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Michael Hofman: For the invitation today. This afternoon, I'm going to be talking on improving outcomes with combination therapies. It's actually-- this year will be our 10th year anniversary since we did our first lutetium PSMA therapy in our center at PeterMac, following on from all the great work done in Germany that led to this clinical trial. And I think as of now, we have five published randomized controlled trials, many more underway, and the last three were just published in last year alone. So the field is changing very quickly.

And our focus, given that we've been doing this for some time, has shifted towards how can we one, predict patients that are going to respond and not going to respond? And what are the mechanisms of resistance and how can we overcome this? This is what we'd like to see with radioligand therapy. These are series of post-therapy SPECTs. We love post-therapy SPECTs like Dr. Hope showed yesterday. The first patient who just doesn't even need six cycles. After four cycles, there's a complete response, undetectable PSA. We pause and then we recommence upon progression or cycle. Patient number two, who just has a progressive response to six cycles but by the end of treatment has a very low PSA.

But this is not what frequently occurs. Quite often we see patients who have stable disease, at least on SPECT, maybe with a PSA drop, but then early progression, so much so that they don't make it to all six cycles, or even worse. A patient with primary progression on treatment despite PSMA avidity. As you can see, when we treated that patient on the bottom there's uptake but it's not radiosensitive.

So how do we overcome resistance? And we have several strategies. This is a review article and talk that I gave a few years ago. And it's nice because now we do have evidence for androgen receptor blockade, thanks to the ENZA-P trial led by Louise Emmett, my colleague in Sydney. Our trial that we ran in our center as well. This was a 10-site Australian trial, randomizing our men with castration-resistant disease and high-risk features for failure on enzalutamide to either enzalutamide alone or enzalutamide in combination with PSMA.

But the very neat thing about this trial was that patients underwent a day 15 PET. All these patients just started on enzalutamide. And here you can see the PSA was 140. It went down to 98 at day 15. So it appears that it's working. But the PSMA PET looks worse. So this is what we call upregulation, or at least that's what we think is occurring. And then we jump in and give this patient a lutetium PSMA. And in blue, we see the post-therapy SPECTs. And by cycle two, actually, there's a complete response. And day 92 undetectable PSA with a completely normal PSA.

This trial has been reported in Lancet Oncology last year showing a significantly improved PSA PFS, radiographic PFS with the addition of lutetium compared to enzalutamide monotherapy. And just a few weeks ago at ASCO GU and with a co-publication in Lancet Oncology, Emmett presented the overall survival. And in this little phase there was a significant improvement in OS, hazard ratio 0.55. Highly significant. I don't think this was anticipated. This trial was never really powered for overall survival. So this was pleasing. So you can see median overall survival 26 months for enzalutamide compared to 34 months with the combination therapy.

And not only that, but improved quality of life, physical function, and overall health status by patient-reported outcomes difference between the two arms. We have some imaging biomarker data now available. And this was presented at the European Nuclear Medicine meeting last year. This is the change in SUV on day 15, SUV mean on these PET scans. Seventy percent of patients across both groups had an increase in PSA expression. And in the enzalutamide arm, those patients with an increased SUV mean did much worse. You can see a significant difference. However, in the lutetium arm, there's no difference between the two arms.

So what it appears is that the lower PSA response rates and short PFS occur with increased SUV mean in the ENZA arm. Perhaps those patients are progressing, whereas in the lutetium arm, either the early progression or sites of increased PSA expression get a large dose of radiation and that difference is attenuated. So this really looks like a very interesting combination early on. This is in the castration-resistant setting. And I guess it would be nice to take it back one step earlier to the castration-sensitive setting and almost redo this exercise because it could be a different phenomenon. This could be something that's exclusively seen in the resistant population. We just don't know.

Another combination of interest is radiosensitizers, and the way I explain this to my patients is when you get radiation, lutetium, that's like going out into the sun and getting a sunburn. And if we could visualize what's happening to your tumors inside your body, you're actually getting a really bad sunburn. And as when you get sunburnt, your skin heals itself. Our tissue has a remarkable capability to repair DNA damage, and we don't want it to repair itself, want like a third-degree burn to the tumors. Are there drugs that will increase the radiation damage? And the principle behind PARP inhibitors is that we're causing a lot of single-stranded DNA breaks, and potentially by adding a PARP inhibitor, we can convert some of these single-stranded to double-stranded DNA breaks. I know, Tom, you're going to maybe have a question about this afterwards.

