Chris Parker: Thank you very much. Thank you. So it's a great pleasure to follow Dr. Saad partly because he is such a giant in the field and partly because he's made my job much easier. So my main argument is that nowadays we need to worry much less about SRE prevention and much more about bone health protection. And of course, I am sure Fred has already convinced you of the latter. Here are my disclosures.

So the story about SRE prevention of course starts with Fred's pivotal trial started more than 20 years ago. It was a three-arm trial looking at two different doses of zoledronic acid compared with placebo in men with bony metastatic CRPC. And as we all know, it showed a benefit for the lower dose of zoledronic acid in terms of SRE prevention.

Now when we saw that result, obviously it's very important and we should have been very excited. We should have thought, right, what are we going to do now? We're going to work out which bisphosphonate to use, which dose to use, what frequency, for how long, who benefits the most, what drug combinations. There are so many questions we can ask with lots of clinical trials, and what did we say? We said all our patients are going to get four milligrams of zoledronate every month, hence forward. 

And that was just so simplistic and as time has gone on, we're starting to learn, I think, how wrong that was. So here's a table of the component parts of the SRE definition and what you can see is that the most significant advantage for zoledronic acid was in terms of fracture prevention. So we haven't got any compelling data here that zoledronic acid actually prevents surgery, orthopedic surgery or radiotherapy or spinal cord compression, but it does prevent fractures.

They're called pathologic fractures in this table, but maybe they were, maybe they weren't. They may have been at the site of metastasis and being pathologic, they may have been fragility fractures because of poor bone health. And the magnitude of reduction was 39% and I'll come back to that later.

Now we should have been much more circumspect about how we interpret this trial for all sorts of reasons. First of all, zoledronic acid was given for a relatively short period of time, median of just nine months. The fractures were detected with the benefit of a skeletal survey every three months. So many of them were asymptomatic and perhaps not worth preventing.

Interesting that the lower dose was better than the higher dose. But that doesn't mean to say four milligrams is the best dose, maybe four milligrams is too much. And fundamentally there are only two reasons why we treat our patients, to help them live longer or to help them live better. And this drug didn't do either of those things. It didn't improve quality of life or overall survival.

Now, quite clearly you don't need to use four milligrams of zoledronic acid every three or four weeks and we've now got data to support that which includes a substantial proportion of prostate cancer patients, a trial comparing monthly versus 12 weekly, zoledronic acid, and there's no difference in terms of skeletal-related events. So if you do want to use zoledronic acid for SRE prevention, then three monthly is certainly enough, if not too much.

Now, so much has changed over the last 20 years and all these changes mean that there's much less benefit for SRE prevention. So first of all, overall survival is more than doubled. So if you're going to use zoledronic acid every month, your patient's going to get it for much longer. And we know that increases the risk of really unpleasant toxicity such as osteonecrosis of the jaw. So we've got safety data from Fred's trial for nine months, but if patients are on this drug for years, this is what's going to happen.

Not only is the toxicity worse now than it was 20 years ago, but the benefits are less now because patients are at less risk of the complications of bone metastases. So on the left is Fred's trial, the median time to SRE in the control arm was 11 months. On the right is data from PREVAIL, it's three times longer. The rate of skeletal-related events is much less in the clinic nowadays.

Now, okay, it's not a fair comparison because not all patients have bone metastases when they went into PREVAIL. What about ERA 223? So they all had bone metastases. But again, the time to SRE median is substantially longer now than it was then. Well albeit, some patients who are getting a bone health agent, but it's not a small difference. It's a massive difference. Patients are much less likely to get SREs now and of course it's because our treatment's more effective. We are controlling the bone metastases for a longer with abiraterone, enzalutamide, chemotherapy, whatever it may be.

Before I move on, there's one very good point about ERA 223. They made a good effort to distinguish between pathologic fractures and fragility fractures and the large majority were not pathologic. They were fragility fractures. So once again, it emphasizes that we shouldn't be so concerned about all the complications of bone metastases, rather we should be focusing on bone health.

Not only are SREs less common than they used to be, they've also changed in terms of their distribution. So here I'm comparing the data from Fred's trial in blue with PREVAIL in orange and you can see the proportion of patients getting spinal cord compression hasn't really changed. Proportion of patients requiring radiotherapy for bone pain hasn't really changed, but a substantial, huge difference in the risk of fractures. And remember, fractures is the one type of SRE that's on zoledronic acid actually prevents. So the potential benefit from giving monthly zoledronic acid is much, much less now than it used to be. Toxicity is greater because of the duration being longer. Benefits are less because the underlying risk is less.

So this slide is a statement of the obvious, but it can't be said often enough. Our patients are on ADT for longer, that means their bone health is worse. We're giving them drug after drug that also impairs their bone health. So SREs are less common because the metastases are controlled better, but fragility fractures are more common.

Now in the UK, we've taken a different approach to this. So this is information from the NICE osteoporosis guideline. So it's not specific to prostate cancer, it's for the general population. And they say that oral bisphosphonates are recommended if the 10-year probability of fragility fracture is 1%, incredibly low. I mean to put it in the context of FRAX, a healthy 60 year old man with no risk factors in the UK has about a 4%, 10-year risk. So in other words, pretty much all our patients should be on an oral bisphosphonate. Now how can it be so low? Well, the reason is because oral bisphosphonates are incredibly cheap, about 10 pounds per year.

If I must divert for one moment, Brexit is an unmitigated disaster. But if you want a silver lining, it does make it easier to convert costs from pounds to euros to dollars because they're all worth the same now. So it's 10 euros per year if you want to treat with an oral bisphosphonate.

So in the UK, the prostate cancer clinical excellence group has met and has come up with this recommendation. So for anybody starting androgen deprivation therapy, we recommend the lifestyle measures you've heard about. And if anybody starting treatment for more than a year, we recommend an oral bisphosphonate. So I mean, Fred said his schema was simplistic. This is even more simplistic, but I think it's so simple. We could actually do it. And this is about what we're doing in practice now.

Now there's a wealth of data concerning oral bisphosphonates and this is one of the first phase three trials that demonstrated. And the reduction in fracture risk is about the same as monthly zoledronic acid in Fred's trial. There's a huge systematic review. It runs to hundreds of pages and the bottom line is it doesn't matter what bisphosphonate you use, it doesn't matter whether it's IV, oral, it doesn't matter what dose you use, they're all equally good at preventing fractures.

Now if you're going to tweet one of my slides, this might be it. This is one of the most interesting trials you've probably never heard of and you've probably never heard of it because it's a breast cancer trial, not a prostate trial, but it's a phase three 1400 patient randomized trial. Patients with metastatic bone metastases from breast cancer, randomized to monthly IVs zoledronic acid versus an oral bisphosphonate. And look, there's no difference in the risk of SREs.

So in summary, back 20 years ago, we probably over interpreted Fred's excellent trial. There never was a good case for giving zoledronic acid every month. But now the case has changed greatly. If we keep on using it for longer, we're going to increase the risk of toxicity. Our patients are going to get less benefit because they're not likely to get SREs anyway.

And in particular, all our patients now should be on an oral bisphosphonate from the time they start ADT to protect their bone health so that when they become bony metastatic CRPC, there is no evidence at all that they benefit from additional zoledronic acid or denosumab or any other intervention. Thank you.