Charles Ryan: Hello from PCF 2019. I'm joined by Professor Michael Hofman, who is a Professor of Molecular Imaging, a Nuclear Medicine Physician at the Peter MacCallum Cancer Centre in Melbourne, Australia. Michael, great to talk to you again. We've talked a couple times about lutetium, and PSMA-targeted therapy, and imaging, and that's coming along therapeutically in clinical trials. I thought it might be good to take an opportunity to talk about where we might go after lutetium becomes more of a standard approach around the world through combinations or other dosing strategies and potentially other radioisotopes. So fill us in on sort of what you might call "beyond lutetium" at this point.

Michael Hofman: Sure. An update from our center is that we have a number of trials running at the moment to answer some of these questions and we think this will compliment the VISION trial, which is the registration global trial currently underway. The first trial we have is the therapy study. This is a randomized 200-patient study, randomizing patients to lutetium PSMA-617 or cabazitaxel chemotherapy. Which is probably particularly relevant in light of some of the research presented at ESMO recently confirming the efficacy of cabazitaxel. In many respects it's similar to the VISION trial, but with an active cabazitaxel control arm. That trial has finished accrual now at 11 sites around Australia and is in the follow-up phase.

Charles Ryan: Great.

Michael Hofman: We hope to present the results of that middle of next year if all goes well. Then we have a couple of other trials open that are a little bit more exploratory smaller trials. One is sponsored by a PCF Challenge Award led by Dr. Shahneen Sandhu, one of our medical oncologists combining lutetium PSMA with a PARP inhibitor. This is not a PARP inhibitor in the sense that it's been used at the moment. We're using it primarily as a radiosensitizer. PARP inhibitors inhibit DNA repair mechanisms and when we damage tissues and tumors with radiation, they try and repair themselves. By giving a PARP inhibitor at the same time, we hope that we will enhance the radiation damage from the lutetium. Analogous to sort of a combination with external beam radiotherapy.

It's a pulsed PARP inhibitor. It's given for 14 days with each cycle of lutetium. It's a Phase I dose-escalation study. We're escalating the dose of the PARP inhibitor to try to see what's the maximum tolerated dose of the combination. We hope that they have non-overlapping toxicities and that we just really enhance the effect of the lutetium. That's the role of the trial.

We have another trial combining lutetium with pembrolizumab trying to enhance the effect. We know that on its own pembrolizumab is not very effective in prostate cancer. The hope here is that the combination will be more effective. When we kill tumors with radiation, it exposes the immune system to these necrotic tumor cells. In combination with immunotherapy, hopefully we can get deeper and more durable responses and also to see whether that combination is well tolerated, are there any unexpected side effects from the combination.

Charles Ryan: So very reasonable biological rationale to combine that PSMA lutetium with a PARP inhibitor or with immunotherapy and a very logical study with the cabazitaxel trial to look at the relative efficacy of these two therapies given in the same clinical space. One of the things that keeps coming up is lutetium is not the only radioisotope that could be targeted to PSMA. What do we know about other potential radioisotopes? Are there any that could be better or what's the state of the art there?

Michael Hofman: Yeah, so there's a whole array of radionuclides we can use. You can look at the periodic table and there's literally dozens. So in part it's determined by the radiochemistry, what can link to the peptide. If you're using an antibody approach as opposed to the small molecule approach, then there's perhaps different isotopes you're going to use. I think lutetium is going to be the dominant form for the short term given the VISION trial and our work. But there's immense interest in other radionuclides. Progenics have a trial open using iodine-131, a more classical radionuclide used in nuclear medicine, also labeled to a small molecule. Iodine's widely available so it's good to compliment that with lutetium.

The disadvantage of radioactive iodine is that there's a lot more gamma emission, which means that people around are exposed to higher levels of radiation. That means in some jurisdictions it can't be done as an outpatient therapy like the lutetium. There's immense interest in using alpha emitters rather than beta emitters. Lutetium and iodine are both beta emitters. Beta emitters travel about one millimeter and have a modest killing effect. They cause a lot of single-stranded DNA breaks. Alpha emitters are much more powerful. They really kill anything in its path. But they have a much shorter path length, in the range of micrometers. They only travel a few cells in diameter, but will really kill anything they touch. In that sense they can be more toxic or more dangerous but by the same token, will have more killing power.

