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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a 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, Dr. Arun Azad, who's an Associate Professor of Medicine and a GU medical oncologist at the Peter Mac in Melbourne, Australia, as well as being the translational chair for the ANZUP Cancer Trials Group. We also have here with us, Dr. Declan Murphy, who is well-known to UroToday, a Professor of Urology also at the Peter Mac in Melbourne. Thank you both so much for being here today to talk about a trial in progress involving Lutetium with us. Thank you.

Declan Murphy: Thank you.

Arun Azad: Yeah, thanks, Alicia. Good morning. Good afternoon. Thanks for having me on. It's a real pleasure.

Alicia Morgans: Wonderful. Arun, can you tell us a little bit about this trial? Tell us, why do we need more Lutetium? What are you studying and what really helped you and the team come up with this design for the Upfront PSMA study?

Arun Azad: Thanks, Alicia. So this is a world-first study, so we're really excited about it, of Lutetium PSMA in metastatic hormone-sensitive disease that's newly diagnosed. So the motivation for the study really was off the fantastic work that Professor Michael Hofman, who is also well-known to your audience and is our stellar nuclear medicine colleague at Peter Mac, did with an initial prospective study of Lutetium PSMA in metastatic castration-resistant prostate cancer. That then led to the TheraP trial that Michael led and was sponsored by the ANZUP Cancer Trials Group, which of course we saw the very exciting results of this year.

Really the motivation was, as with other drugs in prostate cancer, whether it be docetaxel or the AR pathway inhibitors, which have shown great efficacy by moving forward in the treatment paradigm to do the same thing with Lutetium and to test it in a de novo metastatic hormone-sensitive population.


We're actually doing this study with grant support from the Movember Foundation, the Medical Research Future Fund, which is an Australian federal government initiative, and also some funding from the US Department of Defense. We put in the grant applications of this going back over two years now, and really at that stage, knowing that we were seeing these very promising results in the metastatic castration-resistant space, wanted to take it forward.


The study design involves giving men ADT plus docetaxel, so these are men with high-volume disease who we would give in Australia would give docetaxel to. We don't have access via reimbursement of AR pathway inhibitors, so we use a lot of docetaxel in these men. Then it's one-to-one randomization to two cycles of Lutetium PSMA that's sandwiched between the start of the ADT and then the six cycles of docetaxel. It's a very exciting study, and we're really keen to look at the efficacy and outcomes in men by bringing Lutetium forward. Hopefully, we'll see just as good results as we've seen in the later stages of the disease.


Alicia Morgans: That's fantastic. I know there are 12 sites, I think, involved across Australia who are going to be participating, and you have opened and started to enroll. What's your enrollment look like at this point, and what is your goal?

Arun Azad: Yeah, thanks, Alicia. The target accrual is 140 patients, and we will be opening at 12 sites. We've opened at seven currently, and we've recruited just over a quarter of patients. 37 at the moment have been actually randomized. We actually opened at Peter Mac in April of last year. And then, of course, this small problem that we know of as COVID hit and really then the issue ... We're lucky in Australia really in terms of the number of cases we had compared to the rest of the world, and we're very thankful for that ... But a lot of sites around the country, in fact, all the sites participating, really put a pause on opening new trials for about six months. So we didn't actually open our second site for nearly another six months after that, and we've still got five sites still to open.

So we are catching up. We are catching up, but we've recruited very well. We've just got over a quarter of patients now, and recruitment's steady so I don't think we'll fall too far behind. There's been a lot of enthusiasm from the participating sites, as you can imagine. Everyone's keen to get involved in trials and particularly Lutetium trials. I think one of the things that's been really gratifying and looking at Peter Mac, is that, as you know from previous discussions with Declan, we've got a really strong multidisciplinary program. There's been a lot of enthusiasm from our urology colleagues, Declan, Nathan Lawrentschuk, Daniel Moon, and some others who've been really good referrers for the study. Because of course in Australia, like many countries, these patients come from family doctors or general practitioners referred to urologists for initial workup and biopsy and then come to the medical oncologist.


One of the, not challenges, but one of the key factors in the success of this study in terms of recruitment is having strong multidisciplinary links. It's something that I really value as a medical oncologist. It's been great to get support from Declan and his colleagues to help us with recruitment.


Alicia Morgans: Well, let's dig into that a little bit. Declan, we've talked to you before about multidisciplinary approaches, and I think as I consider that of course there's an ideal, and then there's what we face in many practices and what challenges are faced by some practices that don't even have all of these providers in the same physical location. Do you have any advice or recommendations for how to really make this partnership work in the metastatic hormone-sensitive setting, where we are trying to accomplish trials like the current trial and potentially paradigms that are going to shift where we really do need to continue to collaborate in terms of multidisciplinary care for metastatic hormone-sensitive prostate cancer patients?

Declan Murphy: Thanks, Alicia. Regarding this study in particular from PSMA, as Arun has said, the urologists and to some extent radiation oncologists are the ones who diagnose these patients and because we need to get them in the de novo setting before they've had a chance to progress and so on, it's really important that there's visibility of these trials to urologists and radiation oncologists. Actually, Arun and his team have done a fantastic job with that visibility thing by coming out to big urology practices and other multidisciplinary team meetings and talking about the study. That's a really important message at the start in the hormone-sensitive space is if you've got a trial open and there's lots of interesting questions in hormone-sensitive still, it's really important to engage with urologists from the get-go.

That includes, by the way, trial design just to make sure that you're not designing a trial that maybe is not going to recruit well, because there's some nuance that you haven't anticipated because you don't see the metastatic hormone-sensitive patients as often as we do. So they've done that very well from the start with embedding a number of urologists in the steering committees and as chief investigators, and you see it now with fast recruitment even with the pandemic.


