Alicia Morgans: Hi. I'm so excited to speak today with Professor Noel Clarke, who is going to talk with us about a really engaging talk that he gave at EAU 2022. Noel, you walked us through biomarkers in castration-resistant prostate cancer. It was fascinating. Please, can you lend us some of those thoughts today?

Noel Clarke: Well, it is a great pleasure to be here, Alicia, and thank you for the invitation. My endeavor or my remit in the EAU was to talk about clinically relevant biomarkers. That's a pretty broad topic to get it in a short space of time. I think anybody who works with patients in prostate cancer, and you know this, that a number of the patients are... They come in different shapes and sizes and ages and forms, and with different opinions.

Whilst we might sit in a meeting, a big cancer meeting like the European Association meeting or an American meeting, and talk about what we think is best, actually, it's the patient who's at center of the conversation. We have to bear that in mind because they will have different aspirations and they'll have different views. Some will be very well informed. A lot of the patients, particularly from socially deprived backgrounds won't be, and they will have a lot of comorbidities.

The first thing I would say is that it's important to be cognizant of the fact that many of the patients are actually elderly. We've just done a big study in the UK, I don't think the UK's particularly different from the U.S. and many developed Western populations. What we found was that about a third of the patients, we audited... All of the patients presented with primary metastatic prostate cancer and we know that these go on and develop castrate resistant disease, often relatively quickly. A third of them, actually a little bit more, were 80 or over, and a further 15%-16% were 70 or over. So, we know that this comes with a fair amount of comorbidity.

So the first thing to say is what are the comorbidities in a patient? That's a pretty good biomarker. We're not ageists, we look at patients physiologically, but it's the physiological age rather than the chronological age, but inevitably the patients have got additional comorbidities and we need to bear that in mind.

I think then we've got some very basic biomarkers that we tend to ignore. We do the labs, various blood tests, and things. Some of those tests aren't really taken into account. You take alkaline phosphatase as a very good marker really of disease burden and also a predictive marker of skeletal events later down the line as the patient gets further into their disease. These are easily available, often ignored, and perhaps should be taken into account.

One which we found particularly fascinating was lactate dehydrogenase and this is not always assayed in patients, but we did find that it was a very good threshold marker for response to Docetaxel for example. In patients who had a threshold of over 450 international units, we found that Docetaxel simply didn't work, and that's been a good marker for us actually, in determining who should get Docetaxel in late-stage disease and who might benefit from what is actually quite an intensive and at times toxic treatment.

Alicia Morgans: Now I'd love to hear you talk a little bit more about that because as you said, LDH is a very easily available marker in our clinical practices. I'd love to hear, how did you come up with that data and do you think that data is really ready for prime time, prospective decision making? I think we've talked a little bit about this and it seems that this is something that you actually use in your clinic right now so might be ready from your perspective.

Noel Clarke: Well, we came at it from a translational research aspect, in fact as we've done with much of our research. We've combined what's going on in the clinic with real patients, with what's going on in the lab at a cellular level and a genomic level. We did a combined study, which we published in 2018 in European Urology Oncology. We had a cohort of over 300 patients, I think it was about 330 patients. We'd looked at the physical LDH levels and correlated that with response to Docetaxel in metastatic castrate resistance. We cross-correlated that. We took the patients' samples and we did genomic analysis on this looking at the energetics. One thing that we found is that in prostate cancer, whether it's castrate-resistant or castrate naive... Should I say hormone naive, then the cancer is moving very quickly and the energy which is involved in that metabolic process is all booted up.

One of the good markers of this in prostate and other cancers is lactate dehydrogenase because it's directly linked. What we found at a genomic level was that the LDHA, that's one of the genes associated with energetic upregulation, is switched on in these patients. Very early on, we could see this in their primary biopsies. This translated out later on in the disease and manifests itself as the disease burden went up, as the hyper-energetic state and that's pretty easily measurable using the surrogate marker LDH, which did seem to be a very good cross correlate of response to cytotoxic chemotherapy. When it got above a certain level and the disease was really going quickly, the Docetaxel simply didn't work.

