Dr. Phillip Koo:

Welcome to Prostate Cancer Patient Voices. I'm your host today, Phillip Koo, and I'm joined by the Nick James, who is Professor of Oncology at the Institute of Cancer Research and Consultant to the Royal Marsden Hospital in London, United Kingdom. Welcome, Nick.

Dr. Nick James:

Thank you very much.

Dr. Phillip Koo:

So today we're going to talk about clinical trials and try to boil it down in easy terms so patients understand. So let's start off at a high level and why are clinical trials important?

Dr. Nick James:

Well, it's obviously the root for getting a new treatment, a drug, a surgical technique, a radiotherapy technique into practice in order to... Particularly for drugs, just focusing on those for the time being. New drugs are typically very expensive to develop but also and therefore very expensive to buy by healthcare system. So you have to have robust evidence that they do what they say on the tin, that they actually work, they improve outcomes, they have acceptable side effects and so on.

So we have a very well established paradigm for this, which is if you've developed an interesting compound in the lab, the first stage of trials, phase one trials, logically enough, is you're testing it to see what the side effects look like. Are they what you predict? They should be from the previous animal work which would have been done as part of the development process, and do they have early evidence of activity? And typically you'll be doing phase one trials in patients who've got very limited standard treatment options available.

The next stage is, if you've got something that is acceptably toxic or non-toxic and has useful levels of activity, you seem to tumor shrinkage, you then will do a phase two trial and you'll take the optimal dose from your phase one and treat a larger cohort of patients potentially earlier on in the disease course as well with the aim of establishing whether you do indeed have a worthwhile level of activity for the drug with an acceptable level of side effects.

And drugs that get through that hurdle will then go into a phase three trial where you compare your new treatment against whatever is considered the standard of care. So this is randomized. Patients don't select which arm they get and other clinicians, patients are allocated at random between the two. So any differences that arise due to case mix are mitigated by the fact that you've randomly allocated so you haven't selected good patients for one and bad patients for the other.

So that's the broad paradigm. It's changed a bit in recent years by blurring the margins between phase one, phase two, phase three so that you don't stop, start, you just seamlessly perceive. But that's the broad paradigm that we're using.

Dr. Phillip Koo:

I think that's really helpful for patients to sort of see that progression and it is much more complex in reality as you referred to, but sort of that one, two, three progression. So for patients who are diagnosed with prostate cancer, they're getting treatment, when should they think about a clinical trial? When should they talk to their physicians about potentially enrolling in a trial?

Dr. Nick James:

Well, really at any stage. I mean, you can run trials of diagnostics upstream of even being diagnosed. So there's a big trial running in the UK at the moment called TRANSFORM, which is looking at different ways of early detection for prostate cancer. So this is people who haven't even got cancer.

And at every subsequent point, typically the points at which you can enter a trial at the point where downstream will be a given treatment has stopped working. So you have the option then of switching to whatever the standard treatment is versus going in a trial which may be any one of phase one, two or three, as I've just described, there might be a new drug or it might be a phase three trial of something that looks promising against the standard treatment. There's all the options.

Dr. Phillip Koo:

So for patients, I think it's often challenging to deal with that scenario because there's standard of care. Obviously you want to maximize outcomes as much as possible and reduce any toxicities. So how do you know if you are going to get potentially something better than standard of care? And then how do you balance the fact that these trials sometimes are, it's either you get the drug or you don't. And obviously if you're going to go down this path, you would prefer to get the drug.

Dr. Nick James:

Sure, for sure. So for patients, obviously you're going in a trial in the hope of getting a new treatment. So if it's a single arm trial, that's to say everybody in the trial is getting the new treatment, you know you're getting the new treatment obviously. And that is typically the case with... The catch here is that the phase one trials, early phase two trials will often be single arm.

So you've got something that's got a shorter track record and a more uncertainty about how well it works and the side effects, but you've got a 100% chance of getting the drug. If you go into a phase three trial, then you've got a chance of getting something that, you only put something in a phase three trial if you think it's likely to be better than the standard treatment. So it's a reasonably good bet going in a phase three trial because the worst that can happen is you get the treatment you'd have had anyway.

