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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today, a good friend and colleague, Dr. Scott Tagawa, who is a Professor in Medicine and in Urology, at Weill Cornell in New York. Thank you so much for being here with us today, Scott.

Scott Tagawa: Thank you very much for the invitation.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about, some perhaps under-recognized highlights of GU ASCO 2022. We all are aware of some of the big presentations that happened in prostate cancer, but I think that there were so many nuggets of really exciting information throughout the entire program, and I appreciate that you are bringing some additional presentations to light. So why don't you get started with prostate cancer? Let us know, what are some of the things that you are really excited about at the last meeting?

Scott Tagawa: Sure. So a couple of drugs that I think are quite promising in early phase clinical trials, I think are interesting, and I always find data around PSMA-targeted radionuclide therapy, interesting out of personal interest. So those are three buckets.

In terms of up-and-coming potential novel therapeutics, the background is, we all know that the AR pathway remains the main dominant pathway throughout tumors in a patient's life cycle with prostate cancer, but there is resistance to the AR pathway. Our AR drugs are not curative, currently. So a couple of novel agents ARV-110, which is an AR PROTAC, think of it as an AR protein degrader, that had some preliminary data presented a couple of years ago at ASCO. And then, some information from the company came out, this was more information from the ongoing Phase II trial, with a number of different cohorts of patients with metastatic CRPC, either mostly broken down by the number of lines of prior therapy in a minimally pretreated group, and mostly, a more heavily pretreated group. Different versions of the AR i.e., wild type, different point mutations, ARV-7.

Based upon some of the preclinical data, some of the AR point mutations that tend to develop after significant suppression with our potent AR pathway inhibitors pre-clinically, looked like they were sensitive to this drug. And that's what it looked like in the clinical trial, as well.

So, unfortunately, this AR PROTAC doesn't look like it works well across the board but it does look like there is particular sensitivity in this molecularly selected patient population, with significant PSA declines, which I think is a reasonably good pharmacodynamic readout of an AR PROTAC inhibitor. And I think that may be the pathway forward for this drug, in that particular subset.

Another interesting, what I'm going to call AR drug, but not purely AR drug, is a compound referred to as ODM-208, which basically, inhibits the synthesis of all of the hormones past cholesterol, which we classically think of, in the prostate cancer world, as testosterone and DHT. And we think of that, for instance, with CYP17 inhibition with abiraterone, but this potentially, is more potent, as it inhibits much further upstream, maybe decreasing the chance of some of these bypass hormones. So a first-in-human study, quite interesting, pre-clinically, it looked interesting. I was waiting to see, how well does it work? And at what cost? Because inhibiting more of these important hormones might be toxic. And it turns out, in my viewpoint, a little bit of both. So some activity in patients who were heavily pretreated with some toxicity, so there was a replacement of corticosteroids in mineralocorticoids, but there were a handful of patients that did have enough adrenal sufficiency that had to get admitted to the hospital, and that is in selected centers.

I think that we need to learn more about the drug. It sounds like the investigators have, with an increase in replacement of corticosteroids in closer monitoring. But in patients, in tumors, that also look like they really do maintain that AR pathway with similar AR point mutations, to what I mentioned before, with ARV-110, look to be successful. So that is early, this is the first time we are seeing the human data, but I find both of those quite interesting.

Alicia Morgans: Yes. I agree with you. And these were both rapid abstract presentations, I think, really interesting to see these novel mechanisms elevated to that level and really discussed. And there were lots of questions, as you just mentioned, around the toxicity profile, particularly for the ODM compound, versus its benefit. So I agree with you, really interesting, and I'm excited to see where they go too.

Another drug that we are really excited to see where it goes, how it gets there, is Lu-PSMA-617. And there was a really interesting poster that you mentioned, that kind of looked into what life might be like, or at least, the perceptions that we might have, as this drug, potentially, becomes available. Can you tell us a little bit about that?

