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Rana McKay: Welcome to UroToday, and it's a real pleasure to be with you this afternoon. And I've got a dear colleague and friend, Dr. Andrew Laccetti here with us from Memorial Sloan Kettering. Andrew, welcome. How are you?

Andrew Laccetti: Doing very well today. Thanks, Rana.

Rana McKay: You really had some excellent data that were presented at the PCF recent meeting, the scientific retreat this past fall in the CRPC setting. And why don't you tell us a little bit about where we are currently at with treatments in the advanced mCRPC treatment setting?

Andrew Laccetti: No, absolutely. So happy to be discussing the combination trial of masofaniten and enzalutamide. And as you rightly introduced, this is a medication for metastatic castration-resistant prostate cancer, which is a field in which we're experiencing pretty rapid development across a variety of systemic therapies.

This particular agent is a novel hormonal therapy for mCRPC, and we have a rich landscape of first and second generation hormonal therapy strategies, ranging from androgen deprivation therapy and novel androgen receptor pathway inhibitors such as abiraterone, enzalutamide, apalutamide, and the like. However, for the vast majority of patients receiving these treatments, either in the castration-sensitive or castration-resistant setting, resistance does occur. And the development of means to help overcome resistance to hormonal therapies, and develop hormonal therapy strategies beyond what's currently available, is a critical unmet need.

Rana McKay: Absolutely. And especially as these agents now are entering into the metastatic hormone-sensitive setting, there really is that unmet need in the castration-resistant setting. So tell us a little bit about masofaniten, and what's its mechanism of action, and how does it actually work?

Andrew Laccetti: Yeah, absolutely. So masofaniten is a novel first in class N-terminal ligand antagonist for the androgen receptor. Androgen receptor antagonists, to date, such as first-generation agents like Casodex, and second generation agents, like enzalutamide or apalutamide, have all been developed to competitively antagonize the androgen receptor at the ligand binding domain. Masofaniten actually achieves AR antagonism by binding to the back end of the androgen receptor, and it inhibits its interaction with intracellular elements within the nucleus. So in effect, the preclinical data has demonstrated that this alternative mechanism helps to overcome some of the resistance mechanisms we find, particularly at the ligand binding domain, in response to ADT and other hormonal agents.

Rana McKay: That's excellent. And so tell us about the Phase I/II trial of this agent combined with enzalutamide. What's the design of the study? And it seems to be a pretty expansive study with both the Phase I, and the Phase II, and randomized component. So tell us about the design.

Andrew Laccetti: Absolutely. Masofaniten is currently being explored in two relatively large Phase I studies. One is a monotherapy study, also in mCRPC, and this is the second study investigating masofaniten actually in combination with enzalutamide. Preclinical data has suggested the potential for synergy between these two agents. And we know that extrapolating from other areas in prostate cancer combination therapy approaches with hormonal therapy have the potential to hopefully create a deeper and more durable androgen receptor antagonism, and hopefully, improved response and response times.

So this study was developed to investigate escalating doses of masofaniten in combination with enzalutamide. The study incorporates a lead-in period, to help us better gauge the interaction between masofaniten and enzalutamide, understanding that there was a hypothesis of drug-drug interactions that may actually require modifications of one or both drugs.

So the study was initially designed utilizing enzalutamide 120 milligrams daily, that's 40 milligrams below the standard monotherapy dose. Understanding that in vitro, masofaniten was observed to be a CYP2C8 inhibitor, which is the main enzyme involved in the metabolism of enzalutamide. Therefore, the thought was that we may actually increase concentrations of enzalutamide through drug-drug interaction, and that's why the 120 milligram dose was selected.

Similarly, we expected that there may be an opposite effect of enzalutamide on masofaniten as a CYP3A4 inducer. So in effect, there was the expectation that we actually may have less exposure of the set levels of masofaniten.

So the study was designed initially with a fixed dose of 120 milligrams of masofaniten, with escalating dose levels, excuse me, of enzalutamide, with escalating dose levels of masofaniten at 600 milligrams daily, 800 milligrams daily, and then, 600 milligrams twice per day. Standard 3+3 design, looking at safety, tolerability primarily, and secondarily, looking at response, primarily PSA response.

Rana McKay: That's great. And then it sounds like you also, you did have a cohort where patients were treated at the 160 milligram dose. Is that correct for the enzalutamide?

Andrew Laccetti: That is correct. So leading into the next point, we determined relatively quickly in our first couple of cohorts, that the anticipated effect of masofaniten on enzalutamide as an inhibitor of CYP2C8 actually was not observed. Therefore, we realized that we had the potential to increase the dose to, with the full recommended dose, 160 milligrams daily of enzalutamide. So an additional cohort was added, testing that dose level.

