Scott Tagawa:

Hi, everyone. Thank you for joining us. We’re here to give you an update and overview of the potentially practice-changing abstracts that have been discussed at the ASCO GU 2023 Conference. I’m joined with my colleagues Tanya Dorff and Karie Runcie, who are fellow GU oncology specialists. Why don’t we go ahead and start with updates in prostate cancer? Tanya, what have been the most interesting abstracts that you’ve seen?

Tanya Dorff:

Well, I think the big news yesterday in the prostate session was PARP inhibitors. So we saw data from TALAPRO-2, which was in castration-resistant prostate cancer patients unselected for genomic alterations. This was a positive study with a significant prolongation in rPFS, overall hazard ratio around 0.6. Of course, the BRCA and other homologous recombination repair-altered patients had an even stronger benefit, but there was a significant benefit even in genomically-unselected patients.

So this now opens the door to use talazoparib with enzalutamide in mCRPC, potentially, for unselected patients. Of course, we’ll be interested to see how the survival data mature and safety is always a consideration as well as cost for patients. But it was quite a striking benefit that was seen and it follows on the earlier presentation last year of PROpel with abiraterone and olaparib.

And then, at the same time, we got the TRITON3 data with rucaparib. What was interesting about this presentation was not just that this drug was very effective for patients with homologous recombination repair alterations, like BRCA1 or 2, but that the active comparator arm included docetaxel. So I think we’ve all had this lingering question about if I have a patient with a BRCA alteration, should I use a PARP inhibitor first or chemotherapy first? Here we could see that the medium progression-free survival was longer, around 11 months, compared to six months for the comparator arm. And not surprisingly, the chemotherapy patients did better. So their progression-free survival was more like eight months and the second AR-targeted agent treated patients were more like four and a half months.

But again, overall, the PARP inhibitor was superior and so now we have a little bit more data to guide us when we’re thinking about sequencing our treatments.

Scott Tagawa:

Yeah, I enjoyed those and I was waiting for those abstract presentations. I think that for me, in terms of prostate cancer, PARP inhibitors, at least for medical oncologists with systemic therapy, are really kind of the top-line data. I love the fact that TRITON3 did include docetaxel as part of the control arm and I encourage all trials to include all of the relevant and ethical options for the control arm.

So now we have three trials with an unselected patient, well, two trials with an unselected patient population plus another in kind of this mostly AR pathway inhibitor naive patient population. We put them together and that patient population is shrinking. So what do you think that means for our average patient?

Tanya Dorff:

Yeah, that does complicate things. The fact that these patients had not been exposed to a prior AR-targeted agent like abiraterone because many of our patients are being treated with intensified therapy upfront. But I think these trials really underscore that there is some synergy, that there are additional mechanisms of action for PARP inhibitors in combination with AR-targeted agents. And we’ll need some additional data to fill in those kind of gaps. But it’s definitely something I would consider even in a patient who’s pretreated with abiraterone, given how active the doublet of enzalutamide and talazoparib were.

Scott Tagawa:

Yeah, and we did see the overall survival results of the PROpel study. Unfortunately, not powered for overall survival, but strong trend and I hope that we can get pharma to cooperate together. Maybe we can do a pooled analysis at some point in time when the data mature. Any final comments on the prostate data?

Tanya Dorff:

No, I think that’s about it.

Scott Tagawa:

So you may be watching this at a different time, but we are live here and today is the mostly urothelial day. I would say that my overall viewpoint is that there’s nothing that’s tremendously practice-changing, more practice-affirming or some intriguing new data or new drugs. We will, later today, see the final results, overall survival results, of IMvigor130, atezolizumab versus chemotherapy or chemotherapy plus atezolizumab versus chemotherapy. And not surprisingly, confirm that the final survival analysis, there’s no benefit for overall survival. So that really moves, kind of cements that we’re really not using single agent, immune checkpoint inhibition or combinations with traditional cytotoxic chemotherapy in that setting.

