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Optimizing Therapy with Radium-223 for Prostate Cancer

Panelists: Joe OSullivan, MD, FRCPI, FFRRCSI, FRCR, The Northern Ireland Cancer Centre, Belfast City Hospital; Johann de Bono, PhD, MB, ChB, Institute of Cancer Research, Royal Marsden Hospital; Chris Parker, MD, FRCR, MRCP, Institute of Cancer Research, Royal Marsden Hospital; Bertrand Tombal, MD, PhD, Cliniques Universitaires Saint-Luc
Published Online: Thursday, Nov 09, 2017



Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Do you think there’s a benefit with radium-223? Potentially, there’s a cohort of patients who would benefit from more than 6 cycles. What do you think, Chris, of radium-223?

Chris Parker, MD, FRCR, MRCP: I’d be very surprised if the current schedule is the best one. It’s the only schedule that’s ever been tested, and we know that it’s effective. We know that it’s well tolerated. But there must be scope to improve upon it considerably, and one way to do that would be to give more than 6 cycles. I think we know already that it’s possible to deliver more than 6 cycles safely. What we don’t yet know is whether it’s more effective or not. The other obvious thing to consider is giving a higher dose each time. Personally, I’m very attracted to that possibility. I suspect that if we were to give a higher dose of radium each time, even if only for 6 cycles, it would be substantially more effective.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I agree, because as radiation oncologists, we know that with almost every tumor we treat, the more dose that you give up to a certain optimum point, usually the better the outcomes. Or there are less recurrences. It stands to reason, if you can get the dose in safely, the higher dose, the better. Obviously, we’ve spoken about docetaxel and abiraterone in the hormone-sensitive space. Do you think there might be a role for radium-223 in that space?

Chris Parker, MD, FRCR, MRCP: Obviously, we don’t know. It’s never been tested, but I think it’s a really important question to ask. I’m very struck that with both docetaxel and with abiraterone, they seem to be considerably more effective in the hormone-sensitive setting rather than the castrate-refractory setting. So, will that be true of radium as well? Now, you’re doing a trial, Joe, in that situation.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yes, well, we’re basically doing a toxicity trial at the moment looking at men with de novo metastatic prostate cancer getting a combination of ADT and docetaxel—because that was basically the standard at the time we presented the trial—and then moving on to receiving 6 cycles of radium-223. At a point when the PSA has usually gone down to fairly low levels, often below 1 ng/mL, we do a bone scan to make sure they still have active disease, and then they have 6 cycles of radium-223. They also have a radical-type dose radiation to their prostate and pelvic lymph nodes using VMAT (volumetric modulated arc) radiotherapy. We try to use the principle of neoadjuvant hormone therapy—as we do in locally advanced prostate cancer—and then hit with the radiation.

We’re trying to use the same concept with radium-223, but this study really is a toxicity trial. Among other things, we’re trying to make sure that there isn’t much overlapping toxicity, potentially some bowel toxicity from the radium along with the potential bowel toxicity from the VMAT. It’s been amazing to see docetaxel and abiraterone having such good effects upstream. There are obviously similar hazard ratios, but just converted to something a lot better downstream. So, I would hope for the same with radium-223, but I think it would have to be patients with bone-dominant disease who would benefit most, actually.

Chris Parker, MD, FRCR, MRCP: I do have a clinical anecdote. I have treated 2 patients, only 2, in that way. These were guys with bone-only metastatic disease when they first presented, and it was at the time when ADT alone was the standard of care. So, these guys got ADT plus radium, and 3 or 4 years down the track they both have undetectable PSAs, for what it’s worth.

Bertrand Tombal, MD, PhD: For people who know ADT, there is an alkaline phosphatase flare; that is, it’s not linked to the testosterone flare. So, you see that also with the antagonist. But in the week following the first administration of ADT, you have intense remodeling in the bone metastases, meaning that you increase osteoblastic activity. That’s what you want when you’re giving radium. That’s probably the time in a metastatic life when you’ve got the most increased bone remodeling.

I’ve been very surprised that nobody used that kind of opportunity, where you give your degarelix—you give whatever you want—and then if you look 2 or 3 days after that, you’ve got a huge increase in alkaline phosphatase if you do a whole-body MRI. And we did some perfusion studies. You show that, actually, you increase a little bit of perfusion in the bone marrow environment. If you do a fluoride PET scan, you’re going to see increased bone remodeling activity. You would say, as a rationale, that it’s the best time to put in a drug that’s going to go where you want it to go.

Chris Parker, MD, FRCR, MRCP: I agree with you. We have got some preliminary data suggesting that uptake on a fluoride PET scan does predict for benefit from radium.

