Alicia Morgans: Hi, I'm so excited to be here at APCCC 2022, where today I'm talking to Dr. Mark Rubin, who is the Director of Precision Medicine at the University of Bern. Thank you so much for being here.

Mark Rubin: I'm happy to be here with you.

Alicia Morgans: Wonderful. I wanted to speak with you a little bit about emerging therapies and emerging therapeutic targets in prostate cancer. Certainly, as well, the use of biomarkers to identify those targets before we start using treatments. I'd love to hear your thoughts on that general topic. Then, we'll dig into some more specifics a little bit later.

Mark Rubin: Okay. I think right now there's a tremendous interest in trying to understand resistance and different types of resistance, on target resistance related to AR singling therapies, and so, that's something that is obviously very, very important to be able to come up with good diagnostics for that. Are patients still responding to AR targeted therapy, and then off targeted resistance where we see resistance in patients who are no longer responding to AR inhibitors and maybe undergoing neuroendocrine prostate cancer, maybe undergoing double negative, so not neuroendocrine, but not AR receptor-positive prostate cancer. Trying to understand that is really, I think, an emerging gap in knowledge that we've just recognized and now we're trying to address that. I think the therapies addressing those areas are very important, I think.

Alicia Morgans: Are there specific pathways or targets that you're thinking about to address those areas?

Mark Rubin: Yes, well, I think that we're thinking very much in terms of epigenetic therapies. In the case of off target resistance where AR singling is no more active, can you reactivate AR signaling through maybe epigenetic modulation? There've been trials using EZH2 inhibitors, but there are other potential targets, epigenetic targets that I think are emerging, I mean, very early, so basic preclinical studies suggest that this might be an important avenue.

Alicia Morgans: Yeah, that's absolutely true. I was able to participate in some work with EZH2 inhibitors. At this point in time that data's not yet mature, but from your perspective, I'm not sure, is there other data that you're excited about from the EZH2 perspective, or other data that is a little closer to making it to phase one/phase two trials?

Mark Rubin: Yeah, it's early. I think, first of all, recognizing the problem has been a challenge, so where do you actually start to treat those patients, and with EZH2 inhibitors, I'm not exactly sure how those trials were designed, but in thinking about epigenetic regulation, our thoughts are that you have to capture the time point, the earliest possible time point where it's going to make a difference. One concern we have is that once a tumor is full-blown, neuroendocrine, for example, a small cell, it may be too late to actually start those type of therapies. Can we recognize early enough when a patient should be treated and that's probably a key factor. It goes back to molecular biomarkers in this area.

Alicia Morgans: That's so interesting. I think in general, as we're looking at a lot of our therapeutics, the earlier we move them in the disease spectrum, they seem to have more of an effect. Certainly, that movement is not molecularly directed. It's just all comers that we can target, but to have the ability to use biomarkers to specifically intensify in certain areas would be phenomenal. How do you see that playing out over time? Are there things that you're hoping to do as a pathologist to help that process?

Mark Rubin: Yeah. I think there's a lot of exciting data coming out of what you can do with, for example, circulating tumor cells. I know there's been a first, maybe second generation type test that are coming up, but we're seeing some really exciting tests. For example, in Switzerland, there's some early diagnostic testing going on, and in some of the technical universities here where you can see that you can use all sorts of small devices to capture a lot of functional information about tumor cells. That would be, I think, the next direction, which would be instead of having invasive biopsies. Currently what we think is that it's very important to capture the metastatic or the treated lesion and not just the patient's primary lesion. I think that's very important. How do you do that where there's circulating tumor cells or cell-free DNA or metastatic biopsies? I think the least invasive would be probably the most appealing.

Alicia Morgans: Oh, absolutely. Then, of course, thinking about timing, when do we do it? Do we do it over the course of treatment? Do we do it before? Do we do it after? I think there have been some really interesting studies looking at the evolution of molecular expression over time, but that's really hard to think about implementing in a clinical space. Is that something you think we might do at some point?

Mark Rubin: Yeah. I mean, I think in trials, I think it's going to be important to have multiple time points that we can determine what is the best time point before you fix a specific time point for standard of care therapy. Yeah.

Alicia Morgans: Absolutely. Do it in a trial before we put it in the clinic. Always a good plan.

Mark Rubin: Yeah.

Alicia Morgans: If you had a message for viewers in terms of how they think about molecular pathology and its impact in prostate cancer care in the next, say five to 10 years, what would that message be?

Mark Rubin: Well, I think, first of all, it's going to be important to be in close discussion with the molecular pathologists and to try to really understand the types of available tests now and what's missing. I think an important message is that there are a lot of tests out there now, so it's very confusing. I think it's really important to understand that not all tests, there's no one test that does everything. Unfortunately, there are a lot of false negatives in tests and particularly with respect to, for example, BRCA testing. You want to make sure that you have the right tests. I think closed discussions with molecular pathologists who are knowledgeable is important for standard of care, for what's going on today. In the future, I think there'll be a lot of new things coming along, but they still need rigorous testing before they're adopted. You may hear things in meetings, but I would still wait until you're molecular pathologist tells you what you need to do for patients.

Alicia Morgans: I think that's always good advice too. Just to follow up on that, some practical advice for folks who may be using either cell-free DNA, circulating tumor DNA, and looking for things like ATM alterations, would you mind commenting, do you have any advice or comments there regarding chip? I think that can be confusing in clinic and there can be these false positives for ATM.

Mark Rubin: Right. I would just say that you have to understand the strengths and limitations of any test. There are a number of tests out there without commenting on specific tests, so I think it's very important to make sure that you know what's measured in both directions, whether it's a positive or negative test. One of the major concerns is that there are a lot of tests out there that are only testing the tumor DNA, but not the patient's heritable or germline DNA, and that's very important to make sure that you have information on both if you want to make assessments. For example, I mentioned BRCA, extremely important to avoid false negatives.

Alicia Morgans: Absolutely. Well, thank you so much for your time and your expertise. We, of course, look forward to seeing where you and your team of molecular pathologists take the field of prostate cancer over the next few years.

Mark Rubin: It was great being with you.