Early Initiation of Lu177 PSMA Radioligand Therapy Prolongs Survival in Metastatic PCa - Harshad Kulkarni

Where in this treatment regimen would you place lutetium-177-PSMA radioligand therapy? This was the question Harshad Kulkarni, MD posed to the audience at the start of his presentation. The aim of the study which he was presenting during this Society of Nuclear Medicine and Molecular Imaging presentation was to determine the influence of timing of lutetium PSMA radioligand therapy in metastatic prostate cancer. Patients enrolled in this study included patients with progressive disease, almost all the patients had an androgen deprivation therapy and just under one-half of the patients had already undergone either first or second-line chemotherapy.

Biography:

Harshad Kulkarni, MD, Theronostics Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Germany


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Harshad Kulkarni: Thank you for the kind introduction, ladies and gentlemen. So I must admit this is the most favorite slide of the speakers today but the question which I want to pose before the audience here is where in this treatment regimen would you place lutetium-177-PSMA radioligand therapy? So the aim of our study was to determine the influence of timing of lutetium PSMA radioligand therapy in metastatic prostate cancer. Until June 2018 we have treated 274 patients using 824 cycles and with a mean administered activity of 6.7 gigabecquerels and applying up to 11 cycles per patient. So mean age was 71, mean Gleason score was eight, all patients had progressive disease and as you can see that all the patients, almost all the patients had an androgen deprivation therapy and also if you see under chemotherapy just under one-half of the patients had already undergone either first or second-line chemotherapy.

This was the best PSA response. Any PSA decline was observed in 71% of the patients, the best was a biochemical complete remission with undetectable PSA and a decrease in PSA by more than 50% was observed in 55% of the patients. Of course, we also did the follow up using gallium-68 PSMA PET/CT where we measured the percentage change in the SUVmax of the target lesion according to the EORTC criteria, and this was our waterfall plot. So the best molecular therapy response was complete remission and/or a mean followup of 19 months and up to 61 months, we have 35% partial remissions, six complete remissions, about one fourth stable disease, and about one-third patients with progressive disease. We also did the response assessment according to RECIST 1.1 and for followup up to 61 months, we found a partial remission in about one-fourth of the patients, all the six patients showing PSMA PET/CT complete remission. Also the demonstrated complete remission on a morphological imaging.
 We had stable disease in 42% of the patients and 32% of the patients progressed.

So these were the progression-free survival and the overall survival. So the median radiographic progression-free survival in these patients was 9.8 months and the overall survival was a median 30.9 months. Now here's an example of a patient with lymph node and osseous metastatic castration-resistant and chemotherapy-naïve prostate cancer was had androgen deprivation therapy and was 62 years old. PSA at the start of the treatment was 356 and after PSMA radioligand therapy, three cycles here, a complete remission of disease. Now the question you would ask is how is this complete remission also sustainable? So we do longterm followup and even after one year we found that he had a persisting complete remission and of course PSA also was in June 2018 undetectable. He's going to come for a restaging to us next week.

So we see 17 months after the first cycle of radioligand therapy and 28 months after the first cycle of PRLT, according to PSA, we see a complete remission of disease. Now this was his PSA response, 356 at the onset, you can see a progressive decrease in the PSA after the three cycles and which is enduring response even after two years. So what we did was we divided the patient cohort into two. One had chemotherapy either first or second-line and another almost 50/50 who has not had chemotherapy and, and what we observed was that the median overall survival in patients without previous chemotherapy was 38 months, which is clinic, which is highly significantly different from those who had had previous chemotherapy. So the chemotherapy-naïve patients live significantly longer, almost double as compared to patients who had received previous chemotherapy.

So here's an example of a patient with an almost diffuse super scan with a PSA of 1799 nanogram per milliliter and you see a very good response to treatment. Another patient with Gleason nine mCRPC who had undergone 19 cycles of docetaxel as well as one cycle of cabazitaxel which eventually had to be stopped because of intolerance, had a progressive disease under lutetium-PSMA. Of course, this patient then underwent actinium therapy and responded well to treatment. So what we also did was we measured the survival in patients who have not had any treatment before and when I say any treatment before, according to the first slide, the famous slide, so all the patients get some sort of a local therapy, radiotherapy or a surgery but then the patients do develop a biochemical recurrence after a few years and then they started with the anti-hormonal treatment.

