GU Cancers 2021 | Targeting PSMA in mCRPC

I think that there are a couple of topics of interest that we’ve combined into a couple of clinical trials. So, one therapeutic target of interest is PSMA or prostate-specific membrane antigen. And we’ve had a long history of using an antibody against PSMA called J591. Another topic of interest are prognostic and potentially predictive biomarkers. So, one biomarker that is best associated with prognosis of overall survival is circulating tumor cell count. There are several different methods, but CellSearch has been used the most. So, at elevated counts prior to treatment is associated with the worst prognosis. However, a conversion either from an unfavorable to favorable or detectable to undetectable at 12 weeks, has also been associated with overall survival, and that’s potentially in the future, it could be a registration endpoint.

So we have a couple of clinical trials that we have looking at, that we have embedded pre-treatment and post-treatment CTC count in a number of our different prospective clinical trials. And one analysis was presented at the Genitourinary Symposium in 2021, which included 116 men that had baseline count, 90 of whom had both pre and post-treatment count. And of those 70 had available detectable baseline CTC counts with a post-treatment CTC count. These were men that were treated mostly, about 80%, a little less than 80%, with PSMA-targeted lutetium. So that was about half of those were with antibody J591, and about half of those were with a small molecule lutetium-PSMA-617, and about one in five were treated with actinium J591. And what we did is, just in a combined analysis of those 70, 70% of those 70 had a CTC count decline from baseline to post-treatment. About a third converted from detectable to undetectable, and about a third converted from unfavorable to favorable. And the abstract and the poster, we’ll break it down with the different treatments, but the numbers are small enough. I think it’s reasonable to combine those.

So what I would say in kind of, in total, it does look like this type of a therapy, i.e. PSMA-targeted radionuclide therapy, in addition to the PSA decline, and it was at this meeting that the TheraP study was presented with a PFS improvement in selected patients over cabazitaxel. In addition, we can see CTC counts decline. Because of that and because of retrospective observation that a handful of patients, it was actually four out of seven, were having a radiolabeled J591 for imaging. So just indium-111 or zirconium-89 that happened to have a CTC count before and after the imaging had some decline. So we said, well, why don’t we look at that prospectively? So we launched a pilot study and that study was presented at the 2021 Genitourinary Cancer Symposium designed at the time in two stages at different doses.

So we initially started off with a high dose, which was the highest dose back in almost 20 years ago, with the first-in-human initial dose of J591, that cold antibody that was trace-labeled with indium, that was 300 milligrams. And then we had, we built in a lower dose, which is the most common dose that we use both for imaging, as well as the antibody mass when I say dose, of the radiolabeled version of the antibody. Six were treated with the high dose, three were treated with the low dose. All fairly aggressive cancer, so most had CALGB poor risk, and they all had elevated CTC counts to get in, so by definition, they had to have at least a CTC count of five to get in. And we saw some declines. So, three out of the nine had CTC count declines. One went from 35 to 12, another one from 216 to 112, but only one hit the bar that we had pre-specified, which was either going from unfavorable to favorable or detectable to undetectable. So, one patient did both, which was from 9 to 0. So, based on the pre-specified endpoints and the study design and assignment 2 stage, we did not see enough efficacy to go on to assignment stage 2. So, the study was closed after those nine evaluable patients.

So, my conclusion would be that there seems to be some activity of single-agent unlabeled anti-PSMA antibody J591, but I don’t think that the unlabeled version alone is enough to control disease, maybe more in a maintenance fashion or labeled with something else like a radionuclide or a drug. We have moved on from beta-radiolabeled J591 into alpha-radiolabeled J591, and last year at several meetings, we presented the dose escalation results of actinium-225 radiolabeled J591, basically going up to the highest dose did not lead to a DLT.

So, that study has been completed and hopefully we’ll report that at another meeting with the expansion cohort, but what we did with that single dose of radiolabeled J591, or actinium radiolabeled J591, is to launch a new study. And this study was presented in terms of a trial and progress poster that we nicknamed for actinium, it’s actinium J591, that is given in two different cohorts, either a fractionated dose score, where the entire regimen is done in a single cycle that’s fractionated. So half is given on one day and half is given two weeks later. And then there’s what we call the multiple dose cohorts, where it’s more kind of traditional, where a moderate dose is given every six weeks up to four cycles with that. So, that’s a clinical trial that started last August and continues to enroll. That trial like others, includes pre-treatments, PSMA PETs, the results of that PET don’t matter in terms of eligibility, but we’re using as a biomarker. And we also have embedded circulating tumor cell counts and other biomarkers that include genomics, immune effects etc., and that’s a study that continues to enrol.