Modulation of PSMA Expression by Androgen Deprivation Therapy (ADT) - Louise Emmett

March 10, 2020

Louise Emmett presents on the modulation of prostate-specific membrane antigen (PSMA) expression by androgen deprivation therapy (ADT). The study is comprised of serial PSMA PET in men with either hormone-sensitive or castrate-resistant prostate cancer commencing androgen blockade. PSMA may be targeted for either diagnostic and therapeutic purposes in the management of prostate cancer. Dr. Emmett and colleagues aimed to evaluate the effect of ADT on 68Ga-PSMA-11 PET imaging in hormone-naive (luteinizing hormone-releasing hormone [LHRH] ± bicalutamide) and in castrate-resistant men (enzalutamide or abiraterone) with metastatic prostate cancer. This presentation was during the Society of Nuclear Medicine and Molecular Imaging (SNMMI) annual conference.


Louise Emmett, MD, MBChB, FRACP, Associate Professor, Department of Nuclear Medicine, University of New South Wales, St Vincent's Sydney,  Australia 

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Louise Emmett: Hi, I'm going to talk about modulation of PSMA expression by androgen deprivation therapy. So we did serial PSMA PET in men with hormone-sensitive and castrate-resistant prostate cancer who were commencing androgen blockade.

So the influence of androgen deprivation therapy on PSMA receptive density is well known in preclinical work. The FOLH1 gene encodes PSMA in messenger RNA, and FOLH1 is actually upregulated by androgen blockers and down-regulated by testosterone.

Preclinical work has shown that you get up-regulation in both androgen-sensitive and androgen resistant cell lines. In fact, in androgen independency for two cell lines in which enzalutamide has no measurable antiproliferative effect. If you incubate those cells with enzalutamide, PSMA expression increases very significantly over the 21 days and then returns back to baseline in one week after enzalutamide has been removed by very nice study by Murga, et al.

Raises lots of very interesting clinical questions, certainly for me. What's the practical significance of PSMA receptor up-regulation in response to ADT? Does it happen in everyone? In all men or only in some men? How long does it actually take to up-regulate? Does it up-regulate in all Gleason types? And at what stage of disease?

So the aim of this study was to quantify changes in PSMA receptor density in vivo using serial PSMA PET in men commencing androgen blockade both in the cohort of hormone sensitivity and in castrate-resistant prostate cancer. So we did serial PSMA 11 PET/CT at baseline day nine, day 18, and day 28 in two cohorts of men. In eight men with metastatic hormone-sensitive prostate cancer who were commencing ADT, and in cohort two, six men with metastatic castrate-resistant prostate cancer who were commencing either enzalutamide or abiraterone.

We did both testosterone and PSA at all imaging time points, Galleon PSMA 11 PET was acquired with identical parameters at each time point. And we use MIM software for number of lesions, SUV max, total body SUV mean, total lesion PSMA, and total tumor volume.

So in the hormone-sensitive cohort, mean age was 71, PSA at diagnosis 78. The treatment in all cases was LHRH, a Gleason score medium was eight, and testosterone 14. So from the curves, you can see there was a very dramatic PSA response in all men to LHRH occurring progressively from day zero to day 28. When you look at the SUV max from day zero to day nine and day 28, just about all men had a reduction in SUV max at day nine with variable intensity following day nine.

So this patient is one of our median patients. At day zero, PSA was 14. Presented with all of their metastatic disease and the SUV max of 20 in the primary lesion, which was actually within the prostate. And this is one of the bone lesions that you can see here.

By day nine, the PSA dropped to 7.6, the SUV max or the primary lesion had gone down to 10, and this is the lesion that you can see within the bone had significantly reduced in intensity on the scans. Overall, there was a mean 25% decrease in SUV max in all patients by day nine.

This patient was from cohort one, so hormone-sensitive and presented with metastatic prostate cancer with a PSA of 185 and very significant bone pain at the time that he was scanned. SUV max was 45 at the baseline scan. By day nine, his pain symptoms had significantly reduced. He'd had a very marked reduction in his PSMA receptive density. PSA had gone down to 90, SUV max was 20. However, by day 28, what you can see as PSA is 11, and you can see there's significantly reduced volume of disease on his PSMA, but he's had coalescent an increase in intensity of the activity at certain sites. SUV max has gone up to 62, and this patient is progressing very early.