Now in this cohort of patients, 11 patients, they categorically refused hormone therapy for various reasons and we offered these patients PRLT as a first-line treatment for biochemical records and what we saw was extremely good results or immediate followup of 21.7 months, only one patient died. The median overall survival was not reached at 61 months. The median PFS based on EORTC as well RECIST was extremely good, 30.9 months. All of the 11 patients responded extremely well, had a PSA response and decline in PSA by more than 50% was seen in 82% of the patient, and the median PSA-PFS was 20 months. So First-line PRLT was associated with the longest overall survival.

So here is a patient, he was a dentist from California with a Gleason eight metastatic prostate cancer. In fact, he also would not get himself operated. So he had a local disease, of course, as well as lepto metastases and you can see a progressive response in both the primary tumor as well as the metastasis. We can see the primary tumor as well as the metastasis responding according to RECIST as well as EORTC After three cycles of PRLT.

We also measured the influence of concomitant androgen deprivation therapy using either abiraterone or enzalutamide. The second-line hormonal treatment and what we found was almost again 50/50 distribution that the median overall survival in combination with new ADT was 40 months, which is significantly longer than patients who had not received any previous abiraterone or enzalutamide. One of the hypotheses could be the fact that treatment with antiandrogen agents abiraterone or enzalutamide probably had a synergistic effect in combination with PRLT. Now we know that enzalutamide which is an androgen receptor antagonists also increases or upregulates the PSMA expression but this has to be investigated for them.

So this was a patient with a Gleason nine prostate cancer, [7:51 inaudible], ADT and docetaxel. So he had actually a partial response after three cycles of lutetium-PSMA RLT. And as our friend earlier presented, so we did what she calls as a rechallenge therapy, which is a progressive, here a progressive disease after progression interval of 13 months after PRLT and then we did a rechallenge PRLT. So the second phase is what we call addition to enzalutamide and he again showed a good response to therapy.

So again, back to the slide. Again, try to answer the question as Mike also said for actinium, but I would put lutetium-PSMA perhaps should we use it when the disease is still castration sensitive? It's an open question but could be very well debated and on the principle of theranostics, which says if you see it, you treat it. So if you see it, why not treat it so we can also start lutetium-PSMA treatment. It's probably more effective when you start very early in the course of the disease but it should at least be started before chemotherapy.

So to conclude, I would say that early initiation of lutetium-PSMA radioligand therapy is effective in metastatic prostate cancer, offering a significant survival benefit. First-line or de novo PRLT was associated with the longest overall and progression-free survival. Previous chemotherapy, first or second line, was associated with a worse prognosis and additional treatment with newer antiandrogen agents, abiraterone or enzalutamide, probably has a synergistic effect in combination with PRLT. And last but not the least, we need randomized controlled trials to best determine the place of this agent in the management of mPC, for example, at least before chemotherapy. Thank you very much.

Speaker 1: Very interesting talk. I actually have a question in the hormone-sensitive space. Quite often we don't see such intense disease as we do in the castrate-resistant space just because of the upregulation of the receptor with more prolonged disease. Did you have a cutoff of SUVmax or did you have an intensity cutoff that you use for those patients in the early phase?

Harshad Kulkarni: We had actually a visual cutoff, so a significant PSMA expression. There is no typical SUV cutoff so to say, but then we have already based on the experience, let's say around 15-20 it is still quite significant.

Speaker 1: It is a quite intense disease in the early phases as well. Okay. Other questions?

Speaker 3: Yeah, we heard a couple of days ago in the castration-resistant setting that enzalutamide and abiraterone may upregulate the PSMA expression. Do you think that may be accounting for the synergistic that you're seeing here? So was there anything done to ascertain maybe PSMA levels in before and after, and try to correlate that with an upregulation cause I think this is just fascinating.

Harshad Kulkarni: I mean we know that there are a lot of preclinical studies which have really demonstrated the interaction between the androgen receptor two signalings, androgen receptor signaling and the PSMA expression this is a proof of principle in humans. So probably we need more trials, multicenter trials in combination and without to really...

Speaker 3: And it would really argue maybe for staging in of maybe...

Harshad Kulkarni: Exactly.

Speaker 3: Upregulation and then coming back with ... Great work, thank you.

Speaker 1: Thank you very much.

Harshad Kulkarni: Thank you.