Dr Rita Nanda (University of Chicago Medicine): Thank you so much, Dr Waks, for going through all of that, the new updates from San Antonio, as well as the mechanism of action of PROTACs. I am going to focus now a little bit on the PROTACs, the clinical trial data that we have, and some recent updates that we saw at San Antonio this year.

[00:27:16]

Posttest Question 2

Again, as we launch into that, a question for you, which of the following most accurately describes the findings from the VERITAC-2 trial of the PROTAC ER degrader vepdegestrant compared with injectable fulvestrant in patients with HR positive, HER2-negative metastatic disease?

1. Improved efficacy in all patients without regard to ESR1 mutation status;
2. Improved efficacy in patients with mutated ESR only;
3. Similar efficacy in all patients without regard to ESR1 mutation status; and
4. Similar efficacy in patients without mutated ESR1 only.

A little bit of a third, a third, a third of the first 3. Hopefully, we will be able to come to a more uniform choice by the time that I am done.

[00:28:28]

Vepdegestrant (ARV-471) Background

Vepdegestrant is a selective oral PROTAC ER degrader that targets both the wild type as well as the mutated estrogen receptor. Vepdegestrant binds ER and an E3 ubiquitin ligase to induce ubiquitination that then allows for proteasomal degradation of the estrogen receptor. SERDs, on the flip side, as you heard from Dr Waks, induced ER immobilization and/or conformational changes. It is a more indirect degradation of the estrogen receptor, and it indirectly recruits the ubiquitin proteasome system.

Fulvestrant has some challenges. It is IM, so it is intramuscular administration and has limited ER degradation. Even at the optimal dose, about 40% to 50% of the estrogen receptor gets degraded, and in preclinical models, vepdegestrant has been shown to be a much more potent degrader and is associated with more tumor growth inhibition as compared to fulvestrant.

[00:29:33]

VERITAC: Phase I/II Trial if Vepdegestrant Alone or With Palbociclib in ER/HER2-Advanced Breast Cancer

The VERITAC initial trial was a phase I/II trial of vepdegestrant alone, or with palbociclib in patients with hormone receptor–positive advanced-stage disease. There were 3 different cohorts or 3 different parts to the study. Part A. Part B. Part C. For part A and B, patients were treated with vepdegestrant alone. Part A was really trying to understand once-daily or twice-daily dosing. Part B was looking at selecting the recommended phase II dose, looking at 2 different once-daily schedules of 200 or 500 mg. Ultimately, 200 was selected to move forward. And then part C was looking at the combination of vepdegestrant plus palbociclib.

All of the patients who were enrolled in this trial had received prior endocrine-based therapy. Part A, these were more heavily pretreated patients. Some had even had chemotherapy. Then, in part B and C less heavily pretreated. The primary focus of these cohorts was to look at dose-limiting toxicities to determine the recommended phase II dose, and then also to do some PK/PD analyses.

[00:30:54]

VERITAC Part B: Primary Endpint Clincal Benefit Rate in Dose Expansion Cohort

In part B, the primary endpoint here was looking at clinical benefit rate. This was looking at the 2 different doses that were selected as potential recommended phase II doses. You can see that for patients who had prior endocrine therapy, some even chemotherapy, you can see the clinical benefit rate with both doses was in the 38% range.

It did not really seem to vary that much between the 2 doses, but when we looked at the patients who had ESR1 mutations in their tumor, the clinical benefit rates were higher. More in that 50% range. Again, seeing with these PROTAC inhibitors, even early on in the phase I and dose expansion cohort setting that it really does seem to be those who have ESR1 mutations who seem to have the most benefit from these therapies.

[00:31:50]

VERITAC: Progression-Free Survival

Now, again, not a randomized study. These are single-arm phase IIs, but in looking at progression-free survival for overall all patients on the left, and then on the right, patients who have tumors with ESR1 mutations, you can see that the median progression-free survival for the all-comer population is about 3 and a half months. Then, when we look at patients who have got ESR1 mutated tumors, you can see that it is much higher 5.7. Again, proof of concept, these agents are effective and can keep disease under control even in the setting of being heavily pretreated and in the setting of a dose expansion phase I study.

