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Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today a great friend and colleague, Dr. Tanya Dorff, who is a GU Medical Oncologist, and an Associate Professor, as well as being the Head of the GU Cancers Program at the City of Hope Comprehensive Cancer Center. Thank you so much for being here with me today, Dr. Dorff.

Tanya Dorff: Thanks for having me.

Alicia Morgans: Wonderful. So, Tanya, I know that you are a member of the NCCN Guideline Panel and also, of course, a GU medical oncologist who sees many patients clinically, as well as putting many patients on clinical trials. So I always love to pick your brain about how we actually implement what can be a complicated set of guidelines and options for treatment in the metastatic castration-resistant prostate cancer setting.

In this interview, I'd really like to talk to you about how you use radium-223 and how we really choose the right patient for that particular drug and what your timing might be, and what factors you consider when you are choosing that drug. Let's just start with timing. How do you think about integrating this particular tool into your list of options for patients with metastatic castration-resistant prostate cancer?

Tanya Dorff: It's a challenging landscape, isn't it? Especially now that a lot of our castration-resistant drugs are moving to the hormone-sensitive, so lines of therapy have become more complicated. And that is why NCCN really just breaks it down to, what has this patient been exposed to. An advanced AR-targeted agent, docetaxel, both, or neither? I think that is a pretty good way to conceptualize our patients as well until we learn more about any differences between exposures and the different disease states. But radium-223 actually shows up in all four of those boxes, although with some footnotes, some caveats. The ALSYMPCA trial had certain criteria, including two or more bone metastases and symptomatic bone metastases.

So when I'm thinking about radium, I definitely think about the bone burden and, of course, excluding anyone with visceral metastases where we are not going to be adequately treating them. So I don't necessarily only choose people with a high burden, because ALSYMPCA had plenty of patients with two to six bone metastases or six to 20. And then that question of, what is a symptomatic patient, who is symptomatic from the bone metastases, I think, also has more nuance than what people might initially think. You don't have to be on opioid pain medication to have symptomatic bone metastases.

Alicia Morgans: Yeah, I would agree. Just to echo your comments on the NCCN and the updates that have been made most recently, I really love the way things are currently laid out where it is these boxes of what the prior therapies that this patient may have received and then sort of whittling down the treatment options to reflect best practices within the context of prior treatment exposure. Because the changing mechanism of action, I think, is really, really important as we see these cancers developing resistance to prior exposures. And really just to emphasize for anyone listening that I think that has been a major advance in the guidelines and is something that is really appreciated as I'm trying to look at them and certainly as I'm trying to teach fellows and patients about how we think through these options.

To echo your comments about symptomatic bone metastases, I'd like to dig into that just a little bit more because this is also a conversation that I have with trainees and with patients that we don't need, at least in my view, to wait until patients have really substantial pain from metastatic disease in many sites, although those patients can certainly be helped by radium.

This drug seemed to have a survival advantage, of course, it had a survival advantage in ALSYMPCA but really seems to even have a more robust survival advantage perhaps in patients who are less symptomatic in one of the Registry trials that came out of Europe, that may reflect that patient population has a better prognosis in general because it is earlier on and their disease burden is lower perhaps but also may reflect that if we are catching things before the horse is really out of the barn, we may be able to get more cycles into a patient and then hopefully have a bigger bang for our buck with the drug that is delivered. So I use things like fatigue sometimes as a symptom because, at the end of the day, I want the survival advantage, not just the resolution of bone pain, to really drive some of that treatment choice. What are your thoughts?

Tanya Dorff: I completely agree. One of my goals, when I'm treating my patients, is to avoid or at least delay when they might have a symptom, a serious symptom like pain requiring opiates from their bone metastases. So it's wonderful to see some emerging data that supports use in a less symptomatic population. It definitely is important to get all the doses, and we know that low hemoglobin, for instance, predicts patients who won't be able to get through the six courses. And so not waiting until there is so much bone involvement that we are compromising marrow function is also important in selecting the patients who will get the most benefit.

Alicia Morgans: I agree. I think it's also interesting that you and others are using radium in combinations earlier on in the disease setting, even in the metastatic hormone-sensitive setting. Can you tell me a little bit about your particular program?