We’re seeing additional data on antibody drug conjugates. So the main approved drug, enfortumab vedotin, has some updated data. Matt Milowsky is presenting some quality of life data with some improvements in pain and otherwise maintenance of quality of life scores. This is Cohort K of that trial, it was a randomized trial, but it’s not a direct comparison. So it is nice to see with additional datasets some patient reported outcome data.

I think it’s very early, but a similar drug that intrigues me is another Nectin-4-targeted compound. I forget the number of bicycle compound BT8009 or something like that, that in preliminary data looks to be safe with a very low rate of rash and maybe a low rate of neuropathy. I’m not sure about that. But in their recommended Phase II dose had a 50% response rate. Now it’s only four out of eight, but I think that since the Nectin-4 target has already been validated in the clinic, I think having additional constructs, particularly with what might be different safety profiles, I think is important.

Then the other main approved drug, at least in the United States is sacituzumab govitecan. The TROPHY-U-01 study is a multi-cohort study, but three cohorts have been fully enrolled and we’re seeing updated data today. Cohort 1, which led to the initial accelerated approval, has updated data. And the one line summary is that efficacy is confirmed with no new longer-term toxicity that’s observed. And that’s always nice to know in long-term follow up.

Cohort 2, it’s a little bit confusing. So it is at study entry, platinum unfit, meaning carboplatin unfit, although they could have received in the perioperative setting cisplatin or carboplatin in the past. Just to kind of clarify because the chair actually, I think, misspoke and said cisplatin unfit. So it was sicker patient population, but really I would say validated the overall response of the drug was 32%, seemed like the single agent activity of those drugs is approximately 30% with no major differences in terms of toxicity. Still, mild suppression and diarrhea are the two most common adverse events with that particular drug.

Then Cohort 3, which was a combination in post platinum, but IO-naive patients, so different than the EV-103 study in frontline, but in ADC plus immune checkpoint inhibitor with pembrolizumab. When it was presented last year by Dr. Grivas, it was kind of hot off the press. The data barely made kind of late breaking. So now it’s more mature follow-up and the overall response rate has gone up. So some of those that weren’t quite a partial responder have converted to partial responders and now we do see, I wouldn’t say it’s so stable, but we do see a median duration of response of 11 plus months, which we didn’t know at the time before because of short follow-up. Also, no major increases in adverse events with the longer follow-up and exposure. So those I found interesting.

Then there’s a number of different data sets on either urine or plasma cell-free DNA. It would not say that any of our apps are ready for prime time, but I do think that they can be quite useful looking at different genomic alterations in the clinic. We do have a molecular targeted drug, erdafitinib. But also, especially for minimal residual disease, whether we’re talking about muscle invasive or what was presented today, non-muscle invasive in terms of urine. So hopefully, we can get larger validation studies in the clinic.

Tanya Dorff:

Well, speaking of genomic alterations in urothelial cancer, a question that I often struggle with is for your patient with an FGFR alteration, you know, where you have erdafitinib as an option, but you also have these antibody drug conjugates, are we seeing any data that can help give us guidance in which sort of treatment to reach for first?

Scott Tagawa:

I think, I would not say absolutely, is the answer. So I think there’s a couple ways to approach this. One is level of evidence. So only EV has randomized survival data. So I think that is absolutely reasonable for a patient that we think can tolerate that drug, I think that’s absolutely reasonable to use first amongst those three, whether there is let’s say an activating FGFR3 mutation or not.

Between let’s say a patient that has had EV, between SG and erdafitinib, a patient has an activating FGFR mutation, we don’t know. Looks like TROP-2 is expressed in that subset, but we don’t know that SG is better or worse than erdafitinib. So I will often go to the targeted agent because that’s kind of my instinct looking at precision medicine, but I certainly don’t know that’s better. And a lot of times for patients switching from an IV drug to an oral drug is sometimes patient friendly, not that just because it’s oral means there’s no toxicity and we all know we need to monitor that early. I think early identification and intervention in terms of supportive care minimizes the chance of any high grade adverse event.

Then there’s more data, could be from the Unite group, I don’t want to misquote, but there’s more data that hasn’t been fully validated, kind of answering your question, but a little less relevant, on those that have an FGFR activating mutation or fusion may be responding less well to single agent PD1 or PDL1. That’s a hypothesis that’s out there, not all the data’s in line, but there’s another data set in a poster that’s being presented that’s pointing in that direction.