[00:32:32]

VERITAC Updated Phase I Dose Expansion: Efficacy

Here, looking at the waterfall plot of the 83 patients who participated in the dose expansion. These were patients who had received anywhere from 30 to 700 mg. Again, really no dose-limiting toxicity seen even at the highest of doses. You can see that, regardless of dose level, we saw some responses. Partial responses, stable disease, some response, maybe not approaching a partial response. Really exciting to see even in the setting of patients who are heavily pretreated.

[00:33:10]

VERITAC Updated Phase II Expansion Cohort: Efficacy With Vepdegestrant 200 mg QD

Now, looking at the phase II expansion cohort. These were 35 patients who were treated with the 200 mg dose, which is what was selected as the recommended phase II dose. You can see here that the clinical benefit rate was higher in patients who had ESR1-mutated tumors, 47%, and it was 37% in the overall cohort of patients. When you look at median PFS again much higher when you look at that subset of patients who have got ESR1 mutations as opposed to the entire cohort overall. Some signals that perhaps we are going to see with vepdegestrant, what we have seen with the oral SERDs, that the efficacy differences are really going to emerge when you have got these patients with ESR1 mutations.

[00:33:58]

VERITAC Updated Phase II Expansion Cohort: Safety With Vepdegestrant 200 mg QD

In terms of treatment, emergent adverse events, in general, vepdegestrant is very well tolerated. Certainly, we see a lot of adverse events. Here in the table on the right, you can see the adverse events that occurred in 10% or more of patients, but these are predominantly grade 1 adverse events, fatigue, hot flashes, arthralgias, the most common and generally manageable and treatable. Really, no dose reductions were needed. There were very few discontinuations. Only 2 out of 35 patients discontinued because of a treatment adverse event.

[00:34:39]

VERITAC Part C Results: Vepdegestrant + Palbociclib in ER+/HER2- Advanced BC

Here, looking at part C, which, if you will recall, is the vepdegestrant plus palbociclib part of the trial. Here, patients were treated and they could have had prior CDK4/6 inhibitor-based therapy and prior endocrine-based therapies. You can see that overall, with this combination, a clinical benefit rate of 63%. When you look at the ESR1 mutant population, that clinical benefit rate is higher, approaching 75%, and median PFS of over 13 months in these patients. Just to be very clear, 87% of these patients had received a prior CDK4/6 inhibitor. Really exciting to see the high clinical benefit rate, response rate, and median PFS in these pretreated patients with the combination.

[00:35:29]

VERITAC Part C Results: Safety with Vepdegestrant + Palbociclib in ER+HER2-Advanced BC

In terms of safety here, again, there were toxicities that were observed in patients who participated in this arm of the trial, but these were largely related to palbociclib. They were cytopenias. There were a fair number of grade 3, 4 toxicities, but again, cytopenias are more palbociclib-related than vepdegestrant-related.

[00:35:52]

VERITAC Part C Results: Safety

Here you can see the details, in looking at the total 46 patient population, about half and half had had the 200 vs 500 mg of vepdegestrant, and there really did not seem to be any differences in rates of the toxicities with 200 vs 500. These were largely cytopenias, neutropenia, low platelets, anemia, decreased white blood cell count, all largely related to the palbociclib. Then fatigue, which again, palbociclib can cause, but certainly vepdegestrant can contribute. For the most part, this combination is well tolerated. The toxicities that were seen in the dose, modifications that were needed were largely related to the palbociclib addition to vepdegestrant.

[00:36:42]

VERITAC-2 Update (SABCS 2025): Phase III Study of Vepdegestrant vs Fulvestrant in ER+/HER2-Advanced BC

VERITAC-2 phase III clinical trial looked at vepdegestrant vs fulvestrant in hormone receptor–positive, HER2-negative, metastatic breast cancer. Very similar trial design to what we have seen with other oral SERDs. Vepdegestrant vs fulvestrant monotherapy over 600 patients participated in this trial. The primary endpoint was looking at progression-free survival by blind central review in all patients and then separately in the ESR1 mutant population as well. A number of secondary endpoints, including survival clinical benefit response rate again by BICR safety and then some subgroup analyses as well. That was updated just recently at San Antonio.

