A central question in HR+/HER2- metastatic breast cancer is whether oral SERDs should be used up front, after ESR1 mutations emerge, or after radiographic progression. Adam M. Brufsky, MD, PhD, reviews relevant findings from the 2026 ASCO Annual Meeting and explains how circulating tumor DNA (ctDNA) monitoring may help refine treatment sequencing.

Following these presentations, featured expert Adam M. Brufsky, MD, PhD, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Brufsky on these findings are presented here.

A big theme in HR+/HER2- metastatic breast cancer is what to do in the first-line setting. Coming out of ASCO 2026, some of the central themes were not related to simply whether we have more endocrine agents, but when and how we should use them. What is the role of oral SERDs? When do we start SERDs in general, whether they are fulvestrant or oral SERDs? Those are the 2 key questions. Have they been answered? Not really, but we are getting there.

One of the major studies presented at ASCO 2026 was the persevERA BC trial by Nicholas C. Turner, MD, PhD, and colleagues (abstract LBA1006). This was a trial of the oral SERD giredestrant plus palbociclib vs letrozole plus palbociclib as first-line therapy for ER+/HER2- advanced breast cancer. There was an approximately 5-month numerical difference in progression-free survival (PFS; 33.1 months with giredestrant plus palbociclib vs 28.2 months with letrozole plus palbociclib), but persevERA BC did not meet statistical significance.

This result fits with what many of us have said for years, which is that every trial comparing a SERD (whether oral or intramuscular) with an aromatase inhibitor in combination with a CDK4/6 inhibitor has had to show a much better efficacy profile for the SERD to change practice in the first-line setting. We saw that the PARSIFAL trial comparing first-line fulvestrant plus palbociclib with letrozole plus palbociclib, with extended follow-up, confirmed no meaningful difference in PFS or overall survival. We also saw a first-line oral SERD strategy fail with amcenestrant in the AMEERA-5 study. Now we are waiting for the SERENA-4 study, which is examining camizestrant with palbociclib vs anastrozole with palbociclib in the first-line setting. This is a large trial, and it may have enough statistical power to detect a small difference, if one exists.

Layered onto this was the SERENA-6 trial, which I think is answering a different question. SERENA-6 was not designed as a trial of early-vs-late oral SERD switching after radiographic progression. It was designed to ask whether we should intervene when an ESR1 mutation develops before radiographic progression. Most patients starting first-line therapy for ER+ metastatic disease do not have detectable ESR1 mutations. In the PADA-1 trial, for example, baseline blood ESR1 mutations were detected in 3.2% of patients overall and in 6.8% among patients with prior adjuvant aromatase inhibitor exposure. Over time, under the pressure of an aromatase inhibitor, up to 20% to 40% of patients will develop ESR1 mutations as a resistance mechanism.

In SERENA-6, patients were screened for ESR1 mutations; if they had a mutation, the first thing they had was a scan. Patients who had radiographic progression were excluded from the trial. The remaining patients had an ESR1 mutation but no radiographic progression and were randomized to either continue the aromatase inhibitor and the CDK4/6 inhibitor or switch to camizestrant and continue the CDK4/6 inhibitor.

At ASCO 2026, updated SERENA-6 data presented by Francois Clement Bidard, MD, PhD, included the median PFS2 of 25.7 months in the camizestrant arm vs 19.1 months with continued aromatase inhibitor therapy (abstract LBA1007). Patients who remained on the aromatase inhibitor and the CDK4/6 inhibitor had a decline in quality of life, including in pain and in fatigue scores, whereas patients who switched to camizestrant had a preservation of quality of life. The level of tumor-related ctDNA ESR1 mutations in plasma also went down in most patients who received camizestrant. At this year’s ASCO meeting, additional ctDNA data showed that approximately 51% of patients in the camizestrant arm had total ctDNA clearance compared with 1.9% of patients who stayed on the aromatase inhibitor.

So, I think that the practical question is becoming clearer: Do we use an oral SERD up front in an unselected first-line population? Right now, the answer is no. Do we use it in a patient who develops an ESR1 mutation over time? The answer may be yes, assuming US Food and Drug Administration (FDA) regulatory approval.

In the second-line setting for ER+/HER2- advanced breast cancer, the biggest news presented at ASCO 2026 was the success of gedatolisib. Data from VIKTORIA-1 Study 2 presented by Sara A. Hurvitz, MD, FACP, extended the question of whether gedatolisib could improve outcomes across PI3K pathway subgroups, including in patients with PIK3CA mutations for whom alpelisib plus fulvestrant was already a standard targeted option (abstract LBA1008). Patients on the triplet of gedatolisib, palbociclib, and fulvestrant had a median PFS of 11.1 months vs 5.6 months for those on alpelisib and fulvestrant. That is pretty much a doubling of PFS. Nothing that we have in our field has done this. I do not know whether it is a “home run,” but I think that it is a good “double”—maybe even a “triple.” It is a substantial improvement of outcomes. FDA regulatory approval has since been granted in the PIK3CA wild-type setting, but these PIK3CA-mutant data could become the basis for a supplemental application and may meaningfully change the second-line treatment of PIK3CA-mutated ER+/HER2- advanced breast cancer.

Another important study presented at ASCO 2026 in the second-line setting was evERA BC by Komal L. Jhaveri, MD, FACP, FASCO, et al (abstract 1016). In the evERA BC trial, patients with ER+/HER2- advanced breast cancer who had progressed on prior CDK4/6 inhibitor therapy were randomized to giredestrant plus everolimus or standard-of-care endocrine therapy plus everolimus. In the ESR1-mutant population, giredestrant plus everolimus improved outcomes compared with standard endocrine therapy plus everolimus. Further, ASCO 2026 postprogression analyses showed longer PFS2 and chemotherapy-free survival, suggesting that the benefit was sustained beyond initial progression. This may create another post-CDK4/6 inhibitor treatment option for ESR1-mutant disease.

There are also earlier agents and mechanisms that are being developed. At ASCO 2026, early data on TFX06, an investigational oral SERD in prior fulvestrant-treated ER+/HER2- advanced breast cancer, were presented by Wenxing Qin, MD, PhD (abstract 1062); vepdegestrant-based PROTAC ER degrader combinations with abemaciclib or atirmociclib were presented by Rachel M. Layman, MD (abstract 1067), and Melinda L. Telli, MD, FASCO (abstract 1075), respectively; and prifetrastat, a first-in-class KAT6A and KAT6B inhibitor, were presented by Dr Layman (abstract 1068). KAT6 inhibitors are interesting because they try to alter gene expression at the level of chromatin. We do not have phase 3 data yet, but this is a new pathway and may represent one of the first major clinical applications of epigenetic regulation in breast cancer.