So looking forward to tomorrow, which is mostly the kidney day. What do you think are the exciting data?

Karie Runcie:

I think the most exciting data that everyone is waiting to see are the results of the Phase III ZIRCON study, looking at next generation PET imaging in RCC. PSMA PET is, as you all know, has been quite transformative in prostate cancer in terms of diagnosis and therapeutics and it’s changing the way that it’s changing the whole field. And so the ZIRCON study may potentially have the same role or effect in RCC in terms of picking up clear cell RCC at an earlier time. It’s looking at CA9 as a marker in kidney cancer. And so perhaps we may be able to detect clear cell RCC earlier and that may have implications for treatment and cure, which is always the goal. In addition to potentially being a biomarker of response, we have yet to find good biomarkers of response in clear cell RCC. And so this could potentially be an imaging biomarker. So that’s very exciting. So I think that’s the most exciting results that we await in RCC. So far, we know that it has at least at 86% sensitivity in detecting clear cell RCC, 87% specificity. So that is quite impressive compared to our current standard of care.

In addition to that, we have updated results from COSMIC-313. So Toni Choueiri presented results of COSMIC-313, that’s the triplet in advanced clear cell RCC at ESMO, and we have updated results. At ESMO, we found that it’s the intermediate risk group patients that seem to have some benefit from the triplet and nobody really knows why. This presentation is looking closer at the intermediate risk and poor risk group. 75% of the overall patient population was intermediate risk, 25% poor risk. And in the intermediate risk group, the triplet compared to ipi/nivo had a 45% overall response rate compared to 35% response rate and the hazard ratio is improving. It also has a lower progressive disease rate, 7% compared to that of ipi/nivo. So it’s quite promising.

We still need to figure out why though, that it’s intermediate risk population. One hypothesis is that this intermediate risk group had more prior cytoreductive nephrectomy. 70% of those patients had cytoreductive nephrectomy in comparison to 44% in a poor risk group. And so there may still be some role for cytoreductive nephrectomy with our current standard of care. And at Columbia, we do have a trial looking at cabo/nivo and cytoreductive nephrectomy, and so hopefully that may shed some light and add some data to this story.

In addition to that, there was a post hoc analysis looking at biomarkers of response in CheckMate 9ER, either updated results from CheckMate 9ER cabo/nivo, and the biomarker data really showed that we still have more work to do. So looking at our prior biomarkers, CD8 T-cell subsets, looking at CD8 T-cells topology, looking at gene expression analysis, really none of these biomarkers panned out. And so we really do have more work to do as a field and perhaps this next generation imaging may be a good biomarker of response for some of our patients.

Scott Tagawa:

Yah, you know, I think when I look, so a lot of what I’ve done in terms of research is looking at cell surface targeting. And I’ve looked at the timeline for CA9, it’s very similar to PSMA, and I’ve spent decades and then finally something becomes validated. This is not yet approved, but I think there are many useful potentials including workup of renal masses. Is it a lipid-poor AML or is it a clear cell renal cell carcinoma?

Karie Runcie:

Yeah.

Scott Tagawa:

That, I think, can help. And the next step could be therapeutic as well to target that.

Karie Runcie:

Yeah, therapeutic. Just like PSMA PET.

Scott Tagawa:

It’s nice that we have all sorts of different combinations of IO, IO-IO or IO-VEGF. Now, we have Hif, but having another mechanism of action I think would be exciting for the field.

Karie Runcie:

Yeah.

Scott Tagawa:

Well, I would say it’s definitely been enjoyable. I don’t know that this is a record attendance, but nearly 6,000, seems to me that it’s nearly record attendance, combined online as well as in person. For those of you that didn’t make it to the meeting, we can tell you that for many of the sessions, all the seats are full. So it’s I think a combination of wanting camaraderie, scientific discussions, as well as exciting new data that we can take in today and bring to the clinic tomorrow to help our patients. So thank you very much for your attention.

Recording date: 17-Feb-2023