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Alicia Morgans: Hi, I'm so excited to be here with Associate Professor Mark Markowski, who is a GU Medical Oncologist at Johns Hopkins. Thank you so much for being here with me today.

Mark Markowski: Thanks for having me.

Alicia Morgans: Wonderful. I think one of the most pressing issues in advanced prostate cancer is that we have multiple treatments, we're really excited that we do have so many options, but as we continue to treat patients with advanced disease, these cancer cells are evolving resistance mechanisms that certainly require new mechanisms of action to overcome and give us new options for treatment. I think it'd be great to hear from you about some of those mechanisms, particularly things like splice variants and things that have been really described by some of the team members there with you at Hopkins.

Mark Markowski: Yeah, absolutely. For the last 80 years we've been treating patients with advanced prostate cancer with hormone-based therapies. In particular, we're lowering testosterone levels because we know that testosterone drives the growth of prostate cancer. With patients that have metastatic prostate cancer, these therapies are not curative, but they do suppress the cancer for long periods of time, and the more that we put pressure on the androgen receptor, the more the cancer can evolve. And so, at the end of the day, the cancer always wants to grow testosterone or use that testosterone pathway signaling through the androgen receptor to grow. And so it can kind of get around different treatments that we use. And so, over the years, we've developed more potent ways to target the androgen receptor such as oral therapies like enzalutamide or darolutamide, and those target that ligand-binding domain of the androgen receptor.

So when we think about the androgen receptor, we have the N-terminus that's kind of unstructured and has been difficult to target over the years, you have the DNA-binding domain, that's kind of the working end of the molecule, the ligand-binding domain that binds to androgens and also binds to our inhibitors, and that's where a lot of the work comes in with therapeutics, and then a little bit of the C-terminus. So the more pressure we put on the cancer, we start to see mutations develop that will get around some of those inhibitors, and then what we've discovered over the last several years, that the cancer can actually make spliced versions of the androgen receptor so that it will just get rid of the entire ligand-binding domain. So what you're left with is the N-terminus and the DNA-binding domain that can just remain active, so it doesn't even need androgens anymore to signal and grow.

And so there's been a lot of interest in the field to try to target that disorganized N-terminus. And like I said, over the years it's been tough to do. There's a company now called ESSA that developed a novel small molecule-inhibitor that can target that N-terminus of AR. So this is really giving us some hope here that we're going to be able to overcome some of those resistance mechanisms.

Alicia Morgans: Absolutely. I think the drug you're talking about, it was formerly EPI-7386, but now masofaniten, I think is the name that it's been given to it. Data came out or is coming out at ESMO 2023 from the phase I trial, and then certainly excited that we've heard that there's a launch of a phase II that's also studying this. Can you tell us a little bit about the trials that are looking into this agent?

Mark Markowski: Sure. Like you said, the phase I trial has just read out looking for safety. We've been able to identify a dose of the masofaniten that paired well with a full dose of enzalutamide. The full dose of enzalutamide is 160 milligrams given daily, and then the recommended phase II dose that we identified from the phase I of the masofaniten is 600 milligrams by mouth twice a day. So that is going to be the combination that we move forward to the phase II study.

In terms of study design, like I said, this is a phase II study, and it is randomized, so we're taking patients that have metastatic castration-resistant prostate cancer that have not been treated previously with a novel AR-targeted therapy. These are patients that have castration-resistant disease that haven't been treated with enzalutamide or even abiraterone. They're allowed to have had prior chemo, but none of the newer agents. And so this is essentially a first-line mCRPC study. It is randomized, so patients get randomized in a 2:1 fashion to the combination, which is the masofaniten with full dose enzalutamide, or randomized to the control group, which is enzalutamide 160 milligrams by itself. Like I said, it's a 2:1 randomization. We're looking to do 120 patients, so 80 in the experimental arm and 40 in the control arm, and the primary endpoint of the study is PSA50 response rate.

Alicia Morgans: I just want to call out and mention that I love that you and the team that worked on this have really given everybody with this MCRPC first-line study standard of care. And it's a very active agent. Enzalutamide first line is a very active standard of care. So you're expecting that when we add the masofaniten, you're going to be adding to an already effective standard of care, which is good for patients, and really, it's going to answer the question, is this additive? Is it really going to move the needle? My hope is that it will. I wonder, can you tell me how you think, how does the team think that these drugs are going to work in combination to be even more effective than enzalutamide alone?

