Key Ideas
The ER-positive breast cancer treatment landscape continues to expand rapidly, with a new generation of oral selective estrogen receptor degraders (SERDs) and a first-in-class PROTAC-based ER degrader, vepdegestrant, now approved or under FDA review across both early-stage and metastatic settings. Meanwhile, the SERENA-6 trial has opened a genuinely new conversation: switching therapy based on ctDNA-detected molecular progression, before clinical or radiographic progression occurs, meaningfully extends progression-free survival, even though this approach remains far from settled practice.
An Expanding Toolkit in Early-Stage, High-Risk Disease
Despite substantial treatment advances, roughly a quarter of patients with early-stage ER-positive breast cancer still develop recurrence within five years, and all available treatments carry some combination of clinical, physical, and financial toxicity. A next-generation oral selective estrogen receptor degrader, giredestrant , is being evaluated in the adjuvant, early-stage setting (via the lidERA trial) for patients with node-negative disease and higher-risk features (tumor over 1cm, grade 3, Ki-67 over 20%, or a high-risk genomic assay score) or node-positive/larger tumor disease. In this setting, reported data showed a meaningful improvement in invasive disease-free survival with a favorable hazard ratio, and while overall survival data remain immature, an early signal favors the treatment arm as well. Benefit appeared across most subgroups, though possibly less pronounced in stage I disease specifically. Notably, discontinuation due to classic endocrine therapy side effects like arthralgia and hot flashes appeared lower than with traditional aromatase inhibitor therapy, though a new side effect signal, bradycardia (generally low-grade and not requiring intervention), is worth patient counseling. This agent is currently under FDA review, with a decision anticipated later this year.
The Expanding Metastatic Toolkit: Where We Stand
For metastatic ER-positive, HER2-negative breast cancer, first-line treatment remains combination endocrine therapy with a CDK4/6 inhibitor. Beyond the first line, treatment selection increasingly depends on specific co-mutations: PIK3CA-mutated disease can be treated with alpelisib or capivasertib (the latter also approved for AKT pathway/PTEN-altered disease) in combination with fulvestrant, while ESR1-mutated disease now has several options. Elacestrant, an oral SERD approved based on the EMERALD trial, has been a mainstay option for some time. More recently, imlunestrant was approved for ESR1-mutated disease based on the EMBER-3 trial, effective as a single agent. Most recently, vepdegestrant, the first-in-class oral PROTAC (proteolysis-targeting chimera) ER degrader, gained approval based on the VERITAC-2 trial, specifically for ESR1-mutated, previously treated ER-positive, HER2-negative advanced or metastatic disease, where it improved progression-free survival compared to fulvestrant with a favorable hazard ratio.
For patients without identifiable actionable mutations, options continue to expand as well.. A pan-PI3K/mTOR inhibitor, gedatolisib, combined with fulvestrant with or without palbociclib, has also shown efficacy in patients without PI3K pathway alterations. Beyond these targeted options, single-agent chemotherapy and antibody-drug conjugates remain important later-line tools.
A Novel SERD-mTOR Combination After CDK4/6 Progression
One combination worth highlighting pairs giredestrant with an mTOR inhibitor (everolimus), targeting both the ER and mTOR pathways to address the crosstalk resistance that often emerges after first-line CDK4/6 inhibitor and endocrine therapy progression. In a trial evaluating this combination against standard of care ET plus everolimus therapy in patients who had progressed on CDK4/6 inhibitor plus endocrine therapy (with at least six months on that prior regimen, and roughly 55% carrying an ESR1 mutation), the combination showed clear PFS improvement in both the ESR1-mutant subgroup (approximately 9.9 months versus 5.5 months) and the overall intent-to-treat population (approximately 8.7 months versus 5.5 months), with a meaningfully longer duration of response as well. Stomatitis, an expected class effect of everolimus, was managed proactively with dose adjustments and prophylactic steroid mouthwash. This combination is currently under FDA review, with a decision anticipated by the end of this year. Giredestrant is also being studied in combination with palbociclib compared letrozole plus palbociclib in the first-line setting; that trial showed a numerical but not statistically significant PFS improvement, though it did establish reasonable tolerability of the combination.
SERENA-6: Switching Therapy at Molecular, Not Clinical, Progression
The SERENA-6 trial addressed a genuinely novel question: in patients with metastatic ER-positive breast cancer on first-line CDK4/6 inhibitor plus aromatase inhibitor therapy, can serial ctDNA monitoring detect an emerging ESR1 mutation early enough to switch therapy before clinical or radiographic progression occurs, and does doing so improve outcomes? Patients found to have an emergent ESR1 mutation via ctDNA were randomized to either switch to camizestrant (continuing the CDK4/6 inhibitor) or remain on their current aromatase inhibitor plus CDK4/6 inhibitor.