And we also do a neat trick in this trial that we start the PARP inhibitor at 24 hours. So at day one that means we've had plasma clearance of the lutetium PSMA. It's now stuck in the tumor. It's been internalized. And we also have washout from the salivary gland. So when we add the radiosensitizer in, it's also having the effect of increasing radiosensitization to the tumor tissue whilst sparing the normal tissue. So this was the trial design.

We were quite worried that this would be a very toxic combination. So we started very over-cautiously with a 50 milligram BD dose and we escalated all the way up to a standard dose, but still in a 14-day pulse. So starting day one to day 15, and that was actually well tolerated without really increased side effects compared to lutetium monotherapy, which was a little bit surprising. So we've added some additional dose cohorts at the top, the top dose being a starting day −14 going all the way to day 18 at 300 milligrams BD.

The results of the first dose cohorts have been reported, not yet published, by Shahneen Sandhu, our medical oncology lead on this trial. And the PSA response rate is really very encouraging, over 50 and 65%, but it's the deep responses over 90% which were 47%, which is quite a lot higher than our other trials. It's a really encouraging signal. And I can tell you, I think we hope to report out the higher dose cohorts later this year. But the very top dose cohort, starting day −4, we did see quite a lot of increased toxicity. So it was a concerning dose level, and we think that continuous PARP inhibition may not be warranted.

We've built a lot of biomarker work into these clinical trials that we've done, including PSMA PETs every 12 weeks in line with CT bone scans. We've collected plasma for our circulating tumor DNA and other serum biomarkers. So lots of interesting data to come from the translational work in these trials. Can cabazitaxel combined with lutetium PSMA improve response rates or durability? And the idea behind this study, the LUCAB trial, another phase I/II trial, is that the cabazitaxel will target the PSMA-negative cells, but at the same time, taxanes are a potent radiosensitizer, let's say like a PARP inhibitor, but a much cheaper version, with the added advantage of targeting PSMA-negative cells.

Again, we were worried that this could be a toxic combination. So we started at a standard dose of lutetium PSMA-617, 7.4 gigabecquerels, and we started at 12.5 mg/m^2, and we've escalated up to 20 mg/m^2. This trial has just completed recruitment about one or two weeks ago, so patients still have six cycles to go. Again, we do the same little trick as with the PARP inhibitors. We do lutetium day zero. And then the patients come back at 24 hours. They have their SPECT/CT scan. And after the SPECT/CT scans, they go to the chemotherapy day unit to have the cabazitaxel. So we're hoping that the plasma has cleared. We're not going to get the blood radiosensitization at that time point.

Here, the cabazitaxel is given every three weeks, and the lutetium is given every six weeks. The clinical trial protocol was published recently in the Journal of Nuclear Medicine. So you can deep-dive on that. But we did fully recruit, which tells you that the highest dose cohort had reasonable dose tolerance. We hope to report out the results of this trial next year.

ALPHABET is a phase I/II trial of radium-223 in combination with lutetium PSMA I&T. The hypothesis behind this study is that most of the occurrences we see after radioligand therapy are in bone or in marrow. And the PEACE-3 data, radium in combination with enzalutamide, wasn't around when this trial was designed, but that certainly showed some encouraging data for earlier use of radium. That trial, reported at ESMO last year, showed an overall improvement in overall survival, with the combo enza-radium in the castration-resistant population.

There is preclinical data supporting this work. In the chart on the right, you can see a vehicle, radium-223, lutetium PSMA, and then on the far right the combined radium lutetium PSMA. This was in a model of bone metastatic disease, and it did seem that the combination was highly efficacious. This is another dose-escalation design. We started standard dose of lutetium, a half dose of radium, increasing to a full dose of radium. Here, we give the radium day 0 to 5, we've allowed.

Most of the patients on the trial actually had the radium immediately after the lutetium, so that it was a single visit to the hospital. They had their lutetium infusion immediately afterwards. Whilst the IV was in, the radium was infused. So a very practical protocol. The clinical trial protocol has also been published. We just actually locked the database for this two days ago to do our first analysis, an interim analysis of all 36 patients that have been treated. So we hope to report out the results of this trial later this year.

Now, we come to the somewhat tantalizing combination of immunotherapy with Pluvicto, and the idea here is that somehow the radiation will kill some tumor cells, present them to the immune system, and if we can activate the immune system, we'll maybe turn cold tumors into hot tumors and see some benefit from immunotherapy, which on its own has not had good activity in prostate cancer.

