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Sandy Srinivas: I'm going to be sharing some slides, which I think our previous speakers have shown you, but I'm going to give you my take on it. So the task for me is really looking at radiation to the primary in patients with high volume metastatic disease. Here are my disclosures.

So the three trials that I'm going to discuss today that led us to using radiation to the primary-- the first study is HORRAD. It's a small phase II study looking at ADT alone versus ADT plus radiation, 432 men, two different doses. Schedule of radiation therapy was used. And I want to point out that this trial only included men with bone metastases. And you can see the survival curve up here, that there was no difference in overall survival.

If you dig a little bit deep into the kind of patients who were enrolled and breaking them down into the number of metastatic sites, patients who had less than five bone mets, it appeared that there was a trend toward statistical significance. The p-value was-- the hazard ratio was 0.68, but it crossed one. So this was the first hint that maybe radiating patients with low volume disease to the primary may have some benefit.

The larger trial was STAMPEDE. So STAMPEDE Arm H looked at standard of care versus standard of care plus radiation to the prostate. This trial enrolled patients between 2013 and 2016, had 2,061 men. I want to point out that the standard of care here was ADT alone. At that time, 18% of patients had docetaxel. And this trial, too, looked at two different schedule of radiation.

Here are the results summed up between the intent to-- the overall population versus the low volume. So in the overall population, there was no difference, no overall survival. But overall survival was seen in low volume. Failure-free survival was improved. Progression-free survival as well as prostate cancer-specific survival was seen in patients with low volume. So like PEACE-1, STAMPEDE too looked at patients with symptomatic local events. And there was no difference in the entire population.

So here's a little bit more digging into the hazard ratio. It's interesting that if you look at patients for overall survival, the low metastatic burden, the hazard ratio is almost identical to what was seen in HORRAD. Here based on the larger number of patients, this was statistically significant. And you can look at the hazard ratio for some of the other outcomes of interest. And it all was favored in the low volume patients.

These are the Kaplan-Meier curves again. So no improvement in overall for the entire group. But for patients in the low volume, there was improvement in overall survival. And you can see the forest plot again showing a benefit for the low volume patients. There was no difference in the radiation schedule favoring either one.

There was a STOPCAP meta-analysis done incorporating these two trials. And I'm just going to summarize the results here that overall, there was no improvement in overall survival. There was an improvement in radiographic progression-free survival as well as biochemical improvement and failure-free survival.

The benefit of radiotherapy varied based on the metastatic burden. And there was a 7% improvement in three-year survival.

That brings us to PEACE-1. You have seen this slide presented earlier. I'm just going to dive into the results. So there was improvement-- so this is low volume patient. There was improvement in RPFS. But what's interesting is not seen in patients who just got ADT alone. The RPFS was only significant in the triplets, so patients who had ADT, docetaxel, and Abi plus radiation.

Similarly, if you look at the overall survival, like Oliver showed, there was no improvement in overall survival for the low volume patients. We haven't really seen a lot of data on patients with high volume yet in terms of survival, but this was the data that was presented looking at the serious GU events for patients with low volume. And my take is that both radiation therapy arms benefited from this GU events.

Now, this was also seen in patients for the overall group. So it appears that even patients with high volume disease, with the addition of radiation to the prostate, there was a decrease in the serious GU events.

So what are the new learnings from PEACE-1? Number one, there's no difference in overall survival in low volume patients. Unlike STAMPEDE, there is improvement in RPFS, but only in the ADT Abi arm and not the standard of care as was seen in STAMPEDE. And there's improvement in GU-related events in both high volume as well as low volume.

So is overall survival needed for every intervention that we do? So use of bone-modifying drugs is a good example where we prevented skeletal-related events, and it's widely accepted in our GU practice without having an impact on overall survival. Similarly, you could argue that local control to prevent bleeding, urinary retention, catheterization is a quality of life issue.

But could there be other things that help us identify who's going to benefit from this radiation? Is it patients with high Gleason score? Does the volume of cancer in the prostate matter? Are there AUA and SHIM scores that may help us identify who are these patients who are going to benefit from radiation? I think the time to GU events in PEACE-1 may help identify who lives long enough to benefit from radiation to the primary.

And one thing that intrigued me is that the current standard of care is not just ADT alone, it is ADT plus a doublet. So we really don't know the benefit of radiation in patients with ADT intensification. So I questioned could there be a comparison between STAMPEDE arm G and H for this question to be looked at, just like docetaxel versus Abi was done?

So I think that's my last slide. And I'll stop here.