Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago, in the United States. I'm so excited to have here with me today a friend and colleague, Dr. Ian Davis, who is a Professor of Medicine at Monash University and Eastern Health and Professor Michael Hofman, who is a Professor of Nuclear Medicine at the Peter MacCallum Cancer Centre and the University of Melbourne. Thank you both so much for being here today.

Ian Davis: Thank you.

Michael Hofman: My pleasure.

Alicia Morgans: Wonderful. We have the opportunity to speak today about the TheraP trial, which is a trial that you've been performing over the last couple of years, I think. I'd love to hear about this trial. But before we start on the trial specifically, one of the key factors in that trial is the drug lutetium. And I'd love to hear from you, Michael, if you could tell us what's so exciting about lutetium?

Michael Hofman: Yeah, so thanks, Alicia. This is a new class of drug. It's a radioactive small molecule. It's PSMA, which stands for prostate-specific membrane antigen. And it's a peptide-like molecule and it's bound to lutetium-177, which is the radioactive molecule. And lutetium is a beta emitter. It emits quite high energy beta radiation to kill cancer cells. It has a one-millimeter path length. This is given intravenously. It travels around the bloodstream. PSMA ligand binds to the receptor, which is highly overexpressed, particularly in metastatic castration-resistant prostate cancer. It's then internalized into the cell. The lutetium stays there. It actually has a half-life of seven days. High doses of radiation are emitted for several weeks after the treatment and this results in the death of prostate cancer cells and the one-millimeter path length of lutetium really limits damage to normal tissues. We don't see a lot of off-target toxicity with this treatment. Although we do see some, the tracer goes to the salivary glands and also the kidneys so we expect that those are the sites we might see some side effects.

Alicia Morgans: Great. Well, thank you for explaining that. I think many people are really excited about lutetium and also trying to figure out where it will stand in the therapeutic landscape. And Ian, can you tell us a little bit about the TheraP trial? What was the design? And what were you looking to understand with the study?

Ian Davis: Thanks, Alicia. TheraP was a randomized Phase II trial run over 11 centers in Australia by ANZUP Cancer Trials Group. ANZUP is a corporative genital urinary cancer clinical trials group based in Australia and New Zealand that does clinical investigator-initiated clinical trials in all types of cancer. We saw that there was a therapeutic need here, and we also saw the wonderful work that was coming out of Michael's group at Peter MacCallum and from others around the world, suggesting that lutetium PSMA was a very promising agent. We looked at the clinical landscape and tried to understand where the need was. And certainly, in metastatic castrate-resistant prostate cancer, there was a real need in the case of men who had already been failed by docetaxel treatment, may have had a novel androgen receptor-targeted pathway inhibitors such as abiraterone or enzalutamide. And many of those men in Australia would then go on to receive cabazitaxel.

We saw that this was a clinical need because, after cabazitaxel in Australia, there's really not much else that is known to prolong survival. The TheraP study was designed to look at these men who had had that type of prior therapy, who were thought suitable to receive cabazitaxel as the next line of therapy. They had to have progressive disease with a rising PSA and a PSA above 20, obviously good major organ function, good performance status.

As part of the screening they underwent, a PSMA, gallium PET scan, and also fluoro-18-FDG PET scan. And Michael will talk a bit more about why that was necessary, but that was part of the eligibility to show that there was no discordance between those scans. Patients were then randomized one to one to receive lutetium-177 PSMA or cabazitaxel, which was given at a dose of 20 milligrams per meter squared. That was stratified by disease burden above or below 20 sites of metastatic disease, whether they had or had not had prior enzalutamide or abiraterone and by study site. And the primary endpoint was PSA response rate. And I'll let Michael talk a little bit more about that.

Alicia Morgans: That's great. And Michael, while you're talking about that, I'd love to hear about the selection criteria. As Ian mentioned, you used a PSMA scan, which I think is a great way. Many of us understand that that can identify using that biomarker, patients who are expressing PSMA on their cell surface. But I think one of the things that we need to understand better and as a field are learning about is that the FDG PET can also be so important in identifying areas of disease that may not express PSMA. Can you talk about why that was so important?