Bertrand Tombal, MD, PhD: Which makes sense.

Chris Parker, MD, FRCR, MRCP: Yes, which makes me a little bit worried about your design because you’re going after docetaxel. So, maybe that’s a bit too late to be ideal.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Perhaps so.

Transcript Edited for Clarity 

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Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Do you think there’s a benefit with radium-223? Potentially, there’s a cohort of patients who would benefit from more than 6 cycles. What do you think, Chris, of radium-223?

Chris Parker, MD, FRCR, MRCP: I’d be very surprised if the current schedule is the best one. It’s the only schedule that’s ever been tested, and we know that it’s effective. We know that it’s well tolerated. But there must be scope to improve upon it considerably, and one way to do that would be to give more than 6 cycles. I think we know already that it’s possible to deliver more than 6 cycles safely. What we don’t yet know is whether it’s more effective or not. The other obvious thing to consider is giving a higher dose each time. Personally, I’m very attracted to that possibility. I suspect that if we were to give a higher dose of radium each time, even if only for 6 cycles, it would be substantially more effective.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I agree, because as radiation oncologists, we know that with almost every tumor we treat, the more dose that you give up to a certain optimum point, usually the better the outcomes. Or there are less recurrences. It stands to reason, if you can get the dose in safely, the higher dose, the better. Obviously, we’ve spoken about docetaxel and abiraterone in the hormone-sensitive space. Do you think there might be a role for radium-223 in that space?

Chris Parker, MD, FRCR, MRCP: Obviously, we don’t know. It’s never been tested, but I think it’s a really important question to ask. I’m very struck that with both docetaxel and with abiraterone, they seem to be considerably more effective in the hormone-sensitive setting rather than the castrate-refractory setting. So, will that be true of radium as well? Now, you’re doing a trial, Joe, in that situation.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yes, well, we’re basically doing a toxicity trial at the moment looking at men with de novo metastatic prostate cancer getting a combination of ADT and docetaxel—because that was basically the standard at the time we presented the trial—and then moving on to receiving 6 cycles of radium-223. At a point when the PSA has usually gone down to fairly low levels, often below 1 ng/mL, we do a bone scan to make sure they still have active disease, and then they have 6 cycles of radium-223. They also have a radical-type dose radiation to their prostate and pelvic lymph nodes using VMAT (volumetric modulated arc) radiotherapy. We try to use the principle of neoadjuvant hormone therapy—as we do in locally advanced prostate cancer—and then hit with the radiation.

We’re trying to use the same concept with radium-223, but this study really is a toxicity trial. Among other things, we’re trying to make sure that there isn’t much overlapping toxicity, potentially some bowel toxicity from the radium along with the potential bowel toxicity from the VMAT. It’s been amazing to see docetaxel and abiraterone having such good effects upstream. There are obviously similar hazard ratios, but just converted to something a lot better downstream. So, I would hope for the same with radium-223, but I think it would have to be patients with bone-dominant disease who would benefit most, actually.

Chris Parker, MD, FRCR, MRCP: I do have a clinical anecdote. I have treated 2 patients, only 2, in that way. These were guys with bone-only metastatic disease when they first presented, and it was at the time when ADT alone was the standard of care. So, these guys got ADT plus radium, and 3 or 4 years down the track they both have undetectable PSAs, for what it’s worth.

Bertrand Tombal, MD, PhD: For people who know ADT, there is an alkaline phosphatase flare; that is, it’s not linked to the testosterone flare. So, you see that also with the antagonist. But in the week following the first administration of ADT, you have intense remodeling in the bone metastases, meaning that you increase osteoblastic activity. That’s what you want when you’re giving radium. That’s probably the time in a metastatic life when you’ve got the most increased bone remodeling.

I’ve been very surprised that nobody used that kind of opportunity, where you give your degarelix—you give whatever you want—and then if you look 2 or 3 days after that, you’ve got a huge increase in alkaline phosphatase if you do a whole-body MRI. And we did some perfusion studies. You show that, actually, you increase a little bit of perfusion in the bone marrow environment. If you do a fluoride PET scan, you’re going to see increased bone remodeling activity. You would say, as a rationale, that it’s the best time to put in a drug that’s going to go where you want it to go.

Chris Parker, MD, FRCR, MRCP: I agree with you. We have got some preliminary data suggesting that uptake on a fluoride PET scan does predict for benefit from radium.

Bertrand Tombal, MD, PhD: Which makes sense.

Chris Parker, MD, FRCR, MRCP: Yes, which makes me a little bit worried about your design because you’re going after docetaxel. So, maybe that’s a bit too late to be ideal.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Perhaps so.

Transcript Edited for Clarity 
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