Rana McKay: That's excellent. And what did you all find? What were the key results from the Phase I portion, from safety, toxicity, and recommended Phase II dosing?

Andrew Laccetti: Yeah, absolutely. So I already touched upon the pharmacokinetic data regarding masofaniten's effect on enzalutamide. We did confirm that enzalutamide did, in fact, increase metabolism of masofaniten. However, within the study, this effect was not felt to be clinically relevant, understanding that masofaniten drug concentration still remained within the expected therapeutic window tested in preclinical testing. Furthermore, we found with BID dosing, as observed in our 600 milligram BID cohort, the minimum concentration was maintained within an adequate level.

So moving on to safety and tolerability, the combination was very safe and well tolerated across all dose levels, with the majority of observed side effects being that of other oral hormonal therapies. Things like hot flashes, fatigue, and the like. We did observe some Grade 1, Grade 2 diarrhea in select patients. And one patient in cohort four did have a Grade 3 rash, that was felt to potentially be due to the combination, but this was only observed in one patient. The cohort was expanded, and this was not observed to be a dose-limiting toxicity in the end.

Do you want me to speak a little bit about the efficacy data?

Rana McKay: Yeah. No, that would be great. Sort of what were some of the key pearls around the PSA response? I think the data looked impressive that were presented at the PCF meeting.

Andrew Laccetti: So of 18 patients that were enrolled at the time of presentation, we had 16 that were evaluable for PSA response. Importantly, 13 of the 18 patients actually remained on study at the time of presentation, with only three being removed for disease progression. And of the evaluable patients for PSA response, we saw a PSA90 rate of about 69%. The vast majority of patients, 14 of 16, did have PSA reductions. And this observed PSA response was on order, if not even better than previously reported enzalutamide monotherapy studies in the castration-resistant setting, which we're excited by.

Rana McKay: That's excellent. And I know that this study was conducted in patients who were naive to second generation anti-androgens, and you had allowed prior docetaxel to be given in the mHSPC setting, where patients enrolled, had patients that had been enrolled had received prior abiraterone.

Andrew Laccetti: So no, it's a very important point for this study. This was a second-generation oral anti-androgen naive population in the mCRPC setting. So this population is not the typical patient that we're treating in the contemporary era. However, we are hopeful to examine this combination with future analysis in patients that have been previously exposed to oral anti-androgens.

And certainly, it's a really important factor to keep in perspective looking at our PSA response. Regardless of the caveat, again, the drugs worked well together, were tolerated well; and comparing to historical averages, we're doing as well and maybe even a little bit better. So we certainly believe that the data substantiates further examination with a randomized study, in addition to the eventual inclusion of patients that have been exposed to prior second generation oral hormonal therapies.

Rana McKay: That's great. So tell us about the randomized study. I know that's kind of embedded also into this Phase I/II, right? There's a randomized component during the Phase II now that's, I believe, recruiting patients.

Andrew Laccetti: Correct. So the reported data here reflected the completion of our Phase I component. The recommended Phase II dose from this analysis is 600 milligrams of masofaniten twice a day with 160 milligrams of enzalutamide, the standard dosing. And we are proceeding with a Phase II component to this study, that is currently accruing at several sites. The study in the randomized phase will be designed to compare combination masofaniten and enzalutamide with enzalutamide monotherapy.

Rana McKay: That's great. Also, in a patient population that's naive to a prior ARSI.

Andrew Laccetti: Correct, as of now. But again, there is the possibility to adjust the inclusion criteria, which is under discussion.

Rana McKay: That's really exciting. I think there's a lot of these next generation AR pathway targeting agents, dual ligand binding, end terminal domain binding agents, other sorts of testosterone or androgen depleting agents blocking higher up in the axis. So I think this just speaks to the continued dependency and vulnerability of even CRPC to continued antigen targeting.

So really exciting to see this new data, hear about this new agent, see the future direction with regards to the randomized Phase II, and hopefully, we can see also, data evolve from the monotherapy study that you had cited as well. So congratulations on the data, and look forward to hearing more about this agent and targeting of this pathway.

Andrew Laccetti: That's great. Yep. We're very eager to see the drug as it evolves through further study. And as you said, I think there's a lot to be unmasked, and there's a lot of good work to be done in the hormonal therapy area, targeting the appropriate patient to the appropriate therapies amongst an expanding arsenal that we have mechanistically. So I'm excited to discuss the work, and appreciate the opportunity.

Rana McKay: Wonderful. Well, thank you so much for joining us today. And thank you for listening to UroToday.

Andrew Laccetti: All right. Thank you so much.