<p>Advances in treatment have improved outcomes and extended survival for patients with HR+/HER2- metastatic breast cancer. Studies presented at the <strong>ESMO Congress 2025</strong> evaluated late-stage therapeutic options for patients who have progressed after multiple lines of therapy.</p> <p><br></p> <p><em>Following these presentations, featured expert William J. Gradishar, MD, FACP, was interviewed by</em> Conference Reporter <em>Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Gradishar on these findings are presented here.</em></p>

First-line therapy for HR+/HER2- breast cancer is typically a CDK4/6 inhibitor and an endocrine agent, most commonly an aromatase inhibitor. However, fulvestrant is also acceptable. Inevitably, patients with HR+/HER2- disease progress on first-line endocrine therapy. So, the question is: What should come next at the time of disease progression?

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We use the information obtained from next-generation sequencing and circulating tumor DNA to decide what the next best therapy is. We try to put off chemotherapy if we have endocrine options because endocrine therapy is as effective and is better tolerated than chemotherapy. If a patient has an ESR1 mutation, we consider therapy with a SERD such as elacestrant or imlunestrant, which were approved by the US Food and Drug Administration (FDA) in 2023 and 2025, respectively. If a PI3K mutation is present, which happens in approximately 40% of patients with HR+/HER2- metastatic breast cancer, a PI3K inhibitor could be considered. We have at least 3 drugs that work on the PI3K/AKT/mTOR pathway: alpelisib, capivasertib, and inavolisib. A fraction of patients may also have BRCA1/2 mutations, in which case a PARP inhibitor could be considered. If patients do not have a genetic alteration, you could still consider an mTOR inhibitor such as everolimus, which can be combined with fulvestrant. In general, most patients who progress on a CDK4/6 inhibitor will go on to the next line of therapy.

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At the ESMO Congress 2025, 2 important trials were presented: evERA and VIKTORIA-1. The evERA trial by Mayer and colleagues compared standard-of-care (SOC) endocrine therapy (ie, exemestane/fulvestrant/tamoxifen) plus everolimus with the SERD giredestrant (which is not yet FDA approved) combined with everolimus (abstract LBA16). This study investigated whether patients who had received up to 2 prior lines of endocrine therapy and a CDK4/6 inhibitor would benefit from an all-oral regimen of giredestrant and everolimus.

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Data from evERA demonstrated that there was an advantage to combining the newer SERD with everolimus compared with the SOC plus everolimus. Significant improvements in progression-free survival (PFS) were observed in patients with ESR1 mutations receiving giredestrant plus everolimus compared with SOC endocrine therapy plus everolimus (median PFS: approximately 10 months vs approximately 5 months, respectively). In addition, results indicated that patients without an ESR1 mutation also experienced a benefit on this treatment regimen, but this needs to be confirmed. The safety profile of giredestrant combined with everolimus was manageable. However, there was toxicity associated with everolimus, most commonly in the form of stomatitis, which you do have to be vigilant about treating.

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The big issue with ESR1 mutations in most trials, including the original elacestrant and imlunestrant trials, is that, if you use monotherapy, a lot of patients progress rapidly in the first 6 months. evERA demonstrated that when you combine giredestrant with everolimus, you are decreasing the number of patients who are very rapid progressors.

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The second study presented at this year’s ESMO Congress that is worth mentioning is the VIKTORIA-1 trial by Hurvitz et al (abstract LBA17). This trial enrolled chemotherapy-naive patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer who had progressed during or after CDK4/6 inhibitor therapy and aromatase inhibitor treatment. Patients with wild-type PIK3CA tumors were randomized to receive either fulvestrant alone, fulvestrant plus gedatolisib (an intravenous pan–PI3K/AKT/mTOR pathway inhibitor), or fulvestrant plus gedatolisib and palbociclib.

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In this trial, PFS with the doublet or triplet regimen was significantly improved compared with fulvestrant alone. Comparing the doublet and triplet regimens with fulvestrant alone, at least a 5- to 7-month improvement in PFS was observed, which is a clinically relevant improvement. The safety profiles were consistent with those of the individual agents, with low rates of treatment discontinuation due to adverse events. Gedatolisib is an intravenous medication, so this regimen is a little different from an all-oral regimen. Gedatolisib is not yet approved, but we will see how it fares when the FDA review is complete.

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In the future, I hope to see a few more FDA-approved drugs, considering that giredestrant (from evERA) has received Fast Track designation from the FDA and gedatolisib (from VIKTORIA-1) is currently under review by the FDA. Then the question will be: What do we do after that? As we get more treatment options and as treatments move up into earlier lines of therapy, the challenge will be how to treat patients post progression. That is going to be a focus of ongoing trials. We expect a lot of discussion about whether we continue with endocrine therapy or pivot to an ADC. These questions remain unanswered, so we will inevitably hear more about that at future ESMO meetings.