Read the Full Video Transcript

Louise Emmett: Well, hello. Hi again. So I'm going to talk about a similarly controversial subject, which is PSMA and androgen receptors in prostate cancer. And it's actually a really confusing subject. I don't think it's something that we've got a handle on yet, but it's something that I think will be very important in the future.

So the important thing about PSMA, it is not just a cell target. It actually has a role in the cell and it acts along the PI3K-Akt/mTOR pathway. And we know it has a really strong relationship within the cell between the androgen receptor and the PSMA receptor. And that varies depending on whether you're in the hormone-sensitive or castrate-resistant space.

So there was this really nice review that came up quite a long time ago now by Martin Bakht that really highlighted this super interesting relationship between the two receptors and how it could possibly be used in the future.

And then that was followed up by some really nice mouse work and this case report by Tom Hope, also some time ago now, showing that you get this upregulation of the PSMA receptor when you place a patient on hormone therapy. This was a patient with a Gleason score of 10 disease, metastatic hormone-sensitive prostate cancer who had a PSA response to the treatment within a month. But this dramatic upregulation of the PSMA receptor was super exciting for me in terms of what the possibilities were in terms of improving the sensitivity of the scan and possibly also improving the capability of treatment to get deeper responses if you combine the two.

So we did a fairly weird study where we had 15 patients, eight in the metastatic hormone-sensitive space, seven in the metastatic castrate-resistant space. And we essentially did weekly PSMA PETs on these patients to see what the receptor was actually doing and used total body quantitative analysis.

Not going to go into detail on that, but in essence, in the metastatic hormone-sensitive space, to our surprise, we actually saw a reduction in the intensity of the metastatic sites in response to commencing on ADT. That's actually about two or three papers now that have confirmed about 80% of patients will have a reduction in intensity on PSMA PET in the hormone-sensitive space. And about 20% of patients will actually see some stability or increase in expression.

And then in the metastatic castrate-resistant space, in our small study, we actually saw that all patients had an increase in PSMA expression just like had previously been seen in cell lines and mice. Now, further work has shown that that doesn't happen in all patients in the metastatic castrate-resistant space, but we do have other data. So this really nice paper, 16 patients by Steven Rowe and Katherine Zukotynski, where they did two time-point PETs on patients with metastatic castrate-resistant prostate cancer starting on abiraterone or enzalutamide, and then they measured the upregulation of the PSMA receptor on total body imaging and compared that to the time to change in therapy and to overall survival. What they found is if you have an upregulation of the PSMA receptor, you actually have a shorter time to change in therapy and a shorter overall survival. It's really interesting. If you upregulate your PSMA receptor on an androgen receptor, that's a bad thing.

So the hypothesis really at this stage is that if you upregulate the PSMA receptor in response to an androgen receptor, it's probably identifying phenotypes of androgen resistance. It could be a marker of androgen resistance and that's a very early hypothesis and certainly something that we need to test. But it's definitely the basis by which we started the ENZA-P trial.
So the ENZA-P trial is a study that was run in 15 centers around Australia. It was sponsored by the ANZUP Cancer Trials Group. It was Enzalutamide versus Enzalutamide plus Lutetium PSMA in men with poor-risk metastatic castrate-resistant prostate cancer. And it was a randomized phase two trial. The concept of ENZA-P is the idea of giving adjuvant Lutetium PSMA as a secondary treatment, not as a primary treatment, with the primary treatment really being the hormone itself.

And we know that both Enzalutamide and Lutetium PSMA improve overall survival in metastatic castrate-resistant prostate cancer. But when we look at the PREVAIL trial, in mCRPC pre-chemotherapy, there's a significant proportion of patients who fail Enzalutamide early with either primary resistance or early treatment progression.

So, using this data we had pre-clinically, this idea of upregulation, the question was, can we use that to improve patient responses? So within the ENZA-P trial, the rationale is that we know we have a polyclonal population in mCRPC, particularly men who have poor-risk features for early treatment on Enzalutamide. We will have cells that have low PSMA expression and high PSMA expression. If we add Enzalutamide, then those cells that have alternative activated growth pathways, such as the PI3K Akt/mTOR pathway, will increase PSMA expression.

Lutetium PSMA needs very bright disease in order to get the best cell response. So if we add Lutetium to the Enzalutamide, knock off those androgen-resistant clones preferentially, we'll be left with a population of cells that are more likely to respond longer to the Enzalutamide itself.

So the ENZA-P schema is randomized 1 to 1, Enzalutamide versus Enzalutamide plus either two or four doses of Lutetium PSMA in an adaptive dosed schedule. Eligibility was mCRPC with a PSA of greater than 5 nanograms per ml, no chemotherapy for mCRPC, two risk factors for early treatment failure, and a positive PSMA PET. The primary endpoint was PSA progression-free survival, with other progression-free survivals as key secondary endpoints, including pain response, health-related quality of life, and overall survival.

Looking at the screening criteria, it wasn't as strict as therapies. So, we used an SUV max of 15 at a single site, an SUV max of greater than 10 at all sites of measurable disease. It was quite difficult to work out what criteria we should use. We didn't want to be too strict because we knew we were using two active agents. And so, it wasn't totally dependent on the PSMA receptor itself. Possibly, we didn't even need a screening criterion. We didn't use CT or FDG in this screening criterion. And just to point out, this patient has an SUV mean of 4.5. So, we did enroll patients with not particularly bright disease. The patients had to have two risk factors for early treatment failure on Enzalutamide, and they're detailed here.

