Importance of Lifestyle and Prevention of Complications in Advanced Prostate Cancer: How to Take Care of the Bones? APCCC 2022 Presentation - Oliver Sartor
September 1, 2022
A. Oliver Sartor, MD, Professor of Medicine, Urology, and Radiology, Director Radiopharmaceutical Trials, Mayo Clinic, Rochester, MN
Oliver Sartor: It's a pleasure to be here and want to give Silke a really tremendous thank you for the seventh year. Going back to 2015. Remarkable achievement and really a pleasure to be here, not only for the conversations in the room, but for the conversations outside of the room. Enjoy it. So I'm going to talk about the bones and there are a few things that we'll be discussing. And by the way, not a lot of it is very new.
It turns out, we're going to start, with castrate sensitive bone issues, and it's going to predominantly about fractures and bone-mineral density. If we look at what I think is some really good data, and I think one of the first papers to really draw attention to this important problem, it was actually from a Medicare review. And so to emphasize these fractures may be different than what could be measured. It is not necessarily vertebral fractures. These were events that were documented within a Medicare record and all the patients had to be followed for a minimum of five years and they could be either metastatic or non-metastatic. They couldn't really make those distinctions with certainty.
But what you could see is an unequivocal relationship between the use of either GnRH agonist orchiectomy and the risk of fracture. Now you'll also note that fractures occur in this age group, even if you're not on androgen deprivation. That's something to keep in mind. There is an older group of individuals who will have fractures and those are going to be happening no matter if you're on androgen deprivation or not. So you're never going to get down to zero.
One of the new pieces of information we saw from piece one, recently presented, was the fact that bone-mineral density, when you add abiraterone to an ADT docetaxel background, is not particularly consequential. And I was a little bit surprised because we were adding in, not only abiraterone, but prednisone. We all know the effects of prednisone. But the bottom line is that the effects of BMD were not particularly impressive.
If we want to look at some impressive data, we can come to Matthew Smith, and Matthew I know is in the audience, and look at the data from Denosumab. Now, these, if you look are going to be the new vertebral fractures at 12, 24, and 36 months. You see an unequivocal diminishment in that fracture risk by the use of Denosumab. And by the way, this is 60 milligrams q 6 months.
Additional interventions. This actually gets to an interesting topic. The importance of lifestyle and preventative complications. If we actually go to look at the data for calcium, vitamin D, and exercise, we don't actually find a great deal.
Now exercise has many benefits, but if we actually want to point to an intervention trial of exercise to show fracture reduction, well, let's just simply say you can't find that. Nevertheless, I think that exercise is appropriate to recommend for cardiovascular and other fitness importance issues. And also the bisphosphonates. There's a whole variety of oral and IV bisphosphonates indicated for osteopenia and osteoporosis. Not specifically studied in the context that prostate cancer and ADT, but nevertheless, it's proven that we have a variety of bisphosphonates that can be effective in treating osteopenia and osteoporosis. Now, one thing that we know, and again, this is from Matthew Smith, I can't see Matthew, but I know he's out there somewhere, that you look at SRE benefits for bone metastatic castrate sensitive prostate cancer. And there's absolutely no benefits seen whatsoever. So this is important pieces of information. Then we can go on to castrate resistant prostate cancer, and the issues are a little bit different.
You know, now we're talking about bone metastatic disease in addition to the possibility of fragility fractures, osteopenia, osteoporosis, but it's pain and fractures and spinal cord compression and radiation to bone and procedures, orthopedic procedures for bone. And these are captured in SREs and SSEs as composite endpoints. And these are reported in a variety of trials, but often you have to drill down and look at the individual components be able to get a good understanding.
Now, Fred is on the podium and Fred is sort of the master of this particular space. He's going all the way back to 2002 and you see Zoledronic acid, 4 milligrams. Interestingly, the eight four is sort of in between being better than placebo. And by the way, there was almost a survival advantage in this trial. If you look at the survival statistics, it's almost statistically significant for survival, this use of Zoledronic acid. But in 2002, we really didn't have a lot of effective therapies and that has to color the way we view these data. Because there's no ABI, there's no enzo, there's not even any dose in tact. From Kareem's very important article comparing monthly Zoledronic acid in Denosumab and looking at SRE rates, you can see that Denosumab actually comes out with a superiority. There was not an inferiority and a superiority, but actually there's a small superiority you see here with a hazard ratio of 0.82.
Now, if you're using effective therapies, in and of itself, and effective therapies are so critical, you can actually reduce the SRE rate. This is from the [inaudible 00:06:33] 301 trial and you can see [inaudible 00:06:38] was able to present this hazard ratio 0.615 unequivocally improved with the use of abiraterone and prednisone. Here, you can look at SRE rate being reduced by effective therapy with Enzalutamide. This is the prevailed trial.
