Evolving Oral SERD Research Seeks to Redefine Treatment Strategies in Hormone Receptor+ Breast Cancer

The treatment paradigm for patients with hormone receptor–positive, HER2-negative metastatic breast cancer is undergoing a transformative shift with the emergence of oral selective estrogen receptor degraders (SERDs), although best practices based on mutational testing are still being determined.

During a recent OncLive^® Scientific Interchange & Workshop, a panel of breast cancer experts convened to discuss the nuances of ESR1 mutations, the clinical implications of molecular progression, and the practical challenges of integrating novel oral SERDs into daily practice.

Adam Brufsky, MD, PhD, of the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania, who served as the moderator of the workshop, opened the discussion by emphasizing the historic nature of these advancements, saying, “One of the biggest abstracts of [2025 was] the [2025 ASCO Annual Meeting] plenary session on breast cancer [featuring data from the phase 3] SERENA-6 trial [NCT04964934]. We’re having this meeting to talk about oral SERDs and where they’re going. The idea of these oral SERDs is that somehow, they can overcome the resistance that occurs when the estrogen receptor [ER] is auto activated.”

How has the first-line hormone receptor–positive, HER2-negative metastatic breast cancer treatment paradigm evolved?

The current standard of care for patients with first-line hormone receptor–positive metastatic breast cancer typically involves a CDK4/6 inhibitor paired with an aromatase inhibitor, the speakers agreed. However, the panel noted that although this regimen is effective, the development of treatment resistance—often driven by the emergence of ESR1 mutations—remains an inevitable hurdle. They explained that these mutations, which occur in approximately 30% to 40% of patients who have received aromatase inhibition, cause the ER to auto-activate even in the absence of estrogen, rendering standard aromatase inhibitors ineffective.

The introduction of approved and investigational oral SERDs such as elacestrant (Orserdu), camizestrant, imlunestrant (Inluriyo), and giredestrant (GDC-9545) offers a way to degrade the ER and overcome this resistance.

How might the results of ESR1 mutational testing be implemented in breast cancer clinical practice?

A central theme of the workshop was the timing and method of testing for ESR1 mutations. Most panelists favored liquid biopsy in the form of circulating tumor DNA (ctDNA) assays over tissue biopsy due to the ability of ctDNA testing to capture tumor heterogeneity and its ease of use at the point of progression. Sushma Nakka, MD, of the Lakeland Regional Health Hollis Cancer Center in Florida, shared positive anecdotal experience using these tools in a patient who had been heavily pretreated with multiple lines of chemotherapy and aromatase inhibition.

Although the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for breast cancer recommend ESR1 mutation testing via ctDNA at the point of disease progression following prior lines of endocrine therapy,¹ the SERENA-6 trial has sparked a debate about intervening with a treatment switch at the first sign of molecular progression, when the mutation is detected in the blood before it shows up on a scan. The panelists grappled with the findings of this trial, which showed a progression-free survival (PFS) benefit when switching from an aromatase inhibitor to camizestrant upon the detection of an ESR1 mutation even without radiographic evidence of tumor growth in patients with hormone receptor–positive. HER2-negative metastatic breast cancer. Updated efficacy findings presented at the 2025 San Antonio Breast Cancer Symposium showed a median PFS of 16.6 months (95% CI, 14.7-19.4) in the camizestrant arm (n = 157) compared with 9.2 months (95% CI, 7.2-9.7) in the control arm (n = 158; HR, 0.46; 95% CI, 0.34-0.62; P < .00001).²

Muhammad Azim Mirza, MD, of Mercy Cancer Center in Washington, Missouri, advocated for the potential benefits of this proactive strategy, saying that, “if the ESR1 mutation [expression level] is going up, I’ll probably use [camizestrant] early. Why do we give adjuvant chemotherapy? [It’s for] the same reason.”

Conversely, some experts remained cautious about changing therapy based solely on the results of a blood test in an asymptomatic patient. Somasekhara Bandi, MD, of the Mercy Oncology and Hematology David C. Pratt Cancer Center in St. Louis, Missouri, remarked that, “with this mutation in asymptomatic patients, if the final [SERENA-6] data show that early intervention made a difference in preventing significant worsening of disease, then it makes sense. But at this point, it’s hard to justify that.”

