<p>At the recent <strong>ESMO Congress 2025</strong>, several exciting trials examined the evolving role of SERDs, PI3K inhibitors, and ADCs for the treatment of HR+/HER2- metastatic breast cancer. New agents entering the breast cancer treatment armamentarium are expected to provide safe, effective options that extend survival and enhance quality of life.</p> <p><br></p> <p><em>Following these presentations, featured expert Sara M. Tolaney, MD, MPH, was interviewed by</em> Conference Reporter <em>Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Tolaney on these findings are presented here.</em></p>

Some really exciting studies presented at this year’s ESMO Congress looked at using oral SERDs and other targeted agents for HR+/HER2- metastatic disease. For example, the phase 3 evERA trial by Mayer and colleagues enrolled patients who had progressed on prior CDK4/6 inhibitor and endocrine therapy and had not received prior chemotherapy (abstract LBA16). Patients were randomized to receive giredestrant or choice of standard-of-care (SOC) endocrine therapy (ie, exemestane/fulvestrant/tamoxifen) plus the oral mTOR inhibitor everolimus. The study looked at progression-free survival (PFS) in the overall population and in the subset of patients with an ESR1 mutation, which represented approximately 55% of the overall population.

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The giredestrant-plus-everolimus combination had a significantly longer PFS than the SOC plus everolimus in patients with an ESR1 mutation (9.99 months vs 5.45 months, respectively). PFS in the intent-to-treat population was also significantly prolonged in those receiving giredestrant plus everolimus. Overall, the oral SERD plus everolimus was better than the SOC plus everolimus in both the ESR1-mutant and overall populations. While the study was not powered to look at outcomes among patients without evidence of an ESR1 mutation, the exploratory analysis of this subset found no difference in PFS, but there was a trend toward a higher objective response rate and a longer overall survival (OS) with the use of giredestrant plus everolimus. Currently, we do not have a US Food and Drug Administration (FDA)–approved oral SERD combination, and endocrine therapy monotherapy does not work well post CDK4/6 inhibition. We are hoping that evERA leads to an approval in 2026. The question is: Will it lead to an FDA approval in just the ESR1-mutant population, or will it be approved irrespective of ESR1 mutation status?

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Another important study presented at ESMO 2025 was the phase 3 VIKTORIA-1 trial by Hurvitz et al, which looked at gedatolisib, an intravenous PI3K pathway inhibitor (abstract LBA17). VIKTORIA-1 enrolled patients with HR+/HER2- advanced breast cancer who did not have a PIK3CA mutation and had progressed on a CDK4/6 inhibitor and an aromatase inhibitor. Patients were randomized to fulvestrant alone, a doublet of fulvestrant and gedatolisib, or a triplet of fulvestrant, palbociclib, and gedatolisib. Patients who were randomized to fulvestrant were offered crossover treatment with the choice of the doublet or triplet at the time of progression on fulvestrant.

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Overall, the triplet and doublet therapies did much better than fulvestrant monotherapy (median PFS, 9.3 months vs 2 months and 7.4 months vs 2 months, respectively). It was really dramatically better than the control arm. Some would argue that the fulvestrant control arm is not what people use anymore. Most of the time, we give combination therapy with an endocrine agent and targeted therapy after progression on a CDK4/6 inhibitor. However, the regulatory agencies did mandate that VIKTORIA-1 have a fulvestrant comparison to look at the contribution of each of the components that were being added. This study clearly shows that the triplet is highly effective—as is the doublet—in those patients who do not have a PIK3CA mutation.

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Keep in mind that gedatolisib causes stomatitis, so patients taking gedatolisib need to use dexamethasone mouth rinse prophylactically. Gedatolisib can also cause hyperglycemia, although less so than currently FDA-approved alpha-specific PI3K inhibitors. So, although there are some toxicities with the combinations, discontinuation rates in the VIKTORIA-1 trial were low (ie, <4%); patients were able to tolerate—and stay on—therapy.

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Hopefully, we may have new choices if both the evERA trial of giredestrant plus everolimus and the VIKTORIA-1 trial of gedatolisib in combination with fulvestrant (with or without palbociclib) lead to FDA approvals. If gedatolisib gets approved, it would present another option for patients after progression on a CDK4/6 inhibitor. Right now, our treatment options for patients who do not have a PIK3CA mutation are limited, and outcomes have usually been in the 4 to 5–month range. In the VIKTORIA-1 trial, we far exceeded that.

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An additional study of interest presented at the ESMO Congress 2025 was the phase 3 OptiTROP-Breast02 study by Li et al. This study looked at the ADC sacituzumab tirumotecan, compared with standard-of-care chemotherapy in patients who had received at least 1 prior line of chemotherapy for HR+/HER2- metastatic disease (abstract LBA23). The study showed a very impressive improvement in PFS. OS is still immature, but there is a trend toward increased OS with sacituzumab tirumotecan. An ongoing, phase 3, global trial called TroFuse-010 is looking at sacituzumab tirumotecan with or without pembrolizumab vs treatment of physician’s choice in patients with HR+/HER2- metastatic breast cancer who have not had any prior chemotherapy. This study makes us excited because the data in pretreated patients just look so robust.