would try to switch to a... We could try actually lutetium in the beginning and see whether you get a second response. And then, if that doesn't work would switch over to alpha treatment again, which is available maybe in clinical trials in the US but not as for clinical practice.

Ken Herrmann: And overall the idea of continuous PSMA related therapy, for example, patient who have shown continuous decrease after every cycle, but still has a PSA of greater than one. For example, let's say 2.5. After six cycles, what if one patient say it makes sense to continue with cycle seven or eight. Or you also think there's something where we should consider actually switching to alpha?

Johannes Czernin: Now in this case, if they, as you mentioned, continue to decrease their serum PSA level, then I think it would make sense to continue. Which again, we can't unfortunately, or I don't know what the regulatory pathway to that would be to get an exception, but I think that would make sense to continue the treatment because it's still affected with continuing decreasing serum PSA levels.

Ken Herrmann: I'm in a very comfortable position because as we both agree there is no data. I can ask the questions and I know that it's very difficult for you because there are also no real answers. But I think what we want to point out is that there's, despite the success and the very promising data, there's still many, many unanswered questions which we need to raise. And another of these unanswered questions actually, what do we do with patients who don't show any PSA response? When do we stop? After how many cycles would you stop? So there's data which has shown that some of the patients, I think 10% to 50% of the patients, show a significant PSA decrease after the second cycle if they didn't show any significant decrease after the first cycle. But what would be the status where you would decide that it doesn't make sense to continue the four or even six cycles of PSMA radioligand therapy, that we should switch?

Johannes Czernin: So we have of course tumor boards and discussion with oncology colleagues and urology colleagues. We tend to stop after the second cycle if PSA is increasing. But we also consider the patient symptoms. There are patients who are clearly symptomatically improved and is this currently probably the last line of treatment in many patients. You don't want to deprive the patient of the opportunity to have a benefit in terms of quality of life. And we actually had such cases and then we continued treating. And I think in this one patient I have in mind, we continued 'til after the cycle number four when the patient started really deteriorating.

So there's no real absolute time to stop. In general, we explain to the patient the chances for a delayed response after two cycles are fairly low. But we also have seen PSA responses occasionally after the third cycle. So then we would look at the degree of increase. If there's a dramatic increase in PSA of the likelihood is that there's a subsequent favorable is very small, but if there's a subtle increase then probably the likelihood will continue to a third cycle would be greater.

Ken Herrmann: I fully agree it's the same we do. The clinical response is very important. If a patient shows no clinical response and an increase of PSA, we stop after two cycles, same as you. But I also agree with what you said in case that the patient clearly benefits symptom-wise and there is no real other option. We would also on a case by case basis, actually discuss in add additional cycles. I fully agree.

Now coming back to our patient, as you remember, he had treatment 'til mid of 2021. The PSA back then was 0.5 and unfortunately the patient yeah, was presenting again to our department because of a constant increase of the PSA. Since then, we reevaluated him for PSMA radioligand therapy as there were no other options. Remember that he already had those two lines of normal antiandrogen, two lines of chemotherapy.

We performed another four cycles of PSMA radioligand therapy. And again, we are completely honest, that's why we show you also the change of the PSA values. And you can see after one cycle, we indeed saw a drop again of the PSA. And then unfortunately after cycle number three and cycle four, no additional response in PSA values. And this was also the reason why we obviously then after four additional cycles of therapy stopped treatment. And this is pretty much in line with what we kind of suspected initially that already between the fifth and the sixth cycle, PSA was increasing and this was probably already a sign of progression and not responding to PSMA therapy anymore. Now what are the take home messages? I think you can very, very convincingly state the first point.

Johannes Czernin: I want to just add a comment on the prior case. I think it illustrates the fact that you gain, let's say eight month, ten month in the responders and in overall survival, but you are far away from cured. And that leads to the take home messages. There are plenty of prospective clinical trials still needed. The one is optimizing dose schedule, injected activity, cocktail approaches between alpha and beta, combination treatments. That is radioligand therapy combined with pharmacological approaches and the optimal sequencing. We are completely empirical still, we say every six weeks or every four weeks or every eight weeks, but it's completely arbitrary. That has not been optimized and all of this needs prospective clinical trials.

Ken Herrmann: And as you can see, we have many more question and answers. And as we already introduced before, this is our cliffhanger. Stay tuned for season two. I'm very grateful for everyone participating, for everyone watching but that my biggest thanks go actually to the team of UroToday. But of course also my co-chairs, Stefano Fanti, Johannes Czernin, of course, the wonderful Silke Gillessen. Thank you very much. And don't forget, Theranostics remains a field of growth. Thank you.

Johannes Czernin: Thank you.