This is the PRINCE trial, also led by my colleague Shahneen Sandhu, medical oncologist at PeterMac. We gave up to six cycles of lutetium PSMA, 8.5 gigabecquerels down to 6 gigabecquerels for cycle six. This was following a therapy dose schedule, together with a standard dose of pembrolizumab every three weeks, which was continued for up to two years. The results of this have been reported at ESMO a little while ago. And again, a very encouraging signal. PSA ≥ 50% response in 73% of patients. Hard to read too much into these in a phase II design, but certainly encouraging.

PFS and rPFS signals look perhaps a little bit better than the VISION trial or our own therapy trial. But by the same token, a little bit of patient selection here, perhaps higher SUV means patients with higher PSMA expression. But we do see some examples, single cases within this study of patients with deep responses with undetectable PSAs that appear to be very, very durable, like this patient with undetectable PSA at week 60. And you just wonder whether it's the immunotherapy, but we really can't say that.

In the PRINCE trial, we saw the toxicities of pembrolizumab and the toxicities of Pluvicto but no additional toxicity. But I will say as a nuclear medicine physician, we don't like to have side effects. We're not very good at managing side effects. We let our oncology colleagues manage those. And this is a population of elderly men, and some of the immunotherapy side effects do shock us nuclear medicine physicians. We saw type 1 diabetes, optic neuritis, some severe GI toxicities in this trial. Although they were often grade 2, I just wonder how good CTCAE is at rating some of these immunotherapy-related side effects; that toxicity scoring system was never designed to do.

I, of course, have included a slide of your study, Tom Hope, because I do want to be invited back to this meeting. I'm showing mainly Australian trials in this talk today, but this is a very nice trial which was published before us of lutetium PSMA-617-- that should be 617, not 177-- in combination with pembrolizumab. But this was a single dose of lutetium, unlike our PRINCE trial, which was six doses. And this is a pretty good waterfall plot for a single dose of lutetium.

And it actually makes me wonder, what does this mean? Is this the immunotherapy, or is it just that in all our trials we get best bang for the buck from cycle number one and cycle number two? And how much does that cycle 3, 4, and 5 really contribute to the efficacy of our therapies? It's really hard to know. Perhaps I'd like to hear your thoughts, Tom, about-- I think this waterfall plot for one cycle is really very impressive.

Based on the PRINCE trial and your trial, Tom Hope, we went on to do the EVOLUTION trial in Australia, a randomized trial of lutetium PSMA-617 in combination with a CTLA-4 ipilimumab and a PD-1 inhibitor, nivolumab. So two types of immune-activating therapies. This was a randomized trial, 97 patients, I think, randomized 2 to 1 in favor of the immunotherapy.

This trial has completed and you will see the results at ASCO in a few weeks' time. Shahneen is presenting them. So results are coming soon. But you know I will tell you I'm really concerned about the toxicity with this combination. We saw really a lot of nasty immunotherapy-related toxicities, and for us as nuclear medicine physicians it makes us a little uncomfortable.

And this is not quite a combination but a nice sequential combination. The UpFrontPSMA trial that I led together with Arun Azad at PeterMac. So this is the first trial of lutetium PSMA-617 in patients with newly diagnosed high-volume metastatic prostate cancer. And so this is really moving it to a true first-line therapy. The trial design is we took patients with high PSMA expression, high-volume disease, defined using a STAMPEDE-like definition but using the PSMA PET rather than CT and bone scan, and patients were randomized 1 to 1 with lutetium followed by docetaxel-- only two cycles-- or docetaxel alone. That's two cycles of lutetium and up to six cycles of docetaxel.

Endpoint was an undetectable PSA at 12 months. That's quite a challenging endpoint. And we smashed that endpoint. I was actually a little bit worried as we saw PSMAfore data in earlier use of lutetium come out before this. But the undetectable PSA rate was 41% in the lutetium arm compared to only 16% with docetaxel alone. And we know that undetectable PSA at one year in this population-- there's previous evidence that it's strongly correlated with overall survival.

So we are continuing to follow up this population, and we just wonder, like the ENZA-P population, whether in a small phase II design we can get an overall survival signal. Progression-free survival was also improved with the addition of two cycles of lutetium, and radiographic PFS was not reached compared to 22 months. So some really exciting data.