Michael Hofman: Yeah, sure. This trial, everyone underwent those two PET scans and they were centrally reviewed. They were uploaded to a web-based central review s-Server, and we had a team of three central reviewers who looked at those PETs. Importantly, all of the sites also had some quality control checks at their site to make sure that their PET scanners were up to spec. And patients had to have had an SUV max over 20. That's a measure on the PET scan of how intense the PSMA uptake was. And that needed to be over 20 at a site of that metastatic prostate cancer. And also if there were signs of measurable soft tissue disease, they had to have an SUV over 10.

And the FDG helps look for sites that are FDG positive and PSMA negative. In these patients with advanced disease, after several lines of therapy, we can see tumor heterogeneity, and maybe only half the disease actually expresses PSMA to a sufficient level. Those patients were excluded. In this trial, we have actually 10% of patients were excluded because they just had low PSMA expression at all sites. And a further 18% were excluded because they had FDG positive PSMA negative that we call discordant sites of disease. That means actually 28% of patients after the combined FDG and PSMA PET were not eligible for the trial. We think this is an advantage because we are selecting patients that are truly likely to have maximal benefit from this novel therapy.

Alicia Morgans: It absolutely is an advantage to avoid toxicity potentially in patients who may not benefit as much as they should, because they'll have disease potentially that's growing when we need to control it. But it's interesting as your group continues to do these trials, that it may be that we need to use these drugs lutetium in particular, earlier on. Of course, there may be less PSMA expression, but assuming there isn't, if we use it earlier on, perhaps we'll have less tumor heterogeneity. But so fascinating and something for us all to think about, and I'm sure your group is already working on it. Can you tell us a little bit about what you found?

Michael Hofman: Yeah, so the primary endpoint was met, this was a PSA response over 50%, and that occurred in 37% of men randomized to the cabazitaxel arm versus 66% of those randomized to the lutetium PSMA arm. That's a 29% absolute improvement in that PSA50 response rate. And that was highly significant with non-overlapping confidence intervals. And so that was pleasing. That's a fairly large difference between the two arms and the other endpoint that we're reporting at ASCO is the preliminary PSA progression-free survival. Only 157 of the required 170 events for that endpoint have occurred to date so it's a preliminary readout and we await further patient followup. But at the time of presentation, we see a hazard ratio of 0.69 in favor of lutetium PSMA compared to cabazitaxel for delaying PSA PFS. And with placed further follow-up, we'll also report out radiologic PFS overall survival, and some quality of life parameters, but that's still to come.

Alicia Morgans: It's just so interesting. And I'm really excited that the group chose to use such an active comparator arm because there have been a number of trials that have really focused on sequencing AR agents that are maybe different to the other agent that a patient hasn't received previously and using that as the control arm, but the group really, I think, used what we believe and know from multiple trials is quite an active comparator arm. That I think is so important. And the other thing that was interesting that came out of this trial was the safety and toxicity profile. How did patients fare on the study in terms of toxicity, Ian?

Ian Davis: Patients managed quite well in terms of toxicity. We saw no unexpected toxicity in either arm. We deliberately chose the lower dose of cabazitaxel, 20 milligrams per meter squared, based on previous data, and saw the expected rates of [inaudible] neutropenia, and other toxicities with that. Similarly in the lutetium arm, we saw toxicity was very similar to what has previously been reported and probably the most troublesome toxicities are dry eyes and dry mouth as Michael indicated, but these are generally low-grade toxicities.

Alicia Morgans: That's great. Also, you found that these treatments were tolerable in your patients, which is so important. I'd love to hear both of you maybe Michael first and then Ian, talk about how you work together because these kinds of treatments, the lutetium in particular, requires collaboration and a partnership between nuclear medicine physicians. And in most cases, oncologists, perhaps some urologists may partner in the future on these treatments. Can you tell me how does that work? How do you make that happen effectively?