Actinium labeled to the small molecules is of immense interest. Some of the teams in Germany and also South Africa have been using actinium for some years off-label, not on clinical trials protocol. There is some compassionate excess data available, but it's very difficult to read because it's not prospective data, there's no inclusion criteria. I'm a little bit skeptical of the role of alpha emitters until we get some higher quality data. I think it's an onus on the nuclear medicine and medical oncology communities to really come together and do some high-quality studies of the alpha emitters to see exactly where it fits.

Then we can also radio label antibodies. J591 is an older antibody and it seemed that when the small molecules came along, 617, it seemed the small molecules are really vastly superior. No one's really looked at alpha emitters labeled to antibodies and that's an area of interest, to go back to the antibodies and see, well, can we do better with an alpha rather than a beta?

Charles Ryan: But for now it sounds like lutetium is the story of the day and maybe in combination with other pharmacologic agents. We'll look forward to those data coming out. It looks like the other isotopes remain a little bit investigational at this point.

Michael Hofman: Correct.

Charles Ryan: I want to take a moment and talk about what we know or don't know, but the longterm safety of the lutetium PSMA-targeted therapeutic approach. You started these studies many, many years ago. It's probable now I would imagine that there are some patients who've been out months or years even after therapy. Are there any signals that clinicians should know about at this point about what happens beyond the treatment period?

Michael Hofman: We started this therapy in 2015. Most of the men we treated at that stage were really after enzalutamide and abiraterone, docetaxel, even cabazitaxel, so their life expectancy was relatively short. Despite exceptional responses, the median survival in that cohort was around 13 months. That limits the availability to assess longterm toxicities. There are a number of men in that 50-patient cohort that remain alive four years later and we're really not seeing any significant delayed toxicities in those patients. The one of most concern initially was salivary toxicity and we certainly see dry mouth when we use lutetium PSMA but it's usually pretty mild.

Charles Ryan: Does that recover?

Michael Hofman: And it does recover over time and I don't think there has been a single patient where we've stopped treatment owing to a dry mouth. Longer-term toxicities of interest, however, are kidney toxicity. The radiotracer is renally excreted. We see that the kidneys light up quite brightly on our post-therapy scans. With longer follow-up, we certainly do see declines in GFR that are more than we would expect. I think if we do a third experiment and we want to bring this treatment back from a last line of therapy to a first line of therapy in men that maybe have a 10- to 15-year life expectancy, then renal toxicity is probably the one of most concern in that population. We just need to be mindful of that and follow these patients up. Unexpected hematotoxicities longterm particularly myelodysplasias or leukemia are another theoretical concern.

Charles Ryan: Hasn't really been seen yet though.

Michael Hofman: We have not seen a single case of myelodysplasia or leukemia in patients that we've treated, but we need to be mindful of that longer-term followup. It could become apparent.

Charles Ryan: Final question. With regards to the kidney toxicity, very interesting longterm concern. Should we be thinking about doing more hydration as we do with platinum-type chemotherapy when we administer lutetium or is it really something about a more slow excretion of the isotope as opposed to something that happens during the infusion?

Michael Hofman: It seems like a dual mechanism. PSMA is actually expressed in the proximal convoluted tubules of the kidney. So there's specific receptor uptake in the kidney and it's also the root of excretion.

Charles Ryan: Okay.

Michael Hofman: There may be methods to decrease that. Hydration is a simple method that has been proven to work. There are some other tricks you can do to minimize kidney dose, but it increases the complexity of administration from a single slow two-minute infusion to coming in and having an intravenous infusion of some molecule. At the moment, we're not doing anything above oral hydration but it's something that needs to be monitored.

Charles Ryan: Well, thank you so much for the update. It's great that the VISION trial is completed and we're waiting for those results, but it's also interesting and enlightening to know about all the combination studies that you're doing and we'll look forward to future discussions on those results I hope. So, thank you for joining us.

Michael Hofman: Thanks, Chuck.