Daniel George, MD: I want to keep us moving. We’ve got a lot of subjects to cover here. One subject that I think is really important, that has evolved in just the last few years is this space—and PSMA [prostate-specific membrane antigen] PET [positron emission tomography] will come up again—of nonmetastatic castration-resistant prostate cancer. I think it is 1 of these areas that’s a relatively new indication for some therapies. There are some updated data here at ESMO [European Society for Medical Oncology Congress]. Chris, walk us through the basics of how we define nonmetastatic castration-resistant disease. What are some of the prognostic factors that we use in that space? How do you follow patients with nonmetastatic castration-resistant prostate cancer?

Christopher Sweeney, MBBS: The entity of nonmetastatic castration-resistant prostate cancer needs to be put in context as to whether you have a treatment paradigm where you start a patient on androgen deprivation therapy [ADT] for a rising PSA [prostate-specific antigen] after their prostatectomy or their radiation. My practice is actually not to do that, by and large. I see very few patients who matriculate through ADT for the hormone-sensitive setting for a rising PSA to nonmetastatic. In other practices, it’s much more common. Some people say it doesn’t exist. I say it exists depending on what the treatment paradigm is in your area. The next thing is, does this entity exist based on PSMA PET imaging?

The studies are very clear. You’ve enrolled on these studies if you were nonmetastatic to conventional imaging. The entity does exist, and they are occult to conventional CT [computed tomography] scan and bone scan. Yes, when you do a PET scan, a PSMA PET, you will find this. The first thing I would say is, does nonmetastatic castration-resistant prostate cancer exist? Yes. We know these patients had cancer, but it’s occult to conventional imaging. Spending all this time saying it doesn’t exist because you got the PSMA PET is missing the big picture.

What we learned from these studies is that if you start these agents early for established cancer that’s got a rising cancer, whether you see it on a PSMA PET or on conventional imaging, these drugs work. When you have a little bit of active growing cancer with a rising PSA or more cancer that you can see on a conventional scan, these drugs work. We’re starting to see that using them early does translate into possibly an overall survival benefit.

All 3 studies are definitely trending in that direction. These drugs work especially in patients who have a poorer risk for outcome. PSA has got a bad reputation because it gives mixed information in some settings. But a rapid PSA doubling time in this is telling you the cancer is growing more rapidly, you’re more likely to see something on a PSMA PET if you don’t see it on the CT scan, and these are the patients who benefit from it. Which patients don’t benefit from it is the harder question. I would actually say it’s easy to justify it in a patient who is 55 years of age with a PSA doubling time of 5 months and their disease is occult to conventional scans. It’s much more difficult to justify it in the 85-year-old who is frail and has a PSA that’s going up, with a doubling time longer than 12 months. Again, it comes back to patient mix, the patient in front of you, their comorbidities, the treatment burden, and the treatment benefit.

Daniel George, MD: Just really quickly. When you say rapid PSA doubling time, how would you define that? What cutoff? Is there a cutoff you use? How do you think of that?

Christopher Sweeney, MBBS: A rapid PSA doubling time in probably a 55-year-old, I would say, is 10 months or less. A rapid PSA doubling time in a frail 86-year-old, I would say, is probably longer than 6 months. I’m willing to watch this a bit longer, so it really depends on context and patient.

Dan George, MD: Fair enough. Good. Yeah?

Bertrand Tombal, MD, PhD: In Europe, we’ve been using these modern imaging technologies since 2005. It started with whole-body MRI [magnetic resonance imaging] and then PET PSMA. We have learned that we actually have to be careful about what we do here because we are converted. We are converting a lot of patients to a stage that may have no clinical significance. The EAU [European Association of Urology] Guidelines 6 months from now change their recommendation and say that you should image with modern imaging anybody which has a rising PSA after prostatectomy, 0.2 or more. Meaning that technically if you have a 78-year-old guy who had a prostatectomy 10 years ago, he should have a PET PSMA when his PSA is that.

I think we have learned that it’s creating what I call an unstable landscape. This is because we know that with this technology you see more things, but we have no idea what to do with it. It became clear in Europe when the European Association of Nuclear Medicine organized a very nice consensus on imaging and diagnostics in prostate cancer. On 1 side you had physicians like myself who said, “You know, guys, be careful, because you still have to prove to me that somebody who had a prostatectomy 5 years ago—whose PSA is going from 0.2 to 0.3—is at risk of death. Because technically he’s not.” Now that everybody is choosing this technique, we should have a word of caution. To me, we’re probably using less hormone, as Chris said, because if you have a rising PSA and your technology is negative, you would delay the treatment. Besides that, we see a huge explosion of metastatic-targeted therapy—meaning the surgical removal of lymph nodes, irradiation of metastases.

I think that this stage of disease, in the hormone-naïve and in the castration setting, is absolutely chaotic. I think that the message should be that treating these patients should be the exception rather than the rule. Something very striking to me was that in the US, when the FDA approved apalutamide, it approved it for nonmetastatic castration-resistant disease, but in Europe it was approved for high-risk nonmetastatic castration-resistant disease.

It should be clear that so far, the best way to rate the high risk is if your recurrence appears shortly after the local treatment, if the Gleason score was high, and if the PSA doubling time is rapid, then it’s clear you benefit from this treatment. But for the other, we have to be careful, including an attributing full prognosis value to a positive new imaging technology. We don’t know. We don’t know how stable these lesions can be. This is where physicians—I believe we are really in a situation where there is a high risk to do more harm than good. For those who have a lot of experience with that, they are now slowing down because we have to be careful.

Daniel George, MD: I think that’s a very good point, and maybe we’ll see some differences between Europe and the US just as we do with MR [magnetic resonance], with some of this imaging as well.

Transcript Edited for Clarity