[00:37:33]

VERITAC-2: Characteristics: Baseline Characteristics

I have got some new data to share with you in this regard. In looking at the baseline characteristics here, median age was 60 across the board. Pretty typical for what we see with patients with hormone receptor–positive metastatic breast cancer endocrine-based trials. Largely female. About 40% of these patients did have tumors that had ESR1 mutations, 60% to 70% had visceral disease. About 20% bone only. 80% of these patients had had 1 prior line of therapy, and then about 20% 2 prior lines of therapy. All patients who participated in this trial were required to have prior CDK4/6 inhibitor-based therapy. You can see that here, 100% of patients did. About half of the patients had previously had palbo, and then next was ribo, and about 20% had received abemaciclib.

[00:38:33]

VERITAC-2: PFS by BICR

Here were the primary results of the trial in looking at progression-free survival by blind central review. You can see in the panel on the right the overall study population, including those who have ESR1-mutated tumors and those who do not. You can see that the median PFS was pretty similar for vepdegestrant vs fulvestrant, a median PFS of about 3 and a half months. Then, when you look on the left here in those individuals who had tumors with ESR1 mutations, you can see that there was a significant about 3-month improvement in median progression-free survival, favoring vepdegestrant.

[00:39:18]

VERITAC-2 Update (SABCS 2025): BICR-Assesssed PFS by Menopausal Status (ESR1m Population)

Updated at San Antonio last month was looking at PFS in some of the subgroups. Looking by menopausal status. Again, you can see pre-perimenopausal on the left here, postmenopausal on the right. In the orange, you can see that vepdegestrant still performed better numerically than fulvestrant did in terms of median progression-free survival. It does not appear that menopausal status matters. Again, this is the analysis that was conducted in the ESR1 mutant population, which is where we see the differences, again, pre postmenopausal does not matter. Still, vepdegestrant does better than fulvestrant.

[00:39:58]

VERITAC-2: BICR-Assessed PFS by Duration of Prior CDK4/6i (ESR1m Population)

Now focusing on this ESR1 mutant population, looking at the benefit of vepdegestrant vs fulvestrant by the duration of prior CDK4/6 inhibitor-based therapy. You can see here in the panel on the left that, for those patients who did not really benefit much from endocrine based therapy, that there really was a very modest difference in median PFS with overlapping confidence intervals. But, again, looking at those patients who benefited from endocrine based therapies for 12 months or longer, and it really does appear that the longer you are on that endocrine based therapy, the better you do with vepdegestrant vs fulvestrant.

You can see if it was 12 months or more, a 3-and-a-half-month difference, and then that increases to 5 and a half month difference for patients who benefited from their frontline endocrine-based strategy for a year and a half. Again, it does appear that those patients who have endocrine-sensitive tumors with ESR1 mutations do benefit pretty dramatically from vepdegestrant as compared to fulvestrant.

[00:41:10]

VERITAC-2: BICR-Assessed PFS by Presence of Liver Metastases (ESR1m Population)

Now, in looking at the ESR1 mutant population with liver metastases, again, you can see in the orange here that patients do better with vepdegestrant as compared to the blue fulvestrant curves here. Again, maybe not as much benefit in patients with liver metastases as those who do not have liver metastases, but again, vepdegestrant does better than fulvestrant. We are getting into small numbers here. Again, absence or presence of liver mets vepdegestrant is still better than fulvestrant, but perhaps those who do not have liver mets seem to fare a little bit better regardless.

[00:42:32]

VERITAC-2 BICR-Assessed PFS by PI3/AKT/PTEN Alteration Status (ESR1m Population)

Now, looking at the subgroup of patients who have multiple mutations. ESR1 mutations in their tumor and then also alterations in the PI3 kinase AKT/PTEN pathway. You can see here, regardless, vepdegestrant does better than fulvestrant in the absence or presence of alterations of this pathway.

