Vepdegestrant Shows PFS Advantage in ESR1-Mutant ER+/HER2− Breast Cancer

Erika Hamilton, MD

Vepdegestrant (ARV-471), an investigational oral selective estrogen receptor degrader (SERD), has demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with fulvestrant (Faslodex) in patients with pretreated ESR1-mutant, estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer.¹ The phase 3 VERITAC-2 trial (NCT05654623), presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that vepdegestrant achieved a median PFS of 5.0 months vs 2.1 months with fulvestrant (stratified HR, 0.57; 95% CI, 0.42-0.77; P <.001) in this genetically defined subgroup.¹

Six-month PFS rates favored vepdegestrant at 45.2% compared with 22.7% for fulvestrant. These findings support the potential of vepdegestrant as a targeted treatment option in a post-CDK4/6 setting, where therapeutic consensus remains limited.

While the all-comer population did not reach statistical significance (HR, 0.83; P =.07), the robust efficacy observed in the ESR1-mutant subgroup, along with favorable tolerability and low discontinuation rates, underscores the relevance of biomarker-driven therapy selection.

In an interview with Targeted Oncology^TM, Erika Hamilton, MD, director, breast cancer research, Sarah Cannon Research Institute (SCRI), discussed the PFS benefit and favorable safety profile of vepdegestrant in ESR1-mutant ER+/HER2− advanced breast cancer.

Targeted Oncology^TM: What are your initial impressions of vepdegestrant's efficacy compared with fulvestrant, particularly regarding progression-free survival and overall response rate?

Hamilton: VERITAC-2 had a straightforward design—randomization 1:1 to either vepdegestrant, 200 mg orally once daily continuously, or fulvestrant, 500 mg given intramuscularly on days 1 and 15, and then on day 1 of each subsequent cycle. Our primary end point was progression-free survival among patients with ESR1 mutations in ER-positive, HER2-negative metastatic breast cancer. Remember, these patients had all already received a CDK4/6 inhibitor. They were allowed up to 1 prior endocrine therapy but were not allowed prior fulvestrant or chemotherapy.

VERITAC-2 did meet its primary end point. PFS was significantly improved from 2.1 months with fulvestrant to 5.0 months with vepdegestrant. Now, when we went to test the overall population, this was not statistically significant. As we have seen with some of the other endocrine agents in this space, the benefit really is restricted to those patients with ESR1 mutations.

Our key secondary end points were clinical benefit rate and objective response rate. Clinical benefit rate nearly doubled with vepdegestrant from 20.2% to 42.1%, [and the] objective response rate more than quadrupled, from 4% to 18.6%, again among patients with ESR1 mutations.

I think this compares really favorably. One of the challenges is that we don’t have consensus in the post-CDK4/6 landscape on what patients should receive. We’re doing profiling for ESR1, we’re looking at PIK3CA, AKT, PTEN alterations, and we have CDK after CDK. What’s really unique about this trial is it’s very similar to the EMERALD trial [NCT03778931], where everyone had already had a CDK4/6 inhibitor. And remember, that trial showed 1.9 vs 3.8 months. So, if we do the dreaded cross-trial comparison, our 5.0 months does compare favorably. And our fulvestrant arm at 2.1 months vs. EMERALD’s 1.9 performed very similarly—telling me this was a similar population.

We also think ESR1 mutations may be on the rise, because in the first-line setting with CDK4/6 inhibitors, patients are on aromatase inhibitors for a longer duration, which breeds ESR1 mutations. In this study, we saw that 43% of patients had an ESR1 mutation, so this is not a negligible population.

Were there any notable differences in the safety profile or tolerability of vepdegestrant vs fulvestrant that oncologists should be aware of for patient management?

I think it’s really tough comparing safety across trials, but the vepdegestrant safety looked really encouraging. I like to look at dose reductions and discontinuations as an indication of how well patients really tolerate a drug. What we saw discontinuations with vepdegestrant were only 3% and reductions were only 2%. When we looked at what adverse events [AEs] were most frequent, fatigue was the most common. But this also stood out to me as this was any-grade fatigue, and only present in 27% of patients. So said another way, three-quarters of patients had no fatigue at all. Our second and third most common side effects were nausea and AST/ALT elevations, all-grade frequencies in the low teens, under 15%. Compared with some other oral SERDs that have more prominent gastrointestinal [adverse events], what stood out to me was that vomiting and diarrhea were not on our AE table—because across all grades, they were present in only 6% of patients.

Based on the VERITAC-2 results, which specific ER-positive/HER2-negative advanced breast cancer patient populations might benefit most from vepdegestrant, and does this data suggest a shift in standard of care?

This was a global phase 3 trial, and based on this, they will be talking to regulatory authorities for a potential approval of vepdegestrant. I would really be thinking about this option for patients who match those enrolled in the trial, so patients who have already progressed on a CDK4/6 inhibitor, patients who have not yet received chemotherapy, and of course, those with ESR1 mutations.

What are the practical implications of vepdegestrant's potential approval for your clinical practice, considering its mechanism of action and the current treatment landscape for ER+/HER2- advanced breast cancer?

I think this is really compelling. Vepdegestrant certainly works better than fulvestrant. I think it’s well tolerated. Our challenge across all trials is really identifying which patients are still endocrine sensitive. For now, it looks like selecting for ESR1 is our best indicator of that. But if you look across the imlunestrant trials, the lasofoxifene [Fablyn] trials, the vepdegestrant trial—you still see about 30% of patients progressing at the first scan. So, we haven’t really homed in on who still has important signaling through the estrogen receptor axis and who doesn’t. That’s something we’ll continue to work on in the future.

REFERENCE:

Hamilton E, De Laurentiis M, Jhaveri K, 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. J Clin Oncol. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000