The results were striking: median PFS was 16.8 months with the camizestrant switch versus 9.2 months with continued standard therapy (hazard ratio 0.45), and a PFS2 benefit (time to progression on next-line therapy) was maintained as well, with benefit seen across prespecified subgroups. Patients switching to camizestrant also experienced a longer average delay in deterioration of performance status. Overall survival data remain immature, with an early signal but no definitive benefit yet established.
This trial has three important limitations worth weighing. First, there is no OS benefit demonstrated yet. Second, the trial did not allow crossover, which complicates interpretation of the PFS2 endpoint since patients on the standard arm were not permitted to switch to camizestrant upon progression. Third, and most fundamentally, oncology as a field has not fully embraced the idea of switching therapy based on molecular progression (ctDNA-detected mutation) rather than clinical or radiographic progression. That said, SERENA-6 represents a meaningful step toward that paradigm shift, and it is reasonable to expect more trials of this design going forward.
Putting It All Together
There is genuinely a great deal happening in ER-positive breast cancer this year, particularly in the oral endocrine therapy space. Looking ahead, giredestrant's adjuvant data may eventually support its use even earlier in the treatment course, the SERD-mTOR combination may be approved in the metastatic setting , and ctDNA-guided treatment switching is likely to become an increasingly common conversation, even if it is not yet standard of care. Separately, a practical quality-of-life update worth noting: a trial comparing denosumab dosed every 12 weeks versus every 4 weeks in patients with bone metastases found the less frequent schedule to be non-inferior, with less hypocalcemia, fewer cases of osteonecrosis and dental infection, and lower cost, supporting continued use of the extended dosing interval in appropriate patients.
For Patients
Treatment for hormone receptor-positive (ER-positive) breast cancer continues to advance quickly, with several new oral medications recently approved or under FDA review. These drugs work by blocking or breaking down the estrogen receptor that fuels this cancer type, and some appear to cause fewer joint pain and hot flash side effects than older hormone therapies, which matters for people taking these medications for years.
One interesting development uses a blood test detecting tiny amounts of cancer DNA in the bloodstream (ctDNA), which can reveal a cancer developing resistance to treatment months before it would show up on a scan. Recent research shows switching therapy at this earlier "molecular" warning sign, rather than waiting for visible progression, can meaningfully delay the next line of treatment. This approach is still being studied and isn't yet routine, but represents an exciting shift in how oncologists may eventually monitor treatment.
For patients whose cancer has specific mutations, including in genes called PIK3CA, AKT, or ESR1, testing of the tumor or a blood sample can identify targeted options that work against that mutation. Anyone with hormone receptor-positive breast cancer should ask their oncologist whether ctDNA or tumor testing has been done, since it may reveal additional options.
Key Takeaways
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Giredestrant, a next-generation oral SERD, is being studied in the adjuvant, early-stage setting via lidERA trial and appears better tolerated than traditional endocrine therapy for joint pain and hot flashes, though a bradycardia signal warrants monitoring; it remains under FDA review.
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Vepdegestrant, the first FDA-approved PROTAC-based ER degrader, was approved based on VERITAC-2 for ESR1-mutated, previously treated metastatic ER-positive, HER2-negative breast cancer.
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A SERD plus everolimus combination showed meaningful PFS improvement in the post-CDK4/6i, post-endocrine therapy setting (9.9 vs. 5.5 months in ESR1-mutant patients) and is under FDA review.
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SERENA-6 demonstrated that switching to camizestrant upon ctDNA-detected emergent ESR1 mutation, before clinical progression, nearly doubled PFS (16.8 vs. 9.2 months) compared to continuing standard therapy, though no crossover was allowed and OS data remain immature.
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Denosumab dosed every 12 weeks is non-inferior to every 4 weeks for bone metastases, with less hypocalcemia, fewer dental complications, and lower cost.
References
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lidERA Breast Cancer (BC): Phase III adjuvant study of giredestrant vs. physician’s choice of endocrine therapy (PCET) in patients (pts) with estrogen receptor-positive, HER2-negative early BC (ER+, HER2– eBC).
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Turner NC, et al. Camizestrant in ER-Positive, HER2-Negative Advanced Breast Cancer with an Emergent ESR1 Mutation (SERENA-6). New England Journal of Medicine, 2025; updated PFS2 and biomarker analysis, American Society of Clinical Oncology, 2026.
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Jhaveri K, et al. Imlunestrant in ESR1-Mutated Advanced Breast Cancer (EMBER-3). Journal of Clinical Oncology; FDA approval, 2025.
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Hamilton E, et al. Vepdegestrant versus Fulvestrant in ER-Positive, HER2-Negative Advanced Breast Cancer (VERITAC-2). New England Journal of Medicine, 2025; FDA approval, 2026.
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Trial of an oral selective estrogen receptor degrader plus everolimus in metastatic ER-positive, HER2-negative breast cancer following progression on CDK4/6 inhibitor and endocrine therapy.