[00:42:56]

VERITAC-2: Secondary Endpoints

In terms of secondary endpoints, again looking at clinical benefit rate, response rate for patients who have got tumors with ESR1 mutations and those overall, you can see that the clinical benefit rate is essentially double with vepdegestrant as compared to fulvestrant in individuals who have ESR1 mutations and really a quadrupling in the response rate from 4% to 18.6%. Much more modest differences here in the all-comer population, and that is because we are probably not seeing much of a benefit in patients who do not have an ESR1 mutation.

[00:43:39]

VERITAC-2: Safety Summary

In terms of safety with vepdegestrant in the randomized phase III trial, again, no unexpected signals from what we expected from our phase I and dose expansion strategies. For the most part, these are grade 1/2 toxicities not requiring discontinuation of drug or dose reductions. Fatigue was the most common seen with vepdegestrant and fulvestrant, and these were generally grade 1 to 2 toxicities and manageable.

[00:44:14]

Related Ongoing Trials

There is an ongoing phase I/II trial looking at combining vepdegestrant with a KAT6 inhibitor, and so keep your eyes out for that down the road. This trial is currently enrolling, and hopefully, we will have some results in the next year or so.

[00:44:33]

VERITAC-3: vepdegestrant + Palbociclib vs Letrozole + palbociclib in ER/HER2-Advanced BC

Then VERITAC-3 is a large randomized phase III trial looking at vepdegestrant with palbociclib vs letrozole plus palbociclib in patients with hormone receptor–positive advanced breast cancer. This trial is looking to enroll over 1100 patients. The primary endpoint here is looking at PFS with a number of secondary endpoints here looking at quality of life response, duration of response, clinical benefit rate, overall survival. Again, this trial is actively enrolling. The reason for the combination of palbociclib here is concerns about QT prolongation, and challenges with combining with other CDK4/6 inhibitors.

[00:45:20]

Phase I Study With AC699 in Breast Cancer

There is another PROTAC, which has also been studied, called AC699. It is unclear what the development strategy is for this agent moving forward, but again, a small first-in-human phase I study has been presented a little over a year ago now looking at safety, tolerability, with some efficacy, secondary end points.

[00:45:46]

Phase I Study With AC699 in Breast Cancer: Baseline Characteristics

Again, this was a small study of 35 patients, median age of 60. Previously, treated patients, they would had a number of different lines of therapy. You can look here, median prior number of regimens was 5, ranging anywhere from 2 to 10. All of these patients had previously had a CDK4/6 inhibitor, and prior aromatase inhibitor and other endocrine-based therapies, and even half had previously received chemotherapy.

[00:46:16]

Phase I Study With AC699 in Breast Cancer: Safety

This was generally well tolerated. Very similar adverse events that have been seen compared to vepdegestrant, generally very mild grade 1 to 2 toxicities, some nausea, fatigue, dehydration, but generally very well tolerated therapy.

[00:46:38]

Phase I Study With AC699 in Breast Cancer: Tumor Change From Baseline

Here you can see the waterfall plot, proof of concept, we did have patients who responded to this therapy. You look over at the right here, 11 of the 27 patients who were evaluable for response had ESR1 mutations, and the response rate here was 56%. Again, really small numbers, but obviously much higher than the overall study population of 23%. Again, efficacy seems to be most dramatic here in patients who have got ESR1 mutations.

[00:47:11]

Posttest Question 2

Heading back to our question, which of the following most accurately describes the findings from the VERITAC-2 trial of the PROTAC ER degrader vepdegestrant compared with fulvestrant in patients with hormone receptor–positive metastatic disease? Recall this was the randomized phase III trial that compared vepdegestrant to fulvestrant.

There was improved efficacy in all patients without regard to ESR1 mutation status. There was improved efficacy, but only in those patients with mutated ESR1 tumors. A similar efficacy in all patients without regard to ESR1 mutation status, and then similar efficacy in patients without mutated ESR1 only. Please vote.