Scott Tagawa: Sure. There was a survey that was done of, I think a couple, I can't remember the number, but a couple of dozen physicians, practicing physicians, of different specialties, but people who treat prostate cancer, and the perceptions of the data, and expectations about the near term future. I would say, in summary, most of the physicians were excited about the efficacy data, although, with some qualifications, maybe wanted it to be a bigger change, compared to control. But overall, I think, satisfied with the efficacy data. I think, the overall acceptance of the toxicity profile actually, brings up in mind, I'll bring up another poster that was presented. And then, some comments about the trial design, not allowing radium, for instance, was actually a much bigger one than I would have thought of, to these community physicians.

And then, addressing, or at least mentioning, some concerns that we all have, about, if the drug is approved today, how we are going to be able to use it tomorrow, at least, across the board, with some barriers of getting PSMA-PETs for this metastatic CRPC patient population. Assuming, that it is going to be part of the label, as well as, handling the administration of the drug. Which I think, is partly solvable through vendors that will be able to come in, bring in the drug, let the drug be administered, and then take out the waste, so it doesn't have to be there at the site for longer. So there are some solutions that are in place, but I thought it was very interesting to see some of the perceptions and guesses about what's going to happen in the near future.

Alicia Morgans: Yeah. I think you're right. It's based on our excitement, but of course, there are also questions about, how do we make it work? And that always happens when we have a new therapy. So exciting, as we anticipate that. And you mentioned, there was another poster that you wanted to mention as well?

Scott Tagawa: Yeah. I think most of us know, from [inaudible] presentation, and Oliver Sartor et al., in the New England Journal, that there was an improvement in efficacy with the addition of Lu-PSMA-617, to the protocol allowed, the best standard of care. If you look at the adverse event table, there was a higher incidence of adverse events, despite that from Karim Fizazi at ESMO last year, a delay until declining in patient-reported outcomes. But, in actually looking at the profile of almost any positive Phase III trial, the exposure time, or their eligibility time, to have adverse events, is generally, a lot longer in the successful treatment arm.

There was a poster that presented data on adverse events controlling for that. Many of the differences in adverse events between the arms, dropped out. That included, a little bit surprising for me, some of the GI side effects. Because I do think that nausea is, in a way, on target, or PSMA on target, in the small bowel adverse events. But a lot of the other ones fell out. And then, not surprising, what stood out, or the other ones that are maybe more specific to this type of drugs, such as xerostomia and thrombocytopenia. But anyway, with the adjustment for exposure, a lot of the differences in adverse events were ameliorated.

Alicia Morgans: This is really, really interesting, and as you said, is so consistent with what we've seen in some of the newer presentations of adverse events. Of course, we get the upfront totals of adverse events in that initial presentation for all of these phase III trials, but it's really interesting to see how things might change if we adjust for exposure time. So really, really interesting.

Well, let's switch gears just a little bit, and think about urothelial carcinoma, where you also have, actually, a great area, or a great degree of expertise. I know you've been very involved with sacituzumab govitecan, its early development, and certainly, its use in our field. And I've appreciated talking with you about that. Can you tell us a little bit about some of the work that was presented with SG at GU ASCO 2022?

Scott Tagawa: Sure. So the TROPHY-U-01 study is the Phase II study that led to the accelerated approval of the drug. That was cohort one. There are several different other cohorts. So at the meeting, there was a trial in progress poster of cohort four, which is front-line, in combination with cisplatin.

Cohort three was an oral presentation. That was, in a way, like EV, a combination of antibody-drug conjugate, plus an immune checkpoint inhibitor, but in a different patient population. This was in platinum-refractory disease. And as it turns out, the patients were really, platinum-refractory had a low response rate and short progression-free survival. Looking back at those that had received prior platinum in that setting, the combination of, essentially, on label pembrolizumab in that second-line setting, with the addition of sacituzumab govitecan, was designed to have an overall response primary endpoint, designed to have 41 patients where at least 13 had to respond to be positive. And as it turned out 14, well, 14 so far have responded. It was a late-breaking abstract. Some of the patients are relatively early into their treatment. So it's at least, a 34% response rate, it could go up.

