Dan George, MD: I want to go back to some of the patients that Chris described, some of the older, frailer patients, or the really young, healthy patient, but the patient with that rapid PSA [prostate-specific antigen] doubling time in the traditionally imaged occult nonmetastatic setting. I agree, that’s a misnomer. We’re going to consider this really low metastatic disease burden. But Chuck, there’s been 3 studies now, big randomized studies that have demonstrated some clinical benefit to early androgen receptor-targeted therapies. Do you want to summarize some of that data for us, and give us your take on how you think about this field now and how it’s evolving?

Charles Ryan, MD: Sure. As everybody knows, we now have essentially 4 novel hormonal targets for CRPC [castration-resistant prostate cancer] available—abiraterone, enzalutamide, apalutamide, and darolutamide. Three of these drugs were tested in randomized placebo-controlled trials in the nonmetastatic setting. Abiraterone was tested in this setting but not with a placebo control. Essentially, what was demonstrated is that, and I’m just going to speak in aggregate about the space, placebo treatment in the setting of a relatively high-risk nonmetastatic setting leads to the development of metastasis in a period of around 17 months to 18 months.

Treatment with darolutamide, apalutamide, and enzalutamide all prolong those profoundly, in the range of about 40 months for darolutamide, for example, which is the most recent approval. There’s no question that these drugs are active in that space. What’s emerging now are the data on, well, what does that mean in the long run, in terms of when do patients, if they do develop bony-related pain, when do they develop a decline in quality of life and those type of things. There are some data that are emerging that are worth talking about.

Let me focus on the ARAMIS trial, which is the most recent study in this space and the most recent approval. To get to Chris’s point, these patients had a short PSA doubling time, and I believe this is relatively true for all of these studies. The median for the ARAMIS study was 4.4 months. So these are patients who are going to develop a metastasis. These are patients, many of whom are likely to die of prostate cancer ultimately.

Dan George, MD: Or they’d have occult metastases already. We just don’t see it yet.

Charles Ryan, MD: I would say that they do have occult metastases, yes. It’s not nonmetastatic. It’s not visually metastatic CRPC. The metastasis-free survival with darolutamide is 40 months compared to 18 months with placebo. The PSA progression-free survival, so the time until the PSA rises, is relatively quick—7 months in the placebo arm, 33 months in the darolutamide arm. What that’s telling us is that patients are getting 2+ years of disease control out of these agents.

The data were updated by Dr Karim Fizazi, MD, PhD, at ASCO [the American Society of Clinical Oncology annual meeting] in 2019, demonstrating that reductions in quality of life were delayed with therapy. In other words, what we need to look into is if the disease at this point isn’t hurting the patient, we want to make sure that the treatment is not hurting the patient. I think that’s a key point. All these drugs have adverse effects. All of them are hormonal therapies that can induce some fatigue, hypertension, and rash in the case of apalutamide. So these come at a cost.

But the QOL [quality of life] data, for example, demonstrated that with placebo, the median time to quality of life deterioration was 14 months. That’s pretty consistent with the metastasis-free survival. The time to pain, or the pain-free survival, was about 40 months, for example, in the darolutamide-treated patients. They go a long time before they begin to have symptoms of the disease. All of those are important clinical variables. The time to quality of life deterioration in the darolutamide-treated patients was about 23 months. When you put that together aggregately, it says there’s a pretty good case to be made for treating versus not treating nonmetastatic CRPC. I think there are a lot of open questions about when exactly to start that treatment, how to integrate the novel imaging, and which of the 4 drugs to choose. That’s something that we, as a field, have to wrestle with for a while.

Transcript Edited for Clarity