Michael Hofman: This trial was evolved back in actually late 2015 before a lot of people had heard about PSMA PET before really Novartis now owned the IP under a company called AAA and with the PSMA-617. But back then really no one had a lot of interest in this agent. It was on the shelves in chemistry laboratories almost being developed. It was being used as a compassionate access treatment in Germany. And some men were flying out to Germany to receive that therapy. It was very much in the nuclear medicine domain. And our view was that this should only be used in the setting of clinical trials, given that it's an unproven experimental agent and we have approved and effective therapies and the nuclear medicine community on its own have not been very effective, at least in the past, in undertaking prospective randomized trials. That's really been left to the medical oncology world and the commercial industry or cooperative clinical trials group.

An opportunity became available through ANZUP the Prostate Cancer Foundation of Australia. This was an academic grant and a few of us nuclear medicine physicians put in a concept to that process and Ian and his medical oncology team picked up on it and moved it forward as the lead trial. And that then became a very close collaboration between nuclear medicine and medical oncology working in the same room, designing the trial, having all the infrastructure that ends up bringing centers together. And there were lots of nuclear medicine complexities because, unlike the VISION trial where the lutetium PSMA-617 is made commercially and centrally, this trial evolved before that. Actually the PSMA-617 is manufactured on-site in hospital radiopharmacies at each of those 11 sites and bonded to the lutetium. So there's a lot of complexities around quality control of that. That required us in the nuclear medicine domain to be working on those aspects, the medical oncology domain to be working on the trial design and the protocol and infrastructure. And it was really a good partnership.

And each study site has a lead medical oncology investigator and a lead nuclear medicine investigator, and with two arms, one medical oncology, one nuclear medicine it really worked extremely well, and it was a great partnership. And that network that's been created is now being used for a whole variety of future studies.

Alicia Morgans: That's wonderful. And Ian, what are your thoughts on that? And how easily other institutions, other organizations can try to replicate what you've done in terms of that partnership?

Ian Davis: Yeah, thanks, Alicia. This really is a story of fantastic partnerships. We as medical oncologists have worked closely with nuclear medicine physicians for years, and nuclear medicine physicians have looked after metastatic prostate cancer for years using isotopes like strontium and others. And of course, in the diagnostic field. We're used to working with them, but not so much in trial design. This is a wonderful partnership. I've learned an enormous amount about logistics here that I never dreamed of. I think that our nuclear medicine colleagues have learned quite a bit about prostate cancer that they probably didn't want to know. The trial involved bringing together an enormous number of players. It was led by ANZUP's Cancer Trials Group, Prostate Cancer Foundation of Australia was a key partner in all of this. The trial was coordinated through the NHMRC Clinical Trial Center based at the University of Sydney who did a fantastic job.

We've had funding from Movember, Canfor Cancer, It's a Bloke Thing, Cancer Australia, and many of us are supported by various other mechanisms as well. We received the tracer from what is now AAA under Novartis and they've been fantastic supports through all of this as well. And ANZSNM, which is the federal government-run nuclear medicine facility in Australia provided lutetium-177. There were very complex agreements, the whole issue of production and shipping and quality control and image central reading, all of those aspects of that manufacturer were all worked out a very collegially.

And this has obviously led to a successful trial that we hope is going to lead the way for us, certainly in designing future clinical trials and hopefully better opportunities for men affected in this situation. And it's already bearing fruit in other clinical trials that have spun off from this. Now moving this therapy earlier in the disease course. A wonderful story of success, great to have a positive trial, but even more so, sort of built this fantastic network of supporters, of funders, of clinicians, of collaborators, basic researchers and of course the participants in the trial without whom we would be able to do nothing.

Alicia Morgans: Absolutely. And it's all for such an amazing cause of really improving the lives and lengthening the lives of men with prostate cancer. I could not commend you more and I'm really pleased and honored to be able to talk with you guys about that today. And we do look forward to the further followup of the TheraP trial, as well as all of the other great work that you and your team are doing. Thank you so much and keep up the great work guys.

Michael Hofman: Thank you very much.