What we don't know, is the durability of this. So now a different patient population, it's front-line with EV but interesting that EV plus pembro if you respond, the median duration of response is more than two years. So we have yet to see with this combination, but I think it's of interest to have, if you will, a targeted cytotoxic that's, in my mind, what an ADC is, in combination with immune checkpoint inhibition, and can we improve the efficacy? What I think, is important for the patients is the durability of response to a subset. That was an interesting data set with SG.

Alicia Morgans: Absolutely. So what else caught your eye in the urothelial carcinoma presentations?

Scott Tagawa: Additional data with ADCs, I already mentioned enfortumab vedotin.  In a way analogous to the TROPHY study, here is a study called EV-103, which are multiple different combinations with EV, but what was added to that, were a couple of perioperative cohorts. And the first data that we've seen, in a neoadjuvant cohort, in patients who were ineligible for cisplatin, as it turned out, half, due to creatinine clearance, but a reasonable number due to hearing loss. And that was a comment. But 22 patients received three cycles of an altered administration course of EV, so, day one and eight of a 21-day cycle. Some people call it EV light. So three cycles at six doses, rather than nine doses, of the regular schedule. And in patients, who for whatever reason, generally tend to be sicker, because they're cisplatin unfit, had a complete, pathologic complete response rate of about 36%.

In my mind, it's not totally earth-shattering because we've seen that. We see it with chemo, although it's cisplatin-based chemo, as well as immune checkpoint inhibitors. But nice early data to support some of the ongoing phase IIIs in this situation.

A caveat is that there were three perioperative deaths out of 22 patients. So unclear, is that bad luck, or were there some sorts of... they weren't called directly drug-related, and it is a cisplatin unfit patient population. So we know that there is something going on with it, but it's something that will definitely need to be monitored in the ongoing phase III trials.

And then, a couple of abstracts on HER2-directed antibody-drug conjugates, both combinations. One of them is a drug called or used to be called, RC48, a Chinese compound, that's now taken up by [inaudible], ZGen for further development. They had an interesting preliminary presentation at ASCO last year, with a 94% response rate combined with an anti-PD-1. This was an expanded patient population, not quite so high. They looked at different subsets, but overall, higher than 80% response rate in a mixed population, first-line, second-line, third-line, different HER2 expression levels, but interesting data with that drug.

And then another combination, presented by Matt Galsky, of a trastuzumab direct HER2 antibody-drug conjugate, in combination with immune check inhibition as well, and showed some interesting response data with that too. This drug, in other subsets, as well as this one, has incidents of pneumonitis. I think that is something that we need to really be on the lookout for. We have seen in this patient population that a lot of them are former smokers, whether that makes a difference, I don't know, but it's... anyway, all of these ADCs, in my mind, have some interesting efficacy data.

Alicia Morgans: I would agree. And I think, as you bring all of these up, anything that can be successful in urothelial carcinoma, particularly in populations where we don't have great options, and we know that the prognosis is poor, like those cisplatin-ineligible patients that you mentioned, it's important for us to really do our due diligence to investigate.

I think it's interesting that HER2 is coming back around. We've seen attempts at using this approach in the past, and if we can make it work, that's fantastic. I am really eager to see where all of these options go.

But I wanted to also say thank you so much, for really helping us interpret this data in balance. Understanding both, the early possible efficacy that we see, but also really recognizing that there can be real risks. And we, as investigators, need to investigate that, as well. Things like pneumonitis or perioperative death, are things that we need to understand in their entirety and make sure that these approaches are going to be both, efficacious and safe for our patients.

So thank you so much for running through GU ASCO 2022. These were wonderful things to highlight. We always appreciate your expertise and your time Dr. Tagawa. Thank you.

Scott Tagawa: And I always enjoy talking to you.