Most people here voted for improved efficacy in patients with mutated ESR1 only. That is true. Dramatic improvement from the beginning. That is the correct answer. Again, no benefit in patients with vepdegestrant vs fulvestrant in this setting of overall study population or those with ESR1 wild type.

[00:48:42]

Experts Thoughts for the Future: Challenges, Future Perspectives, and Potential Clinical Application of PROTACs

Now I am going to move on to the next part, just to look to the future and see where we are going to be heading with these agents.

[00:48:51]

What Is Next?

What is next? Obviously, predictive biomarkers are a big part of what we hope to identify, not just for PROTAC inhibitors, but for a variety of other therapies that we have that we use to treat our patients in early-stage and advanced-stage disease. We need to understand better which patients with ESR1 mutations can do well on long-term or single-agent endocrine therapy.

As we are shifting more to combination strategies, we should remember that some patients do really well on endocrine-based therapies alone, but I think we need a better sense. Right now, the only way we have been able to identify who are these patients is how long they were on their initial type of therapy, their endocrine-based therapy. Would patients benefit more from a combination approach? Obviously combining with everolimus, like you saw with the evERA or CDK4/6 inhibitors, like we do with aromatase inhibitors and fulvestrant in the frontline setting. That is obviously a strategy for the future. Looking at long term efficacy for some of these trials, they are still immature, and some not reported out yet. That will be obviously very important, and then possibilities for improving on PROTAC trial design vs oral SERDs.

[00:50:14]

Possibilities for PROTACs and the Road Ahead

Where are the possibilities for PROTACs in the road ahead? Certainly, anywhere where we have seen our oral SERDs and other endocrine-based therapies play a role. In the adjuvant setting, or I would argue, even neoadjuvant setting in the frontline setting, the VERITAC-3 trial will hopefully help us with that. Is there a role for this in the frontline setting with CDK4/6 inhibitor second line and beyond? Most of these earlier studies that I presented were in pretreated patients, and we definitely did see efficacy in patients with ESR1 mutations. Obviously, the combination strategies do appear to be better, and so looking at combination strategies moving forward.

[00:50:58]

Takeaways 1

Just for some final takeaways here, despite progression on standard endocrine therapies including CDK4/6 inhibitors, a number of patients do remain endocrine sensitive. The way we have defined that right now, in terms of thinking about who are these patients who benefit from their next line of endocrine-based therapy, from the EMERALD trial, what you saw from the vepdegestrant experiences, it is that 1-year cut point that helps us figure out how likely are patients potentially to benefit from another line of endocrine-based therapy? The longer they are on their front line, the more likely it appears to be able to benefit from another endocrine-based strategy.

Obviously, we need novel estrogen-targeting drugs in this space. PROTACs degrade the estrogen receptor in a very distinct way from SERDs. How we can look at combination strategies and other targeted therapies down the road, obviously is what we need to do.

[00:52:05]

Takeaways 2

Vepdegestrant has shown activity both alone and in combination with palbociclib. In the combination strategy, the progression-free survival was more than 11 months in patients, regardless of ESR1 mutation status. These were patients, as I alluded to, 87% of them had previously received a CDK4/6 inhibitor-based strategy. Novel estrogen degraders are also in development.

The landscape is going to get busier and busier as we move along, although it is unclear if displace the agents, the oral SERDs, and the PROTACs that have already been studied. Combination with CDK4/6 inhibitors appear safe, and I think is potentially a strategy that may happen in the frontline setting if the VERITAC-3 trial is a positive trial, and then I would just ask you to please check the link for updates for ongoing trials and evolving treatment strategies involving PROTAC ER degraders for patients with advanced hormone receptor–positive disease.

Q&A

I think that I will invite Dr Waks to come back now, and we will go through some questions. I thank you all for putting them here in the chat. I think between the 2 of us, we will field these questions. Our first question here is why is there a better efficacy outcome with SERDs or PROTAC in ESR1 mutant patients vs intent to treat? Dr Waks, I know you have answered this question in a great way in the past. Do you want to take a stab at that?