The best that can happen is you get the new treatment and it turns out to be better. And I think that the other thing about phase three trials in particular is in order to be a robust test of the new treatment, you have to ensure that the patient's on the control arm are getting the best possible care as well. So you're comparing to the best standard, not to some random assortment of different treatments.

But often patients find that quite reassuring anyway. And typically, our trials will have a research nurse or other clinical data staff associated with the trial. So you get additional points of contact if you have problems over and above your standard of care. So there's some distinct advantages, potentially some of them are disadvantages depending on how your schedule is. But by and large, there's a lot of effort goes into ensuring A, the quality of the treatments is good, that the treatments are delivered accurately, robustly, and that side effects are monitored.

If you see unexpectedly bad outcomes, they will stop the trial early. But also if you see unexpectedly good outcomes, they will also stop the trial early because you don't want to keep treating people if you already know what the answer is.

Dr. Phillip Koo:

I think that's great. And I think patients really need to hear this carefully that even if you don't get the treatment, you are being followed very closely, which there's advantage to that. And if there's a clear benefit to that drug, they will stop the trial early and then give you access to that drug.

Dr. Nick James:

Often that's the case. Often trial protocols will provide for crossover to, either crossover once whatever treatment you had on the control arm stops working, crossover to the trial treatment. Or as you describe, if the trial comes up positive, patients who are on the control arm in the treatment will often be offered the experimental treatment.

Dr. Phillip Koo:

I think it's really nice to see how much progress has been made in the design just from especially that ethical perspective, because I know that may not have been true decades ago and that's sort of something that we're trying to get past.

We've talked about phase three trials leading to the information to get it approved.

Dr. Nick James:

Yes.

Dr. Phillip Koo:

Let's use sort of ARANOTE as an example, darolutamide in the hormone sensitive setting. We saw the phase three data that last year.

Dr. Nick James:

Yes.

Dr. Phillip Koo:

Walk us through what happens after that and what patients should be aware of.

Dr. Nick James:

Well, there's kind of two parallel tracts here. So the company before the trial was set up would have discussed with the regulatory authorities, the FDA in the USA, for example, what endpoint they had to achieve in order to get the drug an extension of the marketing authorization because darolutamide already licensed in other prostate cancer settings. So technically they can't, until that has then been through the approval process, it'll take six months, a year, it varies.

The company can't promote it for that indication, but what certainly we're allowed to do in the UK, and I think it's the same here, is if there's a reasonable body of evidence with a drug that is already approved for one indication, you can use it in another indication as long as a reasonable number of your peers thinks it's reasonable and a published paper showing positive outcomes would more than satisfy that.

So informally, people are allowed to use it, then it becomes the issue of who's going to pay for it. So for a new drug on patent, expensive, that may or may not be an issue and sometimes the company will make the drug available free. But I run a lot of academic trials where we're testing things that are already off patent.

Dr. Phillip Koo:

So I think that's a good lesson for patients as well. When you hear of these phase three results and you think it might apply to you, talk to your doctors about this and see if you might be able to get this earlier before the label is officially changed.

So final question, a lot of patients out there watching this, how can we empower them or what advice do you have for them to speak with their physicians about clinical trials and how to make sure that they're getting access if appropriate?

Dr. Nick James:

Well, I think obviously, just straight up ask your clinician, "Are there any trials running in your institution that are suitable for me?" But I think also obviously every institution can't run every trial. That's simply not possible. So it is also worth asking whether there are trials running for your condition somewhere else. And to be fair, the clinician may not themselves know the answer to that, but certainly there are publicly accessible databases that you can search and particularly with the growing use of AI, as long as you know enough detail around your own treatment, and so it's very important you try and inform yourself of exactly as much as you can about your own treatment.

Dr. Phillip Koo:

Those are some good points to close on. Ask your physician, but more importantly, get informed and there's so many resources out there. I know UroToday as a clinical trials website and learn. And you're right, learning about that is empowering. So thank you very much, Nick, for joining us. We really appreciate it.

Dr. Nick James:

Yeah, yeah as always. Yeah, pleasure.

This interview was produced with the generous support of Bayer