Erika Hamilton, MD, Sarah Cannon Research Institute, Nashville, Tennessee, discusses results from the phase 3 VERITAC-2 study which compared vepdegestrant vs fulvestrant for patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer and an ESR1 mutation.

Study findings show treatment with vepdegrestrant extended progression-free survival (PFS) vs fulvestrant in this setting, making it a potential new treatment options for these patients.

Dr Hamilton presented these results at the 2025 ASCO Annual Meeting in Chicago, Illinois.

Transcript: 

Hello, I'm Dr Erica Hamilton and this year at ASCO 2025 I'm pleased to present the VERITAC-2 study on behalf of my co-investigators. 

This was a global, phase 3, randomized study of vepdegestrant, an oral PROTAC ER degrader, versus fulvestrant among patients with ER-positive metastatic breast cancer that had already received a CDK4/6 inhibitor.  Briefly, the standard of care post-AI [aromatase inhibitor] and CDK4/6 inhibitor in the second line space, really there isn't a consensus. Drugs that we previously have used quite frequently, such as fulvestrant are really challenged by intramuscular administration and a quite short progression-free survival in the post-CDK4/6 setting, now in multiple trials looking like it's a little bit under 2 months. Vepdegestrant again is an oral PROTAC inhibitor, this harnesses the ubiquitin proteasome system to degrade the estrogen receptor. 

In this phase 3 trial, over 600 patients were randomized, 43% of them did have ESR1 mutations at baseline and they were randomized in a 1-to-1 fashion to receive vepdegestrant 200 milligrams orally once daily continuously or fulvestrant at 500 milligrams intramuscularly on day 1 and day 15 of their first cycle and at day 1 in subsequent cycles. Patients were allowed to have an additional line of endocrine therapy beyond the endocrine therapy and CDK4/6 inhibitor, but they were not allowed to have prior fulvestrant or prior chemotherapy. The statistical design planned for us to look at those patients that had ESR1 mutations first in terms of progression-free survival then if positive, move to the all-comer patient subset for this, and then finally move on to overall survival. I'm pleased to report the VERITAC-2 study was positive for those patients that had ESR1 mutations. 

Progression-free survival was lengthened from 2.1 months with fulvestrant up to 5 months with vepdegestrant. This was a hazard ratio of 0.57 and a P value of .001. There was no difference in progression-free survival when we looked at all patients regardless of mutations; however, when we look at some key secondary end points like clinical benefit rate and objective response rate among those patients that had ESR1 mutations, we also saw quite encouraging data. For a clinical benefit rate, this was doubled essentially 20.2% up to 42.1% for patients that had ESR1 mutations and when we looked at objective response rate among those patients with ESR1 mutations, this was more than quadrupled, 4% with fulvestrant up to 18.6% with vepdegestrant. In terms of overall survival, this data was quite immature. There were only 20% of the anticipated overall survival events at this time, so too early to conclude. 

I also want to talk a little bit about tolerability. We use the term “well tolerated” perhaps a little too frequently, but I really like to look at dose reductions and discontinuations to tell us how well a patient may tolerate a therapy. In terms of vepdegestrant we only saw a 3% discontinuation rate and in terms of dose reductions, we only saw a 2% dose reduction rate, which really tells me that the majority of these patients did in fact tolerate this drug quite well. The most common side effect was fatigue, as was present across all grades of fatigue at only 27% in patients. The second and third most common were LFT [liver function test] elevations as well as nausea present again at any grade in the low teens. In terms of gastrointestinal side effects, we know that this can be a very prominent side effect of some orals SERDs [selective estrogen receptor degraders], and what does not show up on our adverse event table is any vomiting or diarrhea, that's because both of these came in at 6%, any grade, below the threshold of 10% to be included on the table. 

In summary, vepdegestrant did show a statistically significant and a clinically meaningful improvement in progression-free survival for patients that had ESR1 mutations and ER-positive, HER2 negative advanced breast cancer post endocrine therapy and a CDK4/6 inhibitor. This was well tolerated with very low rates of discontinuation or reduction. This data potentially supports vepdegestrant as a monotherapy in patients with ESR1 mutations in the second line setting and beyond. Thank you so much.

Source: 

Hamilton EP, De Laurentiis M, Jhaveri KL, et al. 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. Presented at 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Abstract LBA1000