Alicia Morgans: Hi. I'm so delighted to be here at APCCC 2022 where I have the opportunity to speak with Professor Joe O'Sullivan who is a Professor of Radiation Oncology and a clinical oncologist at the Queen's University of Belfast. Thank you so much for being here with me today.

Joe M. O’Sullivan: Thanks Alicia, great to see you.

Alicia Morgans: Great to see you too. I wanted to talk with you about the landscape that's in flux. In metastatic castration-resistant prostate cancer, at least in the US, there's a new approval of lutetium-PSMA-617, and that is expected to really spread to other systems including your own in the near future, and we have an existing landscape of multiple therapies available for mCRPC. So given all of that, where do you see lutetium fitting in and how does that affect the rest of the landscape?

Joe M. O’Sullivan: Well, I think it's really exciting times in metastatic castration-resistant prostate cancer, and lutetium-617-PSMA is really the first of these radioligand therapies to target PSMA, the molecule PSMA, so I think it's really exciting times because we've seen survival benefit in patients who are really third or fourth line in metastatic CRPC.

The VISION trial results showed an overall survival benefit for patients receiving lutetium-177-PSMA, but patients had progressed on a previous abiraterone and enzalutamide as well as a taxane chemotherapy, so really, it's third line.

We're expecting approval in Europe in the next ... by the end of this year hopefully, and where it's going to fit initially, I think will be in that second, third line slot in metastatic CRPC. Patients who have visible disease on a PSMA PET CT scan, which is the vast majority of patients with mCRPC, and it comes into the landscape where already we have another radionuclide therapy already established, radium-223, aimed at patients with specifically bone metastases from mCRPC, so it's going to be really interesting to see how this new therapy, which really everybody's talking about, fits in with the existing therapeutics.

Alicia Morgans: So how do you think that through? Where do you imagine putting these two agents in succession?

Joe M. O’Sullivan: I think once lutetium-177 is established, I think that would be the dominant radionuclide, because it targets disease not just in bone but really wherever the prostate cancer cells express PSMA on the cell surface. So that really includes visceral, lung, liver, lymph nodes as well as the bone, so I think realistically once it's established and funded, it will be the dominant radioisotope.

However, I think there still will be a subset of patients with bone dominant disease, especially symptomatic bone dominant disease, who would benefit from radium-223. I think radium-223 will continue to be much cheaper, certainly in the European context, so I think that would be attractive in that sense. Also, probably overall less toxic, and in the bone dominant patients it looks to be quite similar efficacy, three or four months survival benefit compared to more or less a placebo, so I think it still will have a role, but I think lutetium-177 will dominate the field in terms of radionuclide therapies.

Alicia Morgans: So, do you have concerns or thoughts about whether these agents can be used close together? Would there need to be separation?

Joe M. O’Sullivan: Yeah. I think I would treat it a bit like cytotoxic chemotherapy, so I think if a patient's bone marrow has recovered, it's quite likely they should be suitable for sequential therapy. I know that in the VISION trial some patients, about 10% actually, had previous exposure to radium-223, and there were no particular issues with those patients who had previous exposure, but I think you'd want to have a little bit of separation, like if you were starting radium or lutetium following docetaxel or cabazitaxel, you'd want the bone marrow to have recovered. I think that would be the main overlapping toxicity. But other than that I would have no particular concerns, and as for long-term toxicity, really that's not so relevant in this patient cohort who are likely having a fairly short survival in any event.

Alicia Morgans: That makes sense, and I think in the VISION trial they did request that there was about six months separation, just because, of course, clinical trial, but I think that your practical approach to cytopenia recovery and thinking about it as almost like a cytotoxic chemotherapy makes a lot of sense.

Joe M. O’Sullivan: I think particularly lutetium, which probably has a quicker recovery time as well, because it's a beta emitter, the nadir counts tend to be 21 days or so after the treatment, so I think patients have a quicker recovery time probably than with chemotherapy, for example.

Alicia Morgans: Well, and I would agree. I wonder what are your thoughts just for ... You are a radiation oncologist as well and so have thoughts about radiation that others may not be as familiar with. What are your thoughts on the differences between the alpha and the beta-emitting agents? What are the benefits, pros and cons of each?

Joe M. O’Sullivan: Yeah, so the big difference is the alpha particle radiation which comes with radium in fact, and there are some drugs in development which target PSMA with an alpha emitter. Alpha is a very powerful form of radiation. It kills everything in sight, but in a very, very short radius, so maybe 20 or so cell diameter, so it's really focused, highly powerful radiation, like a massive nuclear bomb going off with a very short radius.

The beta particles spread over a wider distance, but it takes a lot more beta particles to kill a cell, and really with radiation you're talking about DNA damage. So, an alpha particle causes massive double-strand breaks in DNA. Beta particles maybe it takes one hit or two hits to cause a single-strand break, but takes many more hits to cause lethal damage. So I think there are pros and cons in terms of safety.

I think the big benefit in radium-223 is that the bone marrow gets very little dose, so the bone itself gets a big blast of radiation, but the bone marrow is relatively protected, whereas lutetium-177, which is a beta emitter, the bone marrow does get a significant dose. We do see thrombocytopenia, neutropenia, et cetera, but the benefit is that the radiation spreads out over a wider distance, and that's why you need to sequence, or need to cycle these therapies, a bit like chemotherapy, because you can have one hit, get a drop, and then you recover, and a bit like the way we cycle chemotherapy, I think it's important.

So, I think there'll be further drugs in development using PSMA as a target with actinium and thorium and some other alpha-emitting radioisotopes. I think that's really exciting. The risk being there, the salivary glands might take a major hit and might not fully recover. So there's always a sort of payoff and balance to be struck with these drugs.

Alicia Morgans: Well, I appreciate you walking us through that, and then also giving us a sense of what's to come, because I think we're all really excited about actinium and thorium, and I've actually had patients of course actually fly to Germany —

Joe M. O’Sullivan: Yeah, sure.

Alicia Morgans: ... and get these agents after some of the other radiopharmaceuticals. So really exciting to see where things may go. So, as you think about this landscape and you think about the changes induced by radiopharmaceuticals, what would your message to listeners, clinicians, and patients alike, be?

Joe M. O’Sullivan: Well, first of all, not to be afraid of radiation. I'm a radiation oncologist and there's sometimes a little bit of reticence about having radioactive therapies, but I would say first of all we need to get over that very quickly. These are well-established therapies, very safe. Yes, you need to talk to your nuke med colleagues and you need to incorporate them into your multidisciplinary team. They're very important from the imaging and also helping with the therapeutics.

You need to get to know your physicist, and I think that these types of radioactive therapies are here to stay, so I think it's important that people in training, oncologists in training, both med oncs as well as rad oncs, learn about the mode of action of radiation, DNA damage, because that helps understand the efficacy, but also the potential toxicities and safety aspects.

Alicia Morgans: Well, I could not agree more. Thank you so much for that and thank you for your time and expertise today.

Joe M. O’Sullivan: Pleasure Alicia. Thank you.