Newly approved oral selective estrogen receptor degraders, or SERDs, are changing the treatment environment for people with hormone receptor-positive, HER2-negative advanced breast cancer. These pill-based therapies offer a different approach than traditional aromatase inhibitors by targeting the estrogen receptor itself for degradation, a strategy that may help address treatment resistance linked to specific genetic changes.
How Oral SERDs Differ From Traditional Therapies
Aromatase inhibitors, commonly used as first-line treatment, work by reducing estrogen production. However, Dr. Parvin Peddi, medical oncologist and director of Breast Medical Oncology at Providence Saint John’s Health Center, explains that cancer cells can adapt to these drugs by keeping the estrogen receptor active even when estrogen levels are low. SERDs counter this by breaking down the receptor directly, targeting changes known as ESR1 mutations that allow tumors to grow despite low estrogen.
While injectable SERD fulvestrant has been available for over two decades, the new oral versions represent a significant shift in delivery. Four oral SERDs have received FDA approval since 2023, each based on results from clinical trials involving patients with advanced disease.
FDA-Approved Oral SERDs
The first oral SERD, elacestrant (Orserdu), was approved in January 2023 following the EMERALD trial. Imlunestrant (Inluriyo) received approval in September 2025 based on the EMBER-3 trial. Vepdegestrant (Veppanu), technically a protein degrader, was approved in May 2026 after the VERITAC-2 trial. Camizestrant, granted accelerated approval in September 2026, is approved in combination with a CDK4/6 inhibitor for patients with ESR1 mutations detected during first-line treatment.
These medications are typically considered after cancer progresses on prior endocrine therapy. Dr. Peddi notes that elacestrant and vepdegestrant may be preferred when an ESR1 mutation is found, as their trials included patients in this setting. Camizestrant offers the possibility of treatment adjustment before imaging confirms progression, based on blood test results showing the mutation.
Selecting the Right Treatment
Deciding which oral SERD to use depends on multiple factors, including when the ESR1 mutation was detected, whether the cancer has already progressed, prior treatments received, tumor characteristics, overall health, and potential side effects. Dr. Peddi emphasizes that treatment plans should be personalized, taking into account the specific biology of each patient’s cancer.
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ESR1 mutations develop over time as cancer adapts to aromatase inhibitors and are uncommon at initial diagnosis. Detecting them early through blood tests measuring circulating tumor DNA can guide timely treatment changes, potentially before visible tumor growth occurs.
Clinical Trial Considerations and Biomarker Testing
Dr. Sledge Jr., medical oncologist and executive vice president and chief medical officer at Caris Life Sciences, advises patients to first ask whether their current doctor or cancer center participates in clinical trials for their specific cancer type. If not, he suggests exploring trials at other medical centers. Access to trials may depend on the facility, so referrals or direct contact with research centers can expand options.
Patients considering clinical trials should prepare questions to discuss with their care team, including how trial participation compares to standard treatments. Biomarker testing, such as ESR1 mutation analysis, can influence treatment choices and may help identify suitable trial options. Ongoing studies are evaluating these therapies further to refine their roles in treatment plans.
ESR1 Mutation Testing and Its Importance
Medical professionals recommend testing for ESR1 mutations at two critical moments: at the time of metastatic breast cancer diagnosis and again when cancer begins to grow despite ongoing aromatase inhibitor therapy. Blood tests measuring circulating tumor DNA offer a less invasive alternative to tissue biopsies, allowing repeated monitoring without additional surgical procedures. The American Society of Clinical Oncology guidelines endorse routine ESR1 testing when cancer returns or progresses, favoring blood-based assays for their sensitivity in detecting these genetic changes.
Pipeline Therapies and Clinical Trials
The SERENA-6 trial demonstrated that patients who switched to camizestrant experienced a median of 16 months without cancer progression, compared to 9.2 months for those continuing aromatase inhibitors.
Giredestrant combined with everolimus is currently under FDA review for patients with ESR1-mutated advanced breast cancer, with a decision expected by December 18, 2026, following positive results from the evERA trial. Clinical trials provide opportunities to access emerging therapies and should be explored before initiating new treatments, as each study has specific eligibility criteria that may exclude patients who delay inquiry until after starting therapy.