Dan George, MD: Joe, we talked about this with primary ADT [androgen deprivation therapy] and how you counsel patients around these risks. As Chuck said, they’re going to be on it for a long time, so we’re talking 2+ years of exposure just like in that primary ADT setting. There’s accumulation of the ADT effects, plus now you’re adding new adverse effects and things. What’s been your experience in this space treating patients? How do you manage that? How do you talk to patients? Does any of that factor into which of these agents you think about using in certain patients?

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: Yes. I think it’s really important to remember apart from the fact that these patients are suffering the effects of castration, they’re otherwise very well. As doctors, the last thing we want to do is make people worse. That’s very important. For the adverse effect profile, if we look at the data, they’re all slightly different trials but more or less the same patient population. As Chuck says, it is more or less the same type of results. I think the efficacy is fairly similar between the agents. So in making the decision, if reimbursement isn’t the issue, then really it comes down to tolerability. If you get past all the controversy we just talked about and you’ve decided, yes, this patient will benefit from treatment, then it really does come down to the adverse effect profile. Especially with fit, active patients, I think you have to try and maintain that level of fitness.

Yes, we can give them lifestyle advice, but we see from the agents there is quite a difference I think in the adverse effect profile when it comes to physical functioning and even potentially cognitive functioning. To me, in that patient population, that’s very important. Maintaining quality of life in somebody who is really well, it’s an iatrogenic situation.

We have created this illness, as Chris was saying earlier, we made a decision to castrate them at some point. That may or may not have been the right time, and we don’t know that, but we’ve done it. Now they have a doctor-created illness, doctor-created symptoms, and now we’re going to do something else. You have a perfectly well man and we’re saying, “We’ve seen the data, your PSA [prostate-specific antigen] is doubling in less than 10 months or less than 6 months. We think you’ll benefit from this.” “But Doctor, I’m feeling great at the moment.” You’re saying, “I’m trying to delay the onset of something on a scan.”

Dan George, MD: You keep doctoring them.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: We have a big responsibility when it comes to this. I think we believe it’s the right thing to do, but when you’re explaining that to patients, it’s a big responsibility.

Dan George, MD: They’re not going to see that benefit because there’s nothing to see on images.

Joe M. O’Sullivan, MD, FRCPI, FFRRSCI, FRCR: It stresses them out. If their PSA is rising, they’re stressed. If you tell them there’s something on their scan, of course they’re going to be upset.

Charles Ryan, MD: So if a patient has a PSA of 2, a doubling time of 4 months, and you talk about starting apalutamide, darolutamide, enzalutamide, and so forth, what’s the difference between that patient waiting until he has a PSA of 8? To get from 2 to 4 to 8, that’s 2 doubling times. That’s 8 months that he’s not been on a therapy that may induce some adverse effects. In the United States, we have some substantial financial burdens associated with this. We’ll never have the answer to that question.

Dan George, MD: Although on the study, the median PSA was around 9 to 11, so they did just that. They watched for a few to get an accurate doubling time to really be sure. These are the patients who within 3 or 4 scans had metastases.

Charles Ryan, MD: Right.

Dan George, MD: That’s sort of, I guess, the thinking....

Bertrand Tombal, MD, PhD: Although we have to be careful. If you look at the quality of life that has been published for the 3 papers, keep in mind it was mostly measured before progression. What we have learned is that it’s still yet to be confirmed but very interesting that actually, quality of life deteriorates before you see the metastases on the conventional imaging. When you see bone metastases on a bone scan, we know from MRI [magnetic resonance imaging] studies that on average, it’s been there for 6 months. That’s the time it takes to seed, grow, and induce the osteoblastic reaction. This means that it is very likely that the deterioration on what I’m going to call the body and the health status, is actually anticipating the development of metastasis. So it’s about preventing this.

I really believe that the problem is if you are at high risk of progression, to me there’s no reason to wait. I would even warn against the new imaging technology because what we see now is people say, “Oh, OK, I’m going to do a PET [positron emission tomography] PSMA [prostate specific membrane antigen], I see a bone metastasis, and I’m going to give radiotherapy to that bone metastasis as an alternative to starting apa [apalutamide], enza [enzalutamide], daro [darolutamide],” and that is absolutely unproven.

But I think that this metastasis-free survival was chosen because they didn’t want OS [overall survival] and because the regulator wants something very rigid to measure. Actually, when you look and you do like they do for PFS [progression-free survival], you do a “MFS [metastasis-free survival]-plus,” and you look at everything that is before and after MFS. You get a much clearer picture than waiting until the bone metastasis is there, especially with modern imaging technology, that we have to be careful. We may have already lost a major impact on the quality of life.

Christopher Sweeney, MBBS: Can I pick up on 1 thing? MFS-plus is a nice way of describing it. But recognizing regulatory approvals are driven by 2 things—prolongation of survival or using a surrogate that you will be prolonging survival with a drug, or clinical benefit. None of these studies, none of these drugs was improved on delaying the radiographic scan alone. It is annotated by the strong secondary endpoints, as Dr Ryan just described. The quality of life has to be rigorously measured in these non-OS endpoints, and they did, pain, next-line, secondary therapy, PFS-2, making sure the first therapy didn’t negate the benefit of the second therapy. None of these approvals are based on the radiographic issue. It’s the secondary endpoints, as Bertrand just described, MFS-plus.

When you look at the datasets, yes, great, they made it on the first issue, the radiographic, but let’s look at everything else in greater detail. The other thing that’s consistent is survival is in no way being compromised. In fact, it’s all trending in the right direction that early treatment is leading to longer survival.

Dan George, MD: That was the newest thing at ESMO [the European Society for Medical Oncology annual meeting] that we saw, that Matthew R. Smith, MD, PhD, presented, that we’re almost there. We’re so close. This is on the rim of the whole, that ball to just fall in as a definitive. Do you want to summarize that data real quick?

Christopher Sweeney, MBBS: I do. What I do want to say is when I personally look at datasets, and we’ll come to this moment to talk about the hormone sensitive, I look for consistent and reproducibility across the 3 trials. All 3 trials have had enough survival events that it’s trending in favor of overall survival. If you do it in aggregate, I would have Bertrand eat his hat if we do not see an overall survival benefit if we did an aggregate meta-analysis of these. Team, and I’m talking to the team out there, as we’re treating our patients and we’re counseling them on the benefit, let’s look for consistency and reproducibility across the studies wherever they’re done on the globe.

Transcript Edited for Clarity