Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: What do you when a patient has high-risk PSA after castration? The patient’s expectation is that you can do more; this is where we are with the SPARTAN and PROSPER trials. Do you think there are biomarkers when you’re following a patient if they are castrate or nonmetastatic? Do you think PSA dynamics are important, as well as doubling time and velocity, as important indications of metastatic disease? Or are there other signs that you would look for?

Noel Clarke, MBBS, FRCS, ChM: The critical question is, how likely is a patient to die of prostate cancer? There are some groups around the world who’ve looked at this in a very thoughtful way. If you take the data from Johns Hopkins—which has a pioneering center for radical prostatectomy—you see very brave patients forgoing hormone therapy until they get metastases and Mario Eisenberger, [MD]. The team there has looked at patients who had rising PSAs postprostatectomy. Some critical factors shown were PSAs below 10 and a doubling time combination of the 2. There’s a whole trial for patients who aren’t going to die from their disease—who are 10, 15 years out and not progressing.

By contrast, there is a group with a much higher PSA and rapid doubling. We know that they’re the ones who may potentially be in trouble. The absolute level of PSA level and kinetics is important. I think the grade also plays into that and the biology. We know that certain high-grade tumor faces with cribriform architecture are bad actors; they’re the ones to pick out from the crowd, so to speak.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Nick, would you differentiate a patient who’s recurring postradiotherapy versus postsurgery?

Nicholas James, MD: With postsurgery, you’ve potentially got the option of salvage therapy, and so we tend to put both groups through PET scanning because often you’ll find that the relapse is outside the area you treated and you’ve got a second bite at the cherry, which is at the very least, hormone therapy.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: The idea of stereotactic radiotherapy or some form of local therapy to the metastases.

Nicholas James, MD: And there’s some very important data being presented at the American Society of Clinical Oncology 2018 Annual Meeting, at the other side of the world, showing radical advances in radiotherapy with stereotactic techniques, the oligometastatic disease and prolonged survival at randomized phase II.

In the M0 CRPC setting, again, I agree with Noel. There’s a subgroup of treating in the progressed metastatic disease…who went into the SPARTAN and PROSPER trials, which showed that you’ve got a big delay in your time to progression with metastatic progression by adding upfront androgen receptor [AR]—targeting therapies—2 very similar drugs.

I also saw some quite concerning side effects: increase in falls and deaths from non—prostate cancer causes. You’re certainly harming some of these people—you may be benefiting more, but it’s not without risk and harm. Neither trial has shown an overall survival [OS] gain; however, there was a trend toward an OS gain. I question whether you need to give that much treatment early on.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: You mentioned the endpoint of these studies that we have these drugs and their approval is metastasis-free survival. What do you think about that as an endpoint in this setting?

Nicholas James, MD: I’m a bit worried that it’s not the right endpoint because, by the time they get their metastatic progression on apalutamide or enzalutamide, you have comprehensively used up one of your main CRPC treatments. So you’re left giving them chemotherapy, basically. I know people will say, “Well you can give them abiraterone and enzalutamide together.” But we know that these drug combinations are no different from just giving one really. The median time to progression and the gap between your first and your second assessment are the same; you’re just burning money. They’re going to be looking at chemotherapy and not much else—perhaps radium. I’m skeptical that these will ever mature into much of a survival gain.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: You don’t think it’s a meaningful endpoint? Obviously it’s not, regarding OS.

Nicholas James, MD: I think it is. I was in a session this morning arguing that not relapsing is good for your quality of life, but it depends what price you have to pay to not relapse. If you’re giving agents that are profoundly depleting all your antigens, that is bound to be affecting quality of life—it will affect your muscle bulk and bone density potentially. It certainly affects your energy levels and so on. I’m not sure your quality of life unrelapsed in that state is quite the same—it’s certainly not the same as not being on treatment.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: There’s likely some financial toxicity as well for these agents in this setting.

Nicholas James, MD: Yes.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Noel, what do you think? These drugs have been approved by the FDA in North America. What do you think of the European situation? How would things evolve here in Europe with regard to these agents, apalutamide and glutamide in the M0 CRPC space?

Nicholas James, MD: There will be a demand. It will be different in different European countries as to how it’s handled from a regulator standpoint. Coming from the United Kingdom, we know that the NICE study will look at this—at the cost and benefit, and they’ll turn it into some kind of quality-adjusted life and ask the question: How many life years has this saved and at what cost to the taxpayer? I expect they will turn it down, but we’ll see.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Neither trial showed a quality-of-life or OS gain, so it’s hard to see how there’s any quality gain at all. I think it’s unlikely they’ll approve it. If I were a part of the NICE study, I would reiterate the guidelines, which is to just monitor people and intervene with early metastatic disease. We’ve got good data as to what strategies worked for prolonged survival.

Nicholas James, MD: We know we can prolong survival in that setting.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Maybe we’re overtreating and potentially exposing patients to the risk of bone health as well as general physical decline.

Nicholas James, MD: Absolutely, and there’s not just the financial cost but the cost of time, monitoring and doling out all these pills, assuming they were funded. I’m skeptical that these are really significant advances.

Noel Clarke, MBBS, FRCS, ChM: One thing that we’d be lucky enough to show is the end—your part of the STAMPEDE study, which I have to say has been largely ignored by the international community.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Yes.

Noel Clarke, MBBS, FRCS, ChM: Is that a relatively short burst of intensive treatment, be it with docetaxel [Docefrez] or with abiraterone in the M naught? High-risk settings actually yield a great deal of benefit. For example, in the abiraterone-treated group of M-naught patients, the event rate—failure rate—after 2 years has been very small. What we know is that the delta effect, or the amount of benefit you receive from treating early rather than treating in castrate-resistance setting, is much greater. My gut feeling is that we should concentrate on isolating and identifying those high-risk patients early on and treating them aggressively, rather than treating them after they fail.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: We’re thinking of unmet needs in this area, it’s really that—identifying those patients.

Noel Clarke, MBBS, FRCS, ChM: Yes. Stopping them from failing in the first place.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Better treatment early on, yes.

Nicholas James, MD: I entirely agree: If you look at the failure-free survival hazard ratios of both docetaxel in M0 and abiraterone in M0, they are bigger numerically than the hazard ratios in the M1 setting. It looks as if these drugs work better in the M0 than the M1 setting.

Transcript Edited for Clarity