Alicia Morgans, MD, MPH: Well, wonderful. I'm excited to move us into the next section of discussion where we're really thinking about nonmetastatic castration-resistant prostate cancer [nmCRPC]. Sandy [Sandy Srinivas, MD], I'm wondering if you can talk to us a little bit about the available treatment options for nonmetastatic CRPC [castration-resistant prostate cancer]?

Sandy Srinivas, MD: With nonmetastatic CRPC, there have been a lot of changes that have happened. I think the last, I would say 5 years, the definition that we have had currently uses our conventional imaging, which is really a bone scan and a CT scan, and for patients who are on hormonal therapy, having a rising PSA [prostate-specific antigen] with castrate levels. That's the true definition of nonmetastatic CRPC. Over the years, prior to our approval of many of our next-generation AR [androgen receptor]-targeted drugs based on a unique end point of using metastasis-free survival, we have had patients sit in front of us having this anxiety of seeing their PSA go up. What have we used in the past? We have had the earlier generation of AR inhibitors such as bicalutamide. I still continue to use that in an occasional patient who has a prolonged PSA doubling time just as was alluded to earlier. Somehow, I can't remember the last time I used drugs such as flutamide and nilutamide for this group of patients, but maybe there is a role for those drugs. But the most important thing that I think about is that we have to keep in mind that these patients are asymptomatic. They really have no symptoms. I'm always cognizant of that fact that I don't want to add a therapy that has any worse impact on their quality of life. We have a lot of drugs available to us. Typically, chemotherapy that's approved in prostate cancer, such as taxanes, are not used in this setting, because as we think about toxicity and quality of life, use of chemotherapy in this setting has not been appropriate. Similarly, I think while we are investigating immunotherapy and other novel agents, they are not standard of care in this. We are really left with patients staying on ADT [androgen deprivation therapy] as the backbone, and for those patients who are comfortable, clearly this is, again, a state where shared decision-making is really important. How comfortable is that patient seeing their PSA go up really slowly? For that patient, I think it's completely acceptable to have them just be on ADT. On the other hand, if somebody's really anxious, I think there is an opportunity here for us to discuss what would be the appropriate imaging schedule. Should we be offering them some of our next-generation, AR-targeted drugs?

Alicia Morgans, MD, MPH: Well, that's a perfect segue. Thank you so much for that, Sandy, as we think about the next-generation AR-targeted agents that are actually approved at this point, based on several studies in the non-metastatic CRPC setting. Matthew [Matthew R. Smith, MD, PhD], would you mind walking us through those?

Matthew R. Smith, MD, PhD: Happy to do so. I think in some ways this has been an uphill battle to describe the importance of this disease state. I have a few additional comments to expand on what Sandy already said. If we look at historical data, and even data from the 3 pivotal studies, the control groups are a group of patients whose overall survival with ADT alone is similar to patients who have de novo metastatic disease to bone. This is a serious disease state. It's a fatal disease state. Most of these patients go on to die of their prostate cancer—at least those enrolled in the trials who were somewhat higher risk because of the shorter PSA doubling time. I think, and the fact that they're asymptomatic is important, but so are many patients with de novo metastatic disease, and we happily intensify therapy in that setting. This is an important disease, and most patients go on to die of their prostate cancer. We now have 3 approved drugs with level 1 evidence for massive improvements in metastasis-free survival, and important improvements in overall survival. When I intervene, I'm going to intervene with 1 of those 3 drugs—apalutamide, enzalutamide, or darolutamide—with the purpose of delaying metastasis development test is an improving overall survival. It's the consistency between the trials that I think is compelling as well as the individual trial-level data. We really have strong evidence to intervene in this patient population. You do have to choose carefully. There are patients who are at lower risk for progression, but in those settings, I just will monitor them on ADT alone, and intervene later. It's really a matter of not whether, but when I'll intervene with one of these life-prolonging drugs.

Transcript edited for clarity.