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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have you here with me today, Dr. Shahneen Sandhu, who is an Associate Professor of Medical Oncology at the Peter MacCallum in Melbourne, Australia. Thank you so much for being here with me today.

Shahneen Sandhu: Thank you for asking me to be here. I'm delighted.


Alicia Morgans: Wonderful. Well, I'm delighted to have you and really excited to talk with you about a part of the field of prostate cancer care that you and your team have been incredibly instrumental in developing and innovating over the last few years. I'd like to talk to you about radioligand therapy, targeted radioligand therapy in particular, and get a sense from you of where we started and how we got to where we are in terms of these targeted therapies.

Shahneen Sandhu: So I suppose, given the focus, targeted radioligand therapies have been around much longer than they've been evaluated in prostate cancer. Some of these agents have been evaluated in a range of other cancers like thyroid cancer before finding their role in prostate cancer. I think we would have to say that it's the team in Germany that had initially pioneered a lot of this work.

What we did, and Michael Hofman was instrumental in doing this, was really run the first prospective study. So, therefore... because prior to that there was clinical data, but much of the clinical data for lutetium PSMA, specifically in prostate cancer, was retrospective. And because of the nature of retrospective data collections, unfortunately, you do not get a good sense of safety. Because patients come in, they have treatment, and then they go back to their primary referring physician, and then you may or may not see them, and so that data is lost.


And so, Michael Hofman and the team at Peter Mac were fortunate enough to run a small clinical trial of 50 patients, essentially, where we were prospectively evaluating both the efficacy outcome as well as the safety of lutetium PSMA in prostate cancer.


What we found, of course, was that we certainly saw in these patients who had largely exhausted all conventional options that there were significant response rates - PSA response rates in the range of about 66-68%. Those patients that responded certainly had... It was obvious that they had a clinical benefit because their pain would get better, they would come off their opioids, so there was definitely this quality of life benefit that you could see in real-time as well, and it's an incredibly well-tolerated treatment. I suppose, that then subsequently led to the next stage of clinical trials: one, looking at it much earlier in the disease; and then, two, also trying to combine it.


I think the other part of innovation that certainly Michael and actually Rodney Hicks as well, who really is largely looking at the patient selection, which I think is a key aspect. Not to be lost is the fact that whilst 66-68% of patients might have a PSA response rate, and you see these wonderful waterfall plots that everyone gets very excited about, it's about the durability of the response. It's about how long the patient benefits from a particular treatment. And so, this question of selecting patients that are most likely to benefit I think is key because there is a subset of patients who, despite highly effective therapies and having a target that is clearly evident on the basis of imaging, do not benefit. So really understanding that subgroup and being able to pick the patients who are most likely going to benefit.


I think the other part of innovation that we've been involved in is really combining it with other agents. So, it's rational to try to combine it with an agent that targets the androgen receptor because here, what you're trying to do is you're getting at two different pathways that are clearly very relevant in prostate cancer PSMA and then also AR together. But in addition to that, there is certainly some pre-clinical data and some clinical data that suggests that there is possibly some synergy in combining the two compounds together. So that is one obvious combination with a number of clinical trials currently ongoing, both investigator-initiated as well as actually registration studies that Novartis is now running.


I suppose one of the things that I've been passionate about is really trying to change the field. So I suppose it's high-risk/high-reward sorts of clinical trials where you are trying to not only enhance responses but what you're really trying to do is actually increase the durability of response, and ultimately, it's about survival. And so, for me, my other field is immunotherapy, and so one of the things I've been trying very hard to do is see how we can make prostate cancer, which is a highly immunosuppressed cancer, more immunogenic, and whether that's combining it with a PD-1, some of this lutetium PSMA, combining it with the PD-1, giving a bit of the rationale of not only reducing the size of immune modulation but also the next generation of immunotherapy trials will involve CTLA-4 and NTPD-1 as well.


Alicia Morgans: So I think that's such an interesting combination and certainly is an area of interest. There are all kinds of combination trials, even cabozantinib, and atezolizumab. There are BiTEs. There are so many ways that we are trying to warm up these cold tumors. I would love to hear how you and the team are doing this. Because I know you've mentioned lutetium PSMA and pembrolizumab, for example. Can you share some of the ongoing trials that you and the team are working on in this particular area to combine those two approaches that may be so powerful together?

Shahneen Sandhu: Yes. You make a terrific point, Alicia, that we are certainly not the only group that is thinking along these lines and people have taken the approach of tyrosine kinase inhibitors in conjunction with immunotherapy because that changes the immune microenvironment, Bi-specifics. I think ADCs have got a role to play as well. Certainly, in breast cancer, they've been very effective and certainly something we should be thinking about in prostate cancer as well.

