Alicia Morgans, MD, MPH: Matthew, can you go to the next step on that? What are the factors that describe the patient in whom you're going to do that intensification and you've decided that patient now needs to get that additional therapy?

Matthew R. Smith, MD, PhD: Of course, we all apply the same principle: when are we going to do more benefit than harm? That considers the disease characteristics as well as the age and health of the patient. There are patients who are older and more frail about whom you're going to have your reservations about intervening, whether it be for nonmetastatic CRPC or mCRPC [metastatic CRPC], but the disease characteristics are going to be close to meeting the criteria for the trial, which was PSA [prostate-specific antigen] greater than 2 and a PSA doubling time of less than 10 months. With a few exceptions, I'm going to intervene in those patients unless there's a compelling reason not to do so. Then in the lower-risk population, I think it's more of a judgment call, and those are typically patients who I might choose to initially monitor, but again, it's not a matter of whether, but when you'd intervene, and Scott [Scott T. Tagawa, MD, MS, FACP] made a really nice comment earlier, which is that we now know from PSMA [prostate-specific membrane antigen] PET [positron emission tomography] imaging, that nearly all these patients have metastatic disease, and that should come as no surprise. We knew that when the studies were designed that the terminology is a little problematic, and I like to say we chose the terminology “nonmetastatic CRPC” because the alternative of mCRPC was already taken in the labeled indications of the drugs that were approved in metastatic CRPC.

Alicia Morgans, MD, MPH: That all makes a lot of sense. Thank you for walking us through that. Now, Evan [Evan Y. Yu, MD], there has been additional data that's been released on the SPARTAN, PROSPER, and ARAMIS trials related to quality of life, for example. I wonder if you can talk to us about the extended follow-up data that has been presented and maybe that quality-of-life data, as well as any comments on the subgroups that may respond. What are your thoughts as we have all of this additional data as part of these studies. How do those data points affect your decision making?

Evan Y. Yu, MD: I think I'll start off with saying that when these 3 trials first read out with apalutamide and enzalutamide and darolutamide, the first end point we saw was metastasis-free survival. It took a while for the field to really adopt that, but fortunately, we've seen from some other analyses outside these trials, like the ICECAP trial data, that we do believe that metastasis-free survival is a reasonable correlative end point with overall survival. First off, eventually, the first things that we needed to see after metastasis-free survival was that overall survival was confirmed in these trials, and it was in all 3 trials. Then, there are many other additional long-term follow-up reports looking at safety data. There were some thoughts initially that maybe in 1 of the trials, there might have been a little more cardiovascular events, but you also have to consider that the patients are on the study drug a lot longer, and they're exposed for a longer duration of time. There were some thoughts that we're not supposed to do this, but in cross-trial comparisons maybe some studies showed patients that had more adverse events than others. But when you look at the different studies and you analyze that, it all depends upon how often you ask the patient or how often you see the patient in regards to adverse events. I think the summary is that what we've seen with more long-term data and post hoc analyses and quality of life studies is that we don't see a major decrement in quality of life. These agents are efficacious and they do benefit the patients for multiple long-term outcomes and secondary outcomes. We don't see significant long-term toxicity from these agents. Of course, there are some adverse effects that we expect, like fatigue, for instance. There's always the tiny, tiny risk of seizures that is essentially negligible in these earlier disease states, but the long-term follow-up has been very, I think, beneficial for offering reassurance to all of us that we can start these agents earlier. We can treat these patients for many, many years and not see terrible things happen.

Alicia Morgans, MD, MPH: Well, thank you for walking us through that, Evan; that's very helpful. I wonder from your perspective, Scott, as you think about the overall survival data that Evan and Matthew mentioned, what are your thoughts in terms of the control arm? Really, in most cases, for many of these patients actually getting additional active therapies that should be life-prolonging therapies against prostate cancer, and still we saw this overall survival benefit. How do you interpret that, and how does that affect your treatment decision-making in this space?

Scott T. Tagawa, MD, MS, FACP: Part of the question is, first off, the combination of not just prolongation-free survival, but also overall survival, plus the quality-of-life data overall with no significant detriment—that's how I'd interpret them all together, which would make me say that we should use these drugs appropriately. I agree with them that it doesn't mean that there are no adverse effects. But even if there is a patient that happens to have 1 of these rare fatal adverse effects, whether it's 100% related or not, but a seizure, a myocardial infarction, or something like that, it's very clear that the overall survival or all-cause mortality was improved. I would take it case by case; optimize the control of any comorbidities. If I think someone has a life expectancy for other reasons, and as Matthew mentioned before, if I don't think that's right for that patient, then I don't think that's a good idea. But overall, I think for this patient population, we have 3 trials and we know that they're beneficial. And these are on top of data that came from, like Matthew looked at before, some of the prognostic factors of PSA doubling time in this patient group, whether we're talking about bisphosphate, an endothelium inhibitor, or whatever else.

Scott T. Tagawa, MD, MS, FACP: The other parts of what you asked, if I remember correctly, Alicia [Alicia Morgans, MD, MPH], in terms of the context of crossover, whether it's direct crossover or an indirect crossover, is that they got those therapies, and in my mind, we've seen this multiple times in this setting. And now, in a noncastrate or hormone-sensitive setting, a good drug up front is going to have a bigger impact than we can catch up later. So, it's another reason in this setting, if I see a patient with a particularly rapid rise in PSA and I don't see anything on CT or bone scan, I'm going to start these drugs earlier. Not that they wouldn't work if I can see them on metastasis but I think they have a bigger benefit when they start earlier.

Transcript edited for clarity.