GU Cancers 2021 | 177Lu-PSMA-617 for prostate cancer: TheraP, VISION, UpFrontPSMA and LuTectomy

So of course, with this huge growth in interest in PSMA PET-CT for imaging prostate cancer, this has opened up a whole other opportunity for prostate cancer research and that’s in the field of theranostics. Theranostics is a well-established field in nuclear medicine where, for example neuroendocrine tumors, thyroid cancers, have been managed by nuclear medicine physicians using radioligand therapy.

In prostate cancer, what we can now do is take the images that we see on a PET-CT, the overexpression of the PSMA molecule in advanced prostate cancer, and instead of just imaging that cancer, we can bind a smaller radioactive agent to the ligand. So instead of just showing us the cancer, we can bring a small therapeutic molecule such as lutetium-177, a beta imager, towards the prostate cancer. So, that’s the field of theranostics. It’s a very imaging-directed therapy.

Really what we’ve seen in the past couple of years is some really exciting developments in PSMA theranostics. Like we often see in prostate cancer, this therapy has been evaluated in very end-stage prostate cancer and metastatic CRPC patients who have exhausted all previous lines of therapy. We published the first prospective data on that back in 2018 in Lancet Oncology, where we showed that this therapy is very well tolerated. We saw some really very encouraging results in some of these patients with really very limited options. And like we’ve seen with other therapy areas in prostate cancer, like androgen receptor therapies, et cetera, we bring it forward to earlier stages of cancer.

What we’re seeing here at the ASCO GU meeting in 2021 is the readout of the TheraP trial presented by my colleague from Peter MacCallum Cancer Centre, Professor Michael Hoffman. The TheraP trial is the first randomized trial of lutetium-PSMA theranostics compared with cabazitaxel for metastatic CRPC. It’s really quite exciting news to see how the benefits of lutetium-PSMA, as Professor Hoffman reported here and also published in the Lancet this week.

What we see in summary is that the primary endpoint of PSA response is much better in those patients undergoing lutetium-PSMA therapy compared to cabazitaxel, and also other events such as radiographic and clinical progression-free survival are all in favor of lutetium therapy when compared with a high standard of care such as cabazitaxel. Furthermore, the therapy is very well tolerated compared to chemo, and therefore we’re seeing a whole lot of compelling reasons why this therapy should be supported for this group of men. Of course, this data presented this week from the TheraP study is not determined to show whether the overall survival is also improved. That will take a little bit longer to read out.

There is another pivotal Phase III study running, the VISION study, which is evaluating these other endpoints and we expect that to read out later this year. So, the sum of all that is we now see a radioligand therapy using lutetium-PSMA coming forward in the paradigm, and now randomized evidence supporting the role of lutetium-PSMA. The obvious sequelae from that is to say, “Okay, well that looks encouraging, can we take it further again and further again earlier in the paradigm.”

One of the other trials-in-progress posters that we have at this meeting is for the upfront PSMA study, another prospective randomized study here in Australia. And this is for men with metastatic hormone-sensitive prostate cancer, where we’re comparing men receiving standard of care ADT plus docetaxel compared with ADT docetaxel and lutetium-PSMA therapy. So that will be interesting, it’s a trial-in-progress progress to see whether the addition of lutetium will actually help this group of patients.

Then finally in this space, we’re also presenting another trial-in-progress called the LuTectomy trial. This is taking lutetium-PSMA far forward again, in fact, right into the non-metastatic high-risk prostate cancer space. This is called the LuTectomy trial and it’s based on the ongoing research question we have in prostate cancer based around the high biochemical failure rates for men with high-risk, apparently localized prostate cancer, undergoing surgery or radiotherapy. We know that 40 to 50% of these men will have biochemical failure within two or three years of having a potentially curative local treatment.

Why is that? We think it’s because these men probably are micro-metastatic at the start, or they have very high-grade features, meaning that their disease course is unfavorable. The traditional neoadjuvant studies that we’ve seen come and go over the past 20 years have failed to really impact on these patients. For example, neoadjuvant androgen deprivation therapy combined with AR targeted therapies, or even chemotherapy has not really impacted in a clinically meaningful way on outcomes for patients, but it still remains an important unmet need.

So we have now taken lutetium into this space. What we’re doing in the LuTectomy trial, which we opened six months ago here in Melbourne, is we’re offering patients with high-risk prostate cancer, scheduled to have surgery, the opportunity to have one or two cycles of lutetium-PSMA six weeks before surgery. The primary endpoint is dosimetry because we’re very interested in seeing how much dose of radiation we can get into these target organs. Of course, the secondary endpoints are safety and pathological response, imaging response, biochemical response, and so on. It’s a small Phase I/II study of just 20 men, which is well underway. We’ve recruited six patients already, but we anticipate, or we’re optimistic that if we show that we have good dosimetry and good safety and other factors that we’ll be able to take the LuTectomy principle, the idea of neoadjuvant lutetium into a larger and probably randomized trial.

I think that’s a summary of really a very exciting area in prostate cancer, which is radioligand therapy. Certainly this year, already at this meeting, we are seeing some very interesting concepts and finally seeing some randomized data showing that lutetium-PSMA really has utility and probably will be evaluated in earlier and earlier stages of prostate cancer.