Alicia Morgans: So I think that makes, as you said, that makes biologic sense and it's really interesting. Is that something that you think necessarily is restricted to castration-resistant disease or is this something that you think is across disease states and is more agnostic of that, but is more reflective of chemosensitivity?

Noel Clarke: Yeah, I think it's across disease states and I think it's manifested early on in the disease. It's interesting that a number of studies and being closely involved with a STAMPEDE study, we have got the Metformin arms and Metformin is a down regulator of energetics. It works through what's known as AMPK, the energetic super highway regulator so called.

We think that energy up regulation in cancers is really critical. We found in detailed studies of mitochondrial function, should I say dysfunction? Then the mitochondria are altered. We know that the oxidative phosphorylation, which is a process of mitochondrially actioned energy regulation within the cell is completely disrupted. I think that this is an early effect. I don't think it's restricted to castrate resistance. I think it's going on and it just gets worse and worse as the disease becomes more and more dysregulated and dysfunctional when the burden goes up. I don't think you can measure it early on in localized prostate cancer, certainly not with a broadly base marker like elder age, but in metastatic disease when the burden's up, you can certainly pick it up

Alicia Morgans: So interesting and maybe at some point with among all of the other things that you're describing in STAMPEDE an analysis, even in the Metformin assessment might be interesting. I mean, the standard of care arms has been going on for so long. You must have many patients to just look at and you can certainly stratify and try to give us a sense of how effective LDH is. That's a very, very interesting marker and so applicable to what we do each day.

Noel Clarke: Yeah and in STAMPEDE, we've got about 2,300 patients in the Metformin arms, both [inaudible]. It will be fascinating to see really what effect this has. We'll probably report this in 2023, I would think.

Alicia Morgans: Well, and then depending on the power of LDH, as we're thinking about all of the STAMPEDE arms, I mean, certainly considering future stratification by LDH, if the patients are going to be on Docetaxel or some other adjustment might be important. Who knows? You may have just disrupted our entire paradigm of understanding Docetaxel in that study and in others. So thank you. Thank you for that of course, Professor Clarke. But as you think about that in other biomarkers, what else did you talk about at EAU 2022?

Noel Clarke: Well, I think the first thing that I mentioned or early on in my talk was this notion that leaving aside the age, is that a lot of patients don't actually get beyond the first-line therapy. That if you look at patients, who've got metastatic castrate-resistant disease, we looked at the Flatiron database and what we found was that roughly two and a half thousand patients... Roughly about 2000, got onto first-line therapy and then there's a real drop off after that as patients either they get sicker, their disease progresses, or they simply don't want further treatment.

So that only about of the two and a half thousand that were metastatic castrate-resistant, 2000 got first line, about 900 got second line, and then it really falls off. A large number of patients don't get further treatment. Actually, a clinically relevant biomarker is what stage of the disease is at and what treatment they've had first.

Then if you go on to look at what they've had by a comparison with the earlier treatment. So for example, the abi patients and the enza patients that have been treated up front while they will get a reduced response later down the line. So whilst it's not often denoted as a biomarker, it really is a biomarker because it influences clinicians in what they give next and the clinicians know that the response to treatment after patients have had these upfront therapies is less good.

There are others and I think the PROfound trial has been instrumental in helping us understand, this is the homologous recombinant repair defects, particularly BRCA-1/2, and especially BRCA2 defects. What we know is that their response to treatments further down the line is not as good. They do less well with novel hormone agents. They do less well with Docetaxel and of course, it's a good marker for response of the PARP inhibitor in that setting. So again, it's a very useful marker. It's not universally used in many parts of the world yet, but I think it is becoming increasingly evident that we do need to use that genomic marker in our patients to identify whether they're going to respond and just how well they're going to respond to certain treatments.

Alicia Morgans: And so I wonder just as we think through that, does it matter from your perspective in terms of the prognosis of the patient, whether that is a germline alteration, whether it's a somatic alteration? Because I think ideally we are assessing both, but this obviously is not something that is universally available or even in the near future. So we are trying to gradually make all of this testing available. What are your thoughts on the distinction there and the utility of both of these in prognosis?