Mark Markowski: Yeah, I think that's a great question. We know that the enzalutamide is going to bind to that ligand-binding domain, and there's going to be a good proportion of patients that are going to benefit from that. So I think we're looking at kind of capturing two groups of patients. One, are there patients that are primary refractory to the enzalutamide that the masofaniten will be able to get that PSA response kind of upfront? I think that's the initial question that we're looking at here in terms of a PSA response rate. But also on the backend, are we going to be able to delay some of those resistance mechanisms that we kind of commonly see with enzalutamide? So that development of the splice variant AR-V7, are we going to be able to delay that process or prevent that process from happening because we're now targeting that N-terminus? And splicing the androgen receptor, at least traditionally how we think about it, is not going to be as successful to overcome that enzalutamide.

So I think it's two questions. One is, can we get those patients that were primary refractory, but also, I think looking at the depth duration of response, are we going to see longer or even deeper responses in those patients that get the combination? I think both of those questions should be answered, and I think that's very exciting.

Alicia Morgans: I would completely agree. We have a lot of data that suggests that the better able a patient is to get to PSA50, PSA90, that deeper that response, the better the outcomes, the longer the time to progression. So this is really valuable information. It is not a survival endpoint, but this is a phase II, so it does not need to be, but this is what it takes to move the needle. So it's really, really interesting.

I'd love to hear as we kind of start to wrap up, what are your thoughts in terms of tolerability of this? Because patients do appreciate when we have these hormonal options, that they're generally going to be tolerable symptoms. They're manageable, they're certainly there are side effects, but these are things that most people can deal with. How does that change or not change when you add in the masofaniten?

Mark Markowski: I think you'll see at ESMO, the poster presented at ESMO, that the combination is quite safe and I think we all as investigators felt very comfortable moving this forward to the phase II. Because like you said, does more drug equal more toxicity? Sometimes that is the case. And we're going to find out as we treat 80 patients that are going to get the combination of what's that toxicity look like compared to the enzalutamide by itself, because we do see a fair amount of toxicity from enzalutamide. And the hope here is that we're comparable to the control arm with enzalutamide by itself. But time's going to tell. So how much benefit are we going to get by adding two drugs versus toxicity? The phase I data certainly looks promising from a safety perspective, and I think we're going to flush that out a little bit more in the phase II.

Alicia Morgans: Great. As you think about this, as patients, as clinicians are thinking about potentially getting involved in this clinical trial, we will make sure that we have the clinicaltrials.gov information here on the site so that people can get involved. Is this only open at Hopkins or is this going to be open at multiple sites for patients to potentially engage in different places?

Mark Markowski: This is going to be open at about 20 sites in the US and Canada, initially, and I believe Australia as well and there's some discussion about moving it to the EU. But for right now we're looking at the US and Canada, initially.

Alicia Morgans: Fantastic. So there will be opportunity. We will make sure that that information is there. As you think about this and certainly all the excitement we have with a novel approach to tackling this disease, what would your message be to listeners?

Mark Markowski: Well, I think we're making progress, right? We're understanding resistance mechanisms from those drugs that we developed a decade ago, and now we're building on that to say, "Hey, what is the next phase of this?" Enzalutamide, darolutamide, apalutamide all work great, but they only work for a finite amount of time. How do we make them work better? How do we kind of take this to the next level? What's the next generation of treatments? And I think this fits in that. Now we're fully understanding how resistance works to these drugs. Well, now we're going to work to overcome it. So I think we're making progress, we're understanding more, and I think it's an exciting time to be a clinical investigator. I think if you're somebody going through prostate cancer treatment, there's a lot of hope for you because there's a lot out there on the horizon for different treatments.

Alicia Morgans: I could not agree more. And I think with each trial that we do, we learn. Whether the trial's positive or negative, we can always take something away from it, and I am so hopeful, as you are, that we're going to find that this is a new combination that can really move the needle and make a difference for the patients who need it. I really appreciate your time and your expertise. Thank you for sharing all of this information with us today.

Mark Markowski: I appreciate it, thanks for having me.