Tanya Dorff: Yes. Savita Dandapani is one of our radiation oncologists who focuses on prostate cancer, and she designed a trial for oligometastatic prostate cancer patients with bone involvement in the hormone-sensitive setting that incorporates a defined course of ADT. So nine months in this case, plus SBRT, two mets, and radium-223 for the six doses. So we are about halfway through accrual on that trial, and I think it will provide some really interesting insight into what happens when we use this a bit earlier.

And then Neeraj Agarwal at Huntsman is part of a study also using radium-223 early but without ADT. So we haven't had any studies without ADT and radium-223 that I'm aware of, so that will also be very interesting to see how much the synergy that we think about with hormone therapy and radiation really comes into play with this more novel way of administering the radiation.

Alicia Morgans: That's so fascinating. I mean, one study really sort of intensifying and targeting the bone, not just with radium, but with SBRT, and another study kind of giving us a glimpse of what might happen if we don't suppress testosterone, which of course causes all kinds of complications and is never the favorite treatment of course by our patients. So really exciting to sort of push the envelope in that direction.

I think we would be remiss if we didn't acknowledge that as we are doing research, whether it's with radium or with any compound, we have to make sure that we pay attention to safety. And one safety signal that came out in a study that was published a number of years ago, ERA 223, that looked at a combination in the metastatic CRPC setting of abiraterone plus or minus radium, identified that patients who were, particularly patients who were not on bone health agents, seem to have a pretty high rate of fragility fractures with that combination of abiraterone and radium. Of course, there was a higher than expected rate, from my view at least, of fracture, fragility fractures in the abi alone arm too, suggesting that in general, in metastatic CRPC, we've got to do what we know we are supposed to do in terms of caring for bone health.

This is something that I think whenever I'm treating a patient with radium is absolutely part of my treatment paradigm. One of the checkboxes that I ensure is always checked, have I started some bone health agent in appropriate patients unless there is a contraindication when I'm starting radium. What are your thoughts on that?

Tanya Dorff: Absolutely. I completely agree with everything that you've said. It's so critical. Every castration-resistant prostate cancer patient should really be on bone support at the treatment dose. I tend to do DEXA scans as I'm starting hormone-sensitive therapy to look at the bone mineral density and pick out those patients who can benefit from bone support in the preventative dosing schedules from early on. And certainly, as part of our oligometastatic trial, we are including this kind of assessment and a tendency to use preventative bone support just because of those findings that came out of ERA 223.

Alicia Morgans: Agreed. Importantly, I should mention that in PEACE III, which was mCRPC patients treated with enzalutamide plus or minus radium, there was a drastic reduction in fractures when bone health agents were employed, such that really no patients on the arms seemed to have fractures that were fragility fractures after that implementation. So really knowing that there is a problem and then acting on it can actually make a difference is I think very, very important. So as we wrap up, I'd love to hear your final thoughts or your summary on the use of radium in today's era of treating mCRPC.

Tanya Dorff: I think radium-223 has had an expanding role and as people get more familiar with the fact that it is a survival-prolonging therapy and not a palliative therapy that symptoms, as we've talked about, from bone metastases can be defined a little bit more broadly. And there is a lot of interest in combinations. So there are combinations with PARP inhibitors, combinations with immunotherapy, so I think we will learn so much more about what exactly radium does in the tumor microenvironment from some of these ongoing studies that will help us to move forward with the most promising combinations. But in COVID especially, it's been nice to have this as an option, a little bit less immunosuppressive than chemotherapy, and we can sequence it either way. But it's definitely important that clinicians remember this is a great tool to have for our prostate cancer patients with bone involvement.

Alicia Morgans: Great. Thank you. And as we see more and more therapeutic development with other radiopharmaceuticals with novel combinations, this landscape will continue to shift. But I think it's important to ensure that every patient who is an eligible patient has the opportunity to get every available therapy that may be a good fit for him. If it doesn't work, move on to the next one. But let's try to at least ensure that we are able to offer these therapies to our patients to improve their outcomes as we hope that we can.

So thank you so much for taking the time to talk with me today.

Tanya Dorff: It was great sitting here.