Richard Zelkowitz, MD, of the Hartford HealthCare Medical Group in Connecticut, provided a grounding perspective on the proposed shift in practice based on the SERENA-6 data, saying, “I’m not going to change what I’ve done for 36 years. I think patients can have more symptoms with stable scans, and I would consider that progression. But I think in the asymptomatic patient who has stable scans, I may be more inclined to watch them a bit closer.”

Notably, on April 30, 2026, the FDA’s ODAC voted 6-3 against the clinical benefit of switching to camizestrant upon the emergence of an ESR1 mutation during treatment with an aromatase inhibitor and a CDK4/6 inhibitor ahead of radiographic disease progression in patients with hormone receptor–positive, HER2-negative metastatic breast cancer.³ Final data regarding time to second progression will be presented at the 2026 ASCO Annual Meeting.⁴ Want more insights? Check out our preview article that breaks down the potential significance of these findings and other anticipated breast cancer insights from the meeting.⁵

How do quality of life (QOL) and patient preferences drive oral SERD selection in breast cancer?

The move from fulvestrant (Faslodex), which requires intramuscular injections, to oral SERDs is largely driven by patient preference and QOL considerations, the panelists emphasized. Fulvestrant injections can cause significant discomfort and local tissue issues over time. Nakka described one patient’s struggle with the agent, explaining that, “she stopped it, and now again she has a very small recurrence, which cannot be resected. She does not want fulvestrant, no matter what, because of the injections.”

Liliana Bustamante, MD, of Florida Cancer Specialists & Research Institute in Lee County, highlighted the psychological toll of disease progression and treatment shifts, saying that, “when [patients] have metastatic breast [cancer] that is hormone receptor–positive, they don’t feel like they have metastatic [disease], for a while,” but continuing to add that patients have unique fears regarding more aggressive treatments. “You can have the hardest conversation with patients, and the minute you say [their] hair’s going to fall off, that’s all they hear.”

Sumithra Vattigunta-Gopal, MD, FACP, of Florida Cancer Specialists & Research Institute in Palm Beach County, agreed that these factors must be prioritized, sharing that, “the QOL data are important, especially in a patient with metastatic disease. They want to feel better. We want the patient to have a good QOL.”

What challenges exist regarding treatment sequencing and cost accessibility with oral SERDs in breast cancer?

As more oral SERDs enter the treatment paradigm, the panelists noted that the question of therapy sequencing becomes paramount. They explained the importance of deciding whether to use a SERD as a single agent or in combination with other targeted therapies like everolimus or capivasertib. Vattigunta expressed interest in exploring oral SERDs in earlier lines of therapy.

Cost and insurance coverage also present major hurdles, according to the speakers. Brufsky referred to a temporary window where insurance companies may cover new drugs like elacestrant or imlunestrant before their policies have fully caught up to the specific trial-based indications. He reported that this clinical friction often dictates what therapies a patient receives.

Ultimately, the workshop underscored that although current oral SERD data provide a roadmap, the art of oncology remains centered on each individual patient. As the field continues to evolve, the consensus among the experts was that despite the power of currently available molecular tools, clinical practice must still heavily feature patient-specific decisions to ensure that patient well being remains the primary goal.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 3.2026. May 8, 2026. Accessed May 13, 2026. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
2. Bidard FC, Mayer EL, Park YH, et al. Updated results and an exploratory analysis of ESR1m circulating tumor DNA dynamics from SERENA-6, a phase 3 trial of camizestrant + CDK4/6 inhibitor for emergent ESR1m during first-line endocrine-based therapy and ahead of disease progression in patients with HR+/HER2– advanced breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF7-03.
3. April 30, 2026 meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed May 13, 2026. https://www.youtube.com/live/taCx7enN7hk
4. Bidard FC, Mayer EL, Park YH, et al. First-line (1L) camizestrant (CAMI) for emergent ESR1 mutations (ESR1m) in advanced breast cancer (ABC): final progression-free survival 2 (PFS2) from the phase III SERENA-6 trial. J Clin Oncol. 2026;44(suppl 17):LBA1007. doi:10.1200/JCO.2026.44.17_suppl.LBA1007
5. Wahner A. ASCO 2026 HR+ and HER2+ breast cancer preview: read up on the insights to know before you go. May 6, 2026. Accessed May 13, 2026. https://www.onclive.com/view/asco-2026-breast-cancer-preview-read-up-on-the-insights-to-know-before-you-go