Here you're looking at SSE swipe distinction between SRE and SSE reduced by effective therapy and metastatic CRPC with Radium. And now this was published in the New England Journal. And then you can look at some interesting interactions that occur between the bisphosphonates and Radium. And the bisphosphonates might actually make the Radium bind a little bit tighter because the Radium will be binding to the areas in the bone matrix that are enhanced by the use of the bisphosphonates. It's that osteoblastic reaction; that osteoid in the bone that is the region of radium binding. If you look on the left side, you end up with a hazard ratio of 0.49 for the SSE rate when you combine Radium and bisphosphonates. But no bisphosphonates with Radium the hazard ratio was 0.77 did not meet statistical significance.
Now, one of the things that's been a little bit surprising is the combination of Radium biraterone Enzalutamide together. And the ERA-223 trial, which was a abiraterone prednisone plus or minus Radium-223, it turned out that it was unbinded early by the IDMC because of adverse findings. Now I chose one figure. This is from the pharmacovigilance risk assessment committee of EMA. And what you see is a dramatic increase in the time to first fracture. And about half of these were pathologic fractures about half were non pathologic and really striking data, and quite surprising, and it looked like this was going to be an interesting combination. And then all of a sudden, a bit derailed by these adverse events.
Now, if we go to piece three, and I'm glad that Silky's sitting to my right, because this is her presentation and ASCO 2021 in oral. And if you look on the left hand side, you can look carefully and see that the Enzalutamide and Radium-223, when used without bone protective agents, have a dramatic fracture rate is 52% after 21 months. And with the Enzalutamide is 21.9%. Actually reaches that after 15 months. But this is a pretty striking finding. And if you use the bone protective agents, you can see the dramatic reduction. Now there's a lot of complexities here and I'm not going to go into the detail. This is not a randomized data set, but what it is, is it's after an intervention from the IDMC, which noted some problems and mandated the use of the bone protective agents going forward.
On the next slide, you can see a different graphical representation of these data. And again, if you look at that combination of Radium and Enzalutamide, you can see this tremendous fracture rate going up to over 50%. Enzalutamide is the next line down. And then with the BPAs, you can see how much improvement is detected. Although there are small numbers out on the right hand side.
Now there's some caveats to these important issues. Caveat number one, underuse. Various studies continue to indicate the bone health agents are underutilized, pretty much in all settings. I went to the VISION trial just cause I figured that's a recent data set and I've looked up and concomitant bone health agents. And remember these are people who'd failed either Abiraterone Enzalutamide, also failed [inaudible 00:10:19]. This is metastatic CRPC pretty far advanced. Only 56% of the patients had concomitant bone health agents being utilized. I can cite the real world evidence from multiple countries. I just pulled up some things and looked at data from the Netherlands. I looked at data from Australia. I looked at data from the USA. It doesn't matter. The bone health agents are underutilized in all geographies around the globe.
Now, one of the things that's a little been interesting, and this has not been well publicized, are the rapid bone-mineral density changes that occur after stopping Denosumab. This is post menopause women and was when it was first sort of noted. But if you look here on the lumbar spine, and then on the total hip, you could see the building of the bone-mineral density, and then the loss after discontinuing the Denosumab. And it's really quite striking here. Now, it's not just bone-mineral density. It also turns out that there's a risk of vertebral fracture after stopping Denosumab. And so it turns out that this is a clinically relevant finding and one that has not gotten a lot of publicity along the way. So it's one of the reasons I wanted to bring it into focus here.
Now again, if we go back to another Soki paper, we look at patterns of care and economic consequences for castrate sensitive prostate cancer with boney metastasis. And this study found that in this particular indication, where something like Zoledronic acid used monthly is appropriate in CRPC, it is not appropriate in castrate sensitive. But nevertheless, there was a fair amount of use still going on, despite the fact there's level one data to suggest that we should not be using it. And here Michael Morris and colleagues also noted the same thing in the United States. And it turns out that about a quarter of patients receive, they called it bone modifying agents, and this over years led to excessive cost and potential toxicity.
So perhaps a quick summary of some of these current issues that I think we need to address. Bone health agents continue to be underutilized and that's without regard to geography. And I think it's true both in the context of the castrate sensitive as well as the castrate resistant disease. I think we need to be aware that Denosumab sensation is associated with the rebound risk of fractures that hasn't been very well publicized, but is something that could be appropriate and actually was addressed with an APCC question as well. I have to note that overuse of SRE agents persist in castrate sensitive prostate cancer. We have good data to suggest that this sort of SRE management that we use in castrate resistant disease is not appropriate for those with metastatic castrate sensitive disease.
And I'm also going to say that dosing intervals are not fully resolved. There's still loss of information available about dosing in [inaudible 00:13:34]. It appears as though three month intervals are probably the equivalent of one month intervals for these agents. We have our standard osteopenia regimens, our standard SRE regimens. We don't have doses scheduled comparisons. We do have some comparative trials and I'm not going to go into them, but there's a little bit of complexity. Some are discontinuation, somes are startings, and it turns out that in the breast cancer world, there's pretty good data that Zoledronic acid, about every three months, is not inferior to q monthly. And there's also the react BTA trial, which shows not only breast, but also prostate cancer falls into that domain. And so with that, I'll finish up. Pleasure to be here. And thanks again to [inaudible 00:14:27] for making a great conference.