And importantly, no increase in adverse events. And this was seen in the ENZA-P trial. Two cycles of lutetium are so well tolerated. You can add it in and just zero increase in toxicity. In fact, a little bit like ENZA-P, the patient-reported outcomes actually favor the lutetium arm. So if you can control the prostate cancer better, you're going to have fewer disease-related symptoms. This was published UpFrontPSMA in Lancet Oncology September last year. So if you haven't read it, please do have a read.

Now, second-last combination to discuss is radiotherapy, and there's a few trials in this space. I'm just going to describe our own Aussie POPSTAR2, even though I'm aware there's one here at UCLA, and there's a Novartis-sponsored trial as well, and several others. So this is a bit of a busy space, so we're going to get lots of data. This is a phase II trial where we're taking patients with oligometastatic disease, SABR alone versus combination of SABR with lutetium. It's 96 patients.

We started with an SUV max twice liver, and we actually found it difficult to recruit patients. Patients with small-volume disease often don't have twice that liver SUV. So we've done a protocol revision, so that just needs to be above liver. And we're probably going to revise the protocol again to maybe take out that criterion altogether, because you end up with small-volume disease in these patients, and the SUVs may not be high, perhaps due to partial-volume effect.

In the interventional arm, we have a sandwich protocol. So they get a dose of lutetium, then SABR, followed by another dose of lutetium. So this is a really interesting trial. It's recruiting at three sites: our own site in Melbourne, also Louise Emmett in Sydney, and we've just opened it in Sheba in Israel as a third site.

And the last combination is surgery, just for the urologists in the audience. We don't want you to feel left out. We want to include our medical oncologists, radiation oncologists, and urologists. Our LuTectomy study, published in European Urology, led by Declan Murphy and Renu Eapen. We had some patients that had really amazing dosimetry. This is one of the patients with higher dose, a single intravenous injection of PSMA-617. And you do whole-body imaging and you see virtually no uptake but extraordinary uptake in the prostate cancer.

This is the patient that Dan Spratt showed us earlier with a dose of 115 gray to the tumor. And the average doses were around 50 gray. But really the doses to the tumor were very variable. They were below 20 on the lower end and then up to, I think, 120 was the highest dose. So this is the differentiator between external beam and lutetium PSMA. We simply can't control dose very well with lutetium PSMA; it depends upon the intrinsic PSMA expression of the tumor, whereas with external beam we can choose very precisely.

The reason I think we didn't see histopathologic change in this patient, Dan, if you're still in the audience, is because the prostatectomy occurred at six weeks, which is just too early. We know after radiation it takes many, many months for your PSA to reach the nadir, and that's when you get the deepest pathologic response as well. So ideally, we would like to delay the prostatectomy by three months or even six months after the radiation. But we didn't want to compromise patient outcomes as a phase I trial, so that's why we did an early prostatectomy at a sort-of standard time point.

The PSA reduction in this trial was pretty interesting. Fifty percent of patients had a PSA reduction and 45% of those were over 50%. And if you look at neoadjuvant trials of other drugs, to try to get a 45% reduction in PSA is actually pretty difficult. So I think there's a lot of promise in this approach. High-risk prostate cancer after surgery, about 40% of patients are having biochemical recurrence, and I wonder whether in the select group of patients we can increase the number of patients that are cured by adding in lutetium, either to radiotherapy or our surgery with a curative intent.

And importantly, when the surgeons went to operate on these patients, they had very little difficulty. The soft-tissue planes with the short path length of lutetium mean there's not a lot of fibrosis. It means our surgeons are really very, very happy. So the take-home message is that I think combination trials are needed for theranostics version 2. There are many trials underway, several more than what I've shown in my a little bit of an Australian-dominated selection today. We can combine with drugs, external-beam radiation, surgery, or we can combine other isotopes, alphas and betas. And I think as we do these combinations, you naturally move the treatments earlier and earlier. So a very, very interesting space.

I'd like to thank everyone at PeterMac who contributes to this work. And this is a picture I took about 90 minutes' drive from Melbourne. It's the aurora australis last year, and us nuclear medicine physicians, we like to take dynamic pictures, not static pictures. So here's the moving version. And the moral is that the future of theranostics shines bright. But if you want to try and see the aurora australis, perhaps you can consider coming to our version of this meeting, which is going to be September 3 to 5 next year. Thank you.