Noel Clarke: Well, we haven't got a clear steer on whether germline or somatic makes a big difference. The mere fact that they are mutated seems to be a determinant of how well they'll respond to PARP inhibition in the metastatic castrate-resistant setting when the drugs, this is PARP inhibitors, are given as monotherapy. I don't think we've teased that out yet. Although the pharmaceutical companies and physicians and surgeons who ran the trials in this area are working furiously to try to tease this out.

I think the situation is different when you combine a PARP inhibitor with Abiraterone because then there is clearly a difference. It's not yet resolved in those two trials as you know, the MAGNITUDE and the PROpel trials. Where MAGNITUDE stratified for DDR mutation and they clearly got benefit with the combination Naraparib and Abiraterone. In PROpel, it was different because there were unstratified and there was an effect across the stratification without HRR mutation.

Now that in both those trials, the measured endpoint was radiological progression-free survival and they were positive of course, but we're still waiting to see as those trials mature, just what the overall survival response is. I think the jury's out at the moment. There's a second reading of PROpel at the forthcoming ESMO conference in September and that will be an updated overall survival at the second interim analysis. There'll be a third one probably presented at GU ASCO in 2023. So we'll see, but it is a fascinating scenario and it is moving over the next few months. We'll find out really whether DDR mutation is an absolute prerequisite to use these drugs or whether we can give them across the piece with the combination of Abiraterone.

Alicia Morgans: Yeah. It is incredible how quickly this whole area is evolving. Certainly, that was evident in the discussion and in the case discussion after the presentations as well.

Anything else that you consider in terms of prognosis when you see patients with castration-resistant disease?

Noel Clarke: I think the thing we haven't mentioned is radionuclide therapy and that's a really important area. If one looks at a clinically relevant biomarker, the elaboration of PSMA is important in this area. You take the VISION trial for example, patients were only included if they had PSMA positive lesions and no PSMA negative lesions. That clearly is a biomarker of response in those early trials. Of course, I think we need to validate this still further in other clinical scenarios.

Do we give it just to patients with PSMA positive only? Do we get benefits in patients who have a mixture of lesions? Are we going to see responses even in patients who don't produce PSMA? I don't think anybody's been bold enough to try that yet, but we don't know. I think it's certainly promising and we are testing that as an international community in a number of arenas and pharmaceutical companies are investing heavily in this.

The results look very good. I think we need to see more. Importantly, we need to, A learn how to use it and B learn how to pay for it in our patients. Certainly developed economy like ours in the UK, we don't have universal access to PSMA therapy currently, and it's quite mixed in Europe, but if it's an effective therapy and it does seem to be, we've got an easily available biomarker, which will tell us which patients we can use it on. Of course, we combine that. If we combine that with clinical common sense in our patients... Are they fit enough? Do they have other comorbidities? Are they really going to benefit from what is a therapy that's got some toxicities, significant toxicities? It's also very expensive to give. I think we need to work that out.

Alicia Morgans: Yeah, I agree. I think I am actually just very grateful that we have a biomarker that can identify patients who might benefit the most. We're learning so much more, especially as we think about this SUV mean concept, which of course is not clinically available at this time, but maybe a way to help us identify which patients need Lutetium PSMA 617, or similar targeted drugs early versus others that may still benefit from that treatment, but may equally benefit from other treatments in the interim before they get to that therapy.

I think there's just a lot to sort through and a lot to learn, but we have a biomarker at least that can start to point us in an appropriate direction.

What would your message be, as you think about the concept overall? Biomarkers and castration-resistant prostate cancer. There's so much to say. What is your overarching message?

Noel Clarke: My overarching message is, keep thinking, use the available data that you have, keep the patient at the very center of your thought processes and regard the patient as a whole. Don't regard the patient as somebody with prostate cancer, they've got a lot going on in their lives. I think we need to take that into account. That should be front and center of where we're coming from.

Alicia Morgans: I certainly could not agree more. I think any human being is more than simply his prostate cancer and we have so many aspects of that person's other medical history, their other medications, and then their larger life that we need to think about as we maintain their lives and help support them through their diagnosis and their treatment. It is more than just treating the cancer. Thank you so much for talking us through this. I appreciate your time and your expertise.

Noel Clarke: Thanks, Alicia. It's been a pleasure.