So the approach that we've taken is really largely looking at lutetium PSMA as a means to modulate the immune microenvironment. The first study we've done is called PRINCE and it's looking at the combination of lutetium PSMA in conjunction with the backbone of pembrolizumab for up to two years. We've certainly seen some promising responses. We've certainly seen a PSA response rate of 73%, which is higher than what's been reported in previous studies. I think the data is still fairly immature. However, we have seen radiological progression-free survival at six months of 65% and a PSA risk progression-free survival of 68%.

So look, it is promising, but my sense of it, having taken care of the patients and seeing the patients, is it's not enough. It strikes me that this is a disease that can respond, but I feel we probably need to add something else in addition to these sorts of strategies. TGFβ is certainly something that is highly relevant in terms of the immunosuppressive microenvironment, and there are agents out there that could be utilized to add on to some of these combination studies.


The two next studies that we are currently planning, one is called EVOLUTION, and it's looking at Lutetium PSMA in conjunction with ipilimumab and nivolumab, and this is going to be an ANZUP sponsored study with funding from PCF in Australia, in addition to BMS and Novartis as well. So we are very fortunate to be able to take it to the next level. And then, on the back of two clinical trials, including one that has received PCF funding previously called LuPARP, which is really looking at lutetium PSMA and olaparib as a radiosensitizing. There's a lot to be considered there as well from a perspective of... there, what we are trying to do is induce more DNA damage and prevent the repair in a tumor-specific way. And that looks promising as well so far, and I hope to be able to report that data out next year actually. And on the back of that, what we hope to do is actually have a triple combination study of lutetium PSMA, pembrolizumab, and olaparib.


So it's sort of layering it on incrementally. And then, one of the things that I've been very keen to do is also build a lot of biomarkers into these studies so that we can actually, in addition to understanding whether these drugs are going to be effective for patients, really just try and understand, how does cancer escape? What else do we need to add to the armamentarium so that we can actually ultimately reach our goal, which is actually getting patients to live longer, and have a decent quality of life. Ultimately, my goal is to improve survival. I'd love to say cure, we are certainly there, I would say, with other advanced cancers with immunotherapy, but we've got a long way to go with prostate cancer.


Alicia Morgans: I would agree, but I do commend you and your group for the approaches that you are taking, and even some of the studies that you are doing in earlier stage disease where you may have a better chance of actually increasing cure rates. Can you share some of those?

Shahneen Sandhu: Yeah. So, the couple of studies that we are doing looking really at bringing lutetium PSMA forward, I think one of the exciting studies, in fact, led by Declan Murphy and Michael Hofman, and some of them... in fact, and John Violet as well who unfortunately passed away, is really looking at bringing this mode of therapy much earlier to patients who have high-risk localized disease. And we know that is clearly an area of need because a substantial proportion of those patients, despite effective surgery or radiation, will, unfortunately, develop metastatic disease in a short space of time.


And you're completely right. In fact, that's probably the space where if you could combine lutetium PSMA in addition to perhaps other immunotherapy, you may, in fact, have a much higher impact on somebody's disease and long-term outcome, just because we know, biologically, this disease becomes more heterogeneous and more immunosuppressed the further on it gets. And so, really being able to target that very early on might be effective.


We also know from other cancers that actually the neoadjuvant approach, at least from an immunotherapy perspective, is very effective from a perspective of being able to develop the T-cell repertoire against cancer. It seems to be that when you deliver the same treatment in a neoadjuvant space, you get a better outcome than when you deliver it as an adjuvant treatment. So that whole treatment paradigm needs to be brought all the way forward, but it does require a partnership between urology and medical oncology, and different skill sets and expertise to be brought to the fore, just because these agents are not without their challenges. So that is one of the studies that we are looking at.


And then the other study that is led by Arun Azad and Michael Hofman is called UpFrontPSMA, so really looking at bringing PSMA forward there. The concept behind that is why not debunk cancer with a couple of doses of lutetium PSMA? We know that radiation in patients who have small volume metastatic disease to the prostate is valuable, so here are a couple of doses, two doses of lutetium PSMA, followed then by six cycles of standard docetaxel treatment in conjunction with ADT. That study is also going well. I think it's probably a third or almost half-recruited. So really, the studies are going well, and we've been fortunate to be able to ask some key questions as part of academic-led, investigator-initiated trials, but very much in partnership with granting bodies like DOD and PCFA, and PCF, in addition to leveraging funding from pharma. We've been very fortunate to be able to do that.


Alicia Morgans: Well, I think certainly we should include you and your team in that group of contributors though because the ideas that you come up with are innovative and supportive of patients, and really trying to attack from all different angles, stages, and approaches. I really commend the creativity and the thoughtfulness that you and your group put into that, as well as the diligence that it takes to enroll patients on trials, to get them done, to report them out in a timely way. Your team has really led the way in all of this, so congratulations on that. And thank you so much for taking the time to talk through all of this with me today.

Shahneen Sandhu: Thank you for asking me. It's a delight to have a conversation with you about some of the work we are doing. Thank you.

Alicia Morgans: Thank you.