The second point I'll make about that trial is, of course, it's leveraging off the back of our enthusiasm for PSMA as an imaging tool going back to 2014 really. So there's a lot of experience in Australia using PSMA and also our experience with Lutetium PSMA going back to 2015 when we started the Phase 2 program. So there's a lot of awareness of Lutetium within urologists and radiation oncologists in communities here. Therefore, when a trial comes along, from our point of view for our patients, we're going to recruit very enthusiastically in there. That's just a few comments, I think, on bringing that technology forward into this space and making sure that the initial clinicians are very well engaged in the trial so you get well supported.


Yeah. Regarding general multidisciplinary things, we love talking about this. Much is talked about it, but a lot of the time it does seem like it's just a talking shop saying, "Yes, we do multidisciplinary care." But there are barriers oftentimes. Sometimes in big cancer centers like ours and yours and other big ones, there is a physical environment or traditionally there's been a physical environment where there's a tumor board-style meeting every week. We still run a very entertaining and educational meeting every week with loads of patients in it. But pandemic has meant that it's switched into the virtual or now hybrid environment for us. That creates opportunities for centers or organizations or individuals who haven't got that physical big MDT tumor board environment.


We often talk about this to our Asia-Pacific colleagues who are often very geographically distant or in really challenging physical environments. We'll say to them, "Look, you've heard the message about multidisciplinary care, but all you need to do really is create some links to someone in your region or nearby who has an interest in this area." He or she being a medical oncologist, radiation oncologist, nuclear medicine physician, or so on. You don't have to have the flashy MDT meeting. You just have to have a pipeline or a pathway so that when you see a patient, it goes into your head to say, "I wonder. Is there an option?" And then you fire off an email and maybe have a Zoom call or whatever.


I think what we need to do is not let the very fact that maybe we don't always have big physical MDT meetings get in the way of engaging with our multidisciplinary colleagues even just by an email to say, "I've got this guy who's progressed with mCRPC," or, "I've got this fit young person with hormone-sensitive disease," and so on and so forth and engage with your colleagues. They'll love getting that reach out to say, "Oh yeah, sure. We've got this thing," or, "I'm happy to have a Zoom call with your patient."


Alicia Morgans: Yeah. I love that. Thank you for really emphasizing that. I think at a certain point in time there was some reticence sometimes to participate because, "Well, I'm going to lose my patient." But I would say that there's so much to do for all of these patients that there's probably an opportunity for urologists, medical oncologists, nuclear medicine doctors, radiation oncologists to all play a role in the care. Not even to mention all of the supportive care that can be provided with our dieticians and lifestyle folks and our nursing staff and others. So there's so much to do that really, I'm so appreciative that you and the team continue to emphasize that this is a path forward that really can optimize our patients outcomes and take the best care for them.

As we wrap up, I'm going to ask the two of you, as I do in many of these interviews, just to give us some summary, some closing thoughts for the viewers who are thinking about this trial, who are really anticipating and looking forward to the results, and you know that we all are. So, Arun, what would that be?

Arun Azad: Yeah. Thanks, Alicia. I think we hope to show that the addition of two cycles of Lutetium PSMA in the upfront setting for hormone-sensitive diseases adds additional efficacy to chemo hormonal therapy with ADT plus docetaxel. We know that these men with de novo high volume disease, while there's a significant improvement in their outcomes with traditional docetaxel, we know that their median overall survival is still only around four years. Even though this is a Phase 2 study not powered to show an overall survival improvement, we know that there's a lot of room to still improve outcomes in these men. We're hoping that the addition of Lutetium will help us address that.


We'll also be able to answer some really important additional secondary endpoints. One of the fascinating things in this study is that we've got both baselines and at three months on study, we've got PSMA PET and FDG PET imaging. We'll be able to hopefully identify some early predictors of response or resistance to Lutetium and/or chemo hormonal therapy as well. As this study reads out in a few years' time, I think there'll be some really fascinating insights, not into just efficacy, but also into biomarkers, and we were also collecting quality of life data. There'll be all sorts of other secondary endpoints that will read out. So it'll be a very rich data set and I think a really important study to help shape what we hope will be a Phase 3 trial down the track.


Alicia Morgans: I completely agree. I'm looking forward to it. Declan, what would your comments be to the listeners?

Well, I think especially for medical oncologists and other clinical trialists out there working in hormone-sensitive disease is engage with your urologists and your radiation oncologists. As you bring your therapies forward into what is very much our territory, it's really important to engage with us so we support these trials. I know really in the past year or two, lots of urologists in the US are managing these patients now using AR pathway inhibitors, as they're all widely reimbursed. I think there may well be largely solo decisions because urologists like to hang on to our patients. Of course combining with AR pathway inhibitors is a great option, but I still think we should be engaging with our medical oncologists when we make treatment decisions in the hormone-sensitive space. So that's my message. Engage with urologists, educate us, involve us in your trial design, and we will support these important questions.


Always a wonderful message. At the end of the day, we do what we do to help patients, but it's also a really fulfilling part of our lives. When we get to engage together, it actually makes it that much more fun for all of us, even when we deal with really difficult and challenging situations.


So thank you both for your time, for your continued efforts to really move the ball forward in the treatment of men with prostate cancer and for continuing to keep us on our toes as we look for advances with Lutetium and with so many other ways that you help us make things better for our patients. So thank you.


Arun Azad: Thanks, Alicia.

Declan Murphy: Thank you. Pleasure.