Hormone-sensitive disease. What we can say is there's been a reduction in both PSMA SUV max and mean in 87.5% of men by day nine. The subsequent rise in PSMA intensity at some sites of metastatic disease is seen at days 18 and 28 and there's a marked PSA response in all men with an increase in PSMA intensity at day 18 and 28, which appears unrelated to the PSA trajectory.

What did we find in the castrate-resistant group? So similarly we've had five patients who have completed imaging, seven enrolled. PSA was 117. Four men received enzalutamide, one abiraterone, and all men had suppressed testosterone. Quite different curves. So the PSA response, you see the PSA response is significantly blunted with enzalutamide compared to LHRH. And one patient actually had frank progression throughout the study.

And similarly with the SUV max, what we see is an increase in the SUV max by day nine in these patients. And if you just have a look at this orange curve down here, what we see on the left is the initial baseline scan, and the day nine scan on the right. So on the left, the PSA was 36 for the baseline scan. SUV max is 13. And you can see there were multiple sites of PSMA avidity within bone and also within lymph nodes. By day nine, there's been a significant increase in the number of lesions gone up from 18 to 36, increase in intensity at all involved lesions with an SUV max of 21.

So there was a mean 28% increase in SUV max by day nine in the castrate-resistant group. So all men demonstrated an increase in intensity of uptake compared to baseline though it was a variable. That increase in intensity occurred by day nine in all men, and the change in intensity appeared unrelated to the change in PSA.

When you look at that in tabular form, the PSA dropped very significantly by day nine in the hormone-sensitive group, a mild drop in the castrate-resistant. SUV max dropped very significantly in the hormone-sensitive, from 23 down to 15. Castrate resistant went up from 32 to 45, and there were changes that were not so ... They were a bit more variable between day nine and day 28.

So in conclusion, hormone-sensitive cohort, there's a 25% decrease in SUV max by day nine. I think this is very important for us to factor into our reporting of PSMA PET ligands. In the castrate-resistant cohort, a 28% increase in SUV max by day nine. Also need to factor this into reporting of our PSMA PET ligands, especially if we're assessing for treatment response in the presence of ADT. And also has important implications in PSMA targeted treatments.

So heterogeneity in lesion response suggests that PSMA PET may be able to identify phenotypes of early castrate resistance prior to PSA and could make a good predictive biomarker. Thank you.

Speaker 1: Thank you very much for that very interesting paper. It kind of sheds light and some details on what's going on in the interaction between PSMA and androgen deprivation therapy.

Any questions or comments from the audience? Please?

Speaker 3: I guess I just have one question is I'm a little bit surprised in the hormone-sensitive setting at day nine. Because you expect with an LHRH analog, you expect a surge and a rise in PSA, and it usually takes two weeks for that to actually kind of come down. So I'm a little bit surprised.

Louise Emmett: I was really surprised by the results. Because in fact, I thought I was going to get up-regulation, not downregulation. But in fact, no. So I suspect that in a small percentage of patients you might get a flare. We did not get a flare, but we've only imaged eight patients now. So percentage of flare is probably relatively low, and we didn't catch it.

Speaker 1: Dr. Weber?

Dr. Weber: Very interesting presentation. Congratulations on this. I've just one question. You kind of always mixed SUVs and PSMA expression. How confident are you that there are not other factors also happening like changes in perfusion of these metastases when there's apoptosis of those cells and these kinds of factors?

Louise Emmett: Well, I think it's very mixed. I mean, almost certainly the same thing is happening in the hormone-sensitive and the castrate-resistant group. It's just in the hormone-sensitive group, my feeling is that you've got an involution of those cells. Those cells are dying very, very rapidly.

So in fact, the fact that you don't get an increase in SUV max and you get a reduction in SUV max is almost certainly a composite of all of those things.

But I do think the thing that's really interesting, so you do get a reduction by day nine, I think we need to know that when we're reporting. But I don't think it's absolute that the PSMA density in every cell is going down. Not at all.

Dr. Weber: Okay. Thank you very much.
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