There was an adaptive dosing schedule. And the study is actually almost two trials in one. So, we were doing a translational project looking at serial imaging as well as serial CTCs and ctDNA along the way. So, all patients had a screening PSMA PET, and all patients had a repeat PSMA PET on both arms of the study 15 days after starting the Enzalutamide. It's going to be super interesting to analyze that data to see what actually happens on those scans. We did total body SPECT in the experimental arm, so dose one and two here, total body SPECT. And then at day 92, there was a centrally reviewed PSMA PET. If patients had no residual disease on the PSMA PET at day 92 in the experimental arm, they didn't go on and get any further Lutetium PSMA. They just remained on the Enzalutamide. This other patient, so screening PSMA PET, day 15 PSMA PET, two doses of Lutetium PSMA. On the day 92 scan, there's still residual disease. So, any residual disease above blood pool, the patients went on and got another two doses of Lutetium PSMA. And then, as part of the translational component, but not part of any decision-making in the trial, we did additional PSMA PET and FDG PET at the first PSA rise. Patients had CT and bone scan regularly as well.

So the primary endpoint was PSA-PFS, and we required 160 participants for 158 PSA PFS events for the trial. We had an additional two patients who were enrolled for dropout, and we did an interim analysis at 75% of the PSA PFS events. So in total, 117 patients in this interim analysis were included.

So, 220 patients screened for 162 patients randomized, 79 to Enzalutamide and 83 in the combined arm. In the combined arm, two patients actually dropped out without having received treatment. The screen failure rate was 18%. And at this interim analysis, there were 16 patients still on trial in the Enzalutamide alone arm and 32 patients still on trial in the combination arm. In the combination arm, 81% of patients received all four doses, and the median follow-up was 20 months.

Patients were very high risk. More than half the patients had greater than 20 PSMA-avid metastases. Over half the patients had chemotherapy for M1 disease, de novo metastatic disease at diagnosis. And over half the patients had early docetaxel and had de novo metastatic disease at diagnosis. A small proportion, 13% of patients, had had prior abiraterone.

So the primary endpoint was PSA PFS. And on the interim analysis, this was strongly positive with a hazard ratio of 0.43, and the progression-free survival was 7.8 months for Enzalutamide versus 13 months for Enzalutamide plus adaptive dose Lutetium PSMA. Radiographic progression-free survival had a hazard ratio of 0.67, with 12 months for Enzalutamide and 16 months for Enzalutamide plus Lutetium PSMA. We did have a problem with our PFS. So a lot of our investigators looked at the PSMA PET at first progression, and a number of patients got taken off trial without confirmation of progression, radiographic progression with CT and bone scan. They just stopped doing them. And so you can see here that patients on the combined arm are those patients who are still on trial, while about half the patients who are censored on the Enzalutamide alone arm have actually come off trial without confirmation. I think that's a really important lesson for all future trials that are doing PSMA PET serially. We need to be very careful how we do that and how our investigators manage that.

Clinical progression-free survival is actually radiographic progression-free survival but includes whether a patient came off trial. So that was also positive with a hazard ratio of 14 versus nine months.

Depth of response was significantly different between the two. So, a 68%, 50% response rate with Enzalutamide alone and 93% was Enzalutamide plus Lutetium PSMA. And looking at the 90% response rates were 37% with Enzalutamide and 78% with the combination.

Adverse events were similar between the two arms. Adverse events of grade three were 4% versus 10%. This is predominantly hematologic. So, there were an additional three patients who had grade three anemia compared to no patients on Enzalutamide and one patient who had grade three thrombocytopenia.

The translational component of the study is super important, and we'll be analyzing this when we do a full analysis for overall survival from July this year, and I'm super looking forward to that. We did serial PSMA PET at multiple time points, including FDG and PSMA, in addition to CTCs and circulating tumor cells. So, we are doing a comprehensive analysis of this, and that's part of a PCF challenge award, which is great. So this will all happen towards the end of this year. We'll be able to look at the evaluation of baseline predictive biomarkers, looking at ctDNA, and imaging. Super interested in this upregulation possibility. We'll have that in the Enzalutamide arm and the Enzalutamide plus Lutetium arm. We will be able to see whether patients who do upregulate early do in fact have poorer overall survival and whether that poor overall survival is mitigated with the addition of Lutetium PSMA. We will be able to compare PSMA PET to CT and bone scan for progression and get some criteria hopefully for reporting PSMA PET serially and also compare PSMA PET and PSMA SPECT for treatment response with Lutetium PSMA. And of course, composite biomarkers. Can we look at genetics and imaging together to see if we can come up with predictive nomograms for good treatment response with this combination?

And these are a lot of the composites of the images that we're getting from the SPECT images, which have been harmonized across Australia in quite a complex process.

So, in conclusion, it's the first randomized trial to combine an ARSI with Lutetium PSMA 617. It shows strong evidence of enhanced anti-cancer activity on its primary endpoint, PSA-PFS. This is compared to an active life-prolonging control treatment arm. It's the first trial to use adaptive dosing in a randomized trial of Lutetium PSMA based on an interim PSMA PET. I think that's a really important concept, particularly if we take Lutetium PSMA earlier in the disease process, in the hormone-sensitive space. It gives us the possibility of reducing toxicity by only administering if we have persistent disease. We only gave two to four doses in this study, but if we had given two to six and had a more flexible adaptive dosing schedule, allowing us to start again at the first PSA rise, we might even have had longer progression-free survival than we showed. We've got planned follow-up until July 2024, and as I said, extensive translational imaging.

And just want to thank everyone who was involved in the trial and looking forward to presenting some more results. Thank you.