Dr Waks: Yes. To my knowledge, like the answer to this is not entirely completely known and worked out. This is not an absolute, we know the answer to this question for sure. My understanding of at least part of this answer has always been that, when you identify an ESR1 mutant population, then you basically know with a reasonable level of certainty that you have found a patient who is still endocrine sensitive. Their tumor is still proliferating because of ER-mediated signaling, but they have become resistant to aromatase inhibitors, for example.

You have picked out a population where endocrine pathways are still driving the proliferation of their tumor. In that setting, since you have got this endocrine sensitive endocrine driven subset of ER positive metastatic breast cancer, then if you develop a really good endocrine targeting therapy, then it is going to work preferentially in those particular patients because they still have this estrogen driven proliferation of their tumor cells, and if you get better and better ways of targeting that estrogen, then it will work better in them. That is my best possible answer, but I do not think it is 100% worked out. Do you have anything to add to that?

Dr Nanda: No. I think it is hard to know. I do think it all boils down to that is the mechanism of resistance to endocrine-based therapy, and these tumors are potentially still endocrine sensitive. I will say it is just a subset of them, probably that are still endocrine sensitive, which is why everybody does not respond when we are talking about clinical benefit rate. It is a mechanism of resistance to AIs, and some of these tumors are still going to be endocrine sensitive, and some are not, and so when we look at these clinical benefit rates of oral SERDs or even PROTACs, it is not 100% because-

Dr Waks: Exactly. It is clearly more complicated for most people than just this 1 mutation has explained everything, but totally agree.

Dr Nanda: Before I get to the next question, because I do not know how to answer it. There is a person who has been like, having difficulty getting credit. If we could have the Decera team potentially help her figure out how to get credit, that would be super helpful.

Then there is this question about - I am just going to read it because I do not know that everybody else can hear this or know the question, but there is another population of ESR1 known as membrane-bound ESR. How does this figure into the PROTAC-mediated degradation? I am not sure I completely understand the question, but I am not sure that if - I do not know if you know Dr Waks.

Dr Waks: I do not know the answer. No. I am sorry.

Dr Nanda: I do not know that we know. What I will say is, we certainly know that, I do not know if it is - I just do not know. I am not even familiar with that potential mechanism.

Dr Waks: I had 1 question for you. I always like to ask this across the country, although I do not have to ask it if anybody else has any questions-

Dr Nanda: No other questions, so go ahead.

Dr Waks: What do you do for the patient who is progressed on their first line AI, CDK, and they do not have ESR1, and they do not have a PIK3CA mutation? What is your regimen of choice there? Do you switch the CDK4/6 inhibitor? Do you use that for alignment? I think that there is a lot of heterogeneity here if they do not have something targetable in the second line.

Dr Nanda: I have to say it really depends on the patient, what their amount of disease is, and maybe how much mileage they got out of the first CDK4/6 inhibitor, and what the first CDK4/6 inhibitor was, and what I think they may be able to put up with in the way of side effects. I think strategies are, in the absence of a mutation, it is generally fulvestrant-based therapy. Whether I want to try to milk the CDK4/6 inhibitor along for a little bit more time.

I have these patients who were on palbociclib for years and years, and I never messed with it. Then, when they progress, I am probably more excited to consider fulvestrant in another CDK4/6 inhibitor, because I do think that may be the others are potentially a little bit more effective. At least when we look at the MAINTAIN trial and the switch trials, that is what people were on and then switched over.

Generally, I would want to switch out the CDK4/6 inhibitor and not keep the same one going. If they were on something like an abema and a ribo and they were not on it for super long, then I am probably looking to do something like everolimus. Although I do think we are going to have new options in the not too distant future. I think for the ESR1 mutations, we have now got imlunestrant plus abemaciclib listed in the NCCN guidelines. Is that a strategy for at least the ESR1 mutations, where we maybe do not feel as comfortable or do not want to just do single-agent therapy? I think that is certainly a strategy. Not that you asked, but I felt like we do not have any other Q and A, so we could sit here and kick things around. I will say, the NCCN guidelines for all of you out there were just updated last Friday. Go look at them because there are some changes there that might inform your practice across the board for all the different subtypes of breast cancer in the metastatic setting.