The VERITAC-2 trial is a pivotal, randomized phase III trial evaluating vepdegestrant, a novel oral PROTAC estrogen receptor degrader, in patients with ER-positive, HER2-negative advanced breast cancer. In this interview, Dr Erika Hamilton (Director, Breast Cancer Research, Sarah Cannon Research Institute, Nashville, TN, USA) discusses the rationale behind VERITAC-2, the unique mechanism of PROTAC degraders, and what the data could mean for future treatment strategies.

The late-breaking abstract, ‘Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study’ (LBA1000) was presented at the American Society of Clinical Oncology on May 30 to June 3 2025 in Chicago, IL, USA.

Questions

1. What was the rationale and main motivations behind the VERITAC-2 trial? (0:14.00)
2. Can you elaborate on how PROTAC ER degraders differ mechanistically from traditional endocrine therapies? (0:58.43)
3. How does the safety and tolerability of vepdegestrant compare to fulvestrant, and were there any unexpected adverse events observed during the trial? (1:54.77)
4. How does vepdegestrant’s efficacy compare to other emerging therapies targeting ER+/HER2– advanced breast cancer? (3:19.97)
5. How might the VERITAC-2 results impact future clinical practice, and are there any future studies planned? (4:51.13)

Transcript

Hi, I’m Dr Erica Hamilton. I’m the Director of the Breast Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN, USA.

So the VERITAC-2 trial looked at a novel oral PROTAC or a different twist on an ER degrader. And, really, the rationale is that fulvestrant has been the mainstay of treatment in the second-line setting post-endocrine therapy and CDK4/6, but we really don’t have a consensus in that line.

We know that fulvestrant is plagued by intramuscular administration. We know that in a post-CDK4/6 setting that fulvestrant is only giving us a PFS of about two months. And so, based on the phase I activity and tolerability, this was looked at to really be a drug that can outperform fulvestrant.

Q2. Can you elaborate on how PROTAC ER degraders differ mechanistically from traditional endocrine therapies?

So, how they’re differentiated is is really an important question. So PROTAC stands for proteolysis targeting chimera, and essentially it is a way to get rid of the estrogen receptor that has a couple of differences from what you would think of as an oral SERD. So essentially, this harnesses the ubiquitin proteasome system. So our PROTAC molecule binds our target on one side, so the estrogen receptor, and then on the other side it binds E3 ligase. When E3 ligase is brought into close proximity without binding to the estrogen receptor, the estrogen receptor gets you proximity without binding to the estrogen receptor, the estrogen receptor gets ubiquitinated and ultimately then the proteasome or the garbage disposal system moves in and chomps that up and gets rid of it. So you can kind of mentally file it as a degrader with a different mechanism of action.

Q3. How does the safety and tolerability of vepdegestrant compare to fulvestrant, and were there any unexpected adverse events observed during the trial?

Yeah. So, again, this was a a pretty straightforward design, 1:1 vepdegastrant 200mg orally once daily or fulvestrant, which we know is given intramuscularly 500mg twice in the first month and then monthly thereafter.

I think what impressed me the most was really how well vepdegastrant was tolerated. I like to look at discontinuations and dose reductions as a true indicator of how well people are doing, on the drug, and we saw that vepdegastrant was only discontinued in 3% of patients and was only dose reduced in 2% of patients. So said another way, really less than 5% dose reductions and discontinuations.

The most common side effect was fatigue, but this was only 27% across all grades and almost uniformly this was grade 1 fatigue. The second and third most common were nausea and LFT elevations.

Again, across all grades this was less than 15% for these. So, really reassuring, I think, some of the oral SERDs have more prominent gastrointestinal side effects. And so what you note not seeing on our adverse event table is vomiting or diarrhea because across all grades, this was 6%. So really, quite well tolerated.

So our primary endpoint was progression-free survival among those patients that had ESR one mutations. And then from a statistical analysis plan, if that was positive, then we would go on to test progression-free survival among all comers regardless of mutation. VERATAC-2 did meet its primary endpoint.

Progression-free survival among those patients with ESR1 mutations was lengthened from 2.1 months with fulvestrant up to 5.0 months with vitegasterant. This was a hazard ratio of 0.57, a statistically significant p-value of less than 0.001. And then when we went on to test progression-free survival among all comers, we did not see a difference. So set a different way, progression free survival improvement really was limited to those patients with ESR one mutations, which is not unlike the other drugs that we’ve seen in this space. We also had key secondary endpoints, clinical benefit rate as well as objective response rate.

Clinical benefit rate was doubled with vepdegastrant, 20.2% of those patients receiving fulvestrant, 42.1% percent of those patients receiving vepdegastrant, and objective response rate was more than quadrupled, up from 4% with fulvestrant up to 18.6% percent with vepdegastrant. We also do have a key secondary endpoint of overall survival, but at this data disclosure, only about 20% of events have happened, and so it’s premature to comment on that at this time.

That’s a fantastic question. So this was a global phase III registrational trial, meaning that based on the positive data from this trial, there will be conversations with global health authorities for a potential approval.

That being said, you know, a drug like vepdegastrant is an endocrine agent, and sometimes we can also combine these. So there would be a potential role for vepdegastrant in earlier lines and first-line, perhaps with the CDK4/6, in the adjuvant setting or in this second-line setting in combination with other agents, whether that’s a PI3 kinase inhibitor or continued CDK4/6 inhibition. So, definitely a versatile molecule as an endocrine backbone.

View full #ASCO25 coverage here!

Disclosures: Dr Erika Hamilton is a consultant/advisor for Accutar Biotechnology, Arvinas, AstraZeneca, Daiichi Sankyo, Gilead Sciences, Lilly, Mersana Therapeutics, Olema Pharmaceuticals, Pfizer, Roche/Genentech and Stemline Therapeutics (all payments to institution).

This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the American Society of Clinical Oncology (ASCO). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.

Interviewer/Editor: Sophie Nickelson

Cite: #ASCO25 late-breaker: How vepdegestrant could reshape ER+ breast cancer. touchONCOLOGY. June 18th, 2025.

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