Giredestrant ± LHRH analogue fares well in ER+/HER2– early breast cancer

In the PREcoopERA window-of-opportunity trial, the selective estrogen receptor degrader (SERD) giredestrant shows robust anticancer activity, either alone or in combination with the luteinizing hormone-releasing hormone (LHRH) analogue triptorelin, in premenopausal women with ER+/HER2– operable invasive breast cancer.

At week 4, all three regimens—giredestrant monotherapy, giredestrant + triptorelin (GT), and anastrozole + triptorelin (AT)—substantially reduced Ki67 from baseline, with GT delivering the greatest antiproliferative effect (geometric mean percent [GMP] change, –79.6 percent) followed by AT (GMP change, –73.7 percent).

However, a comparison between groups fell short of statistical significance (log difference, –0.19; p=0.18). Hence, GT was not superior to AT. [ESMO Breast Cancer 2026, abstract LBA 2]

With giredestrant alone, the GMP change in Ki67 was –68.2 percent. “This did not meet noninferiority to GT. The difference on the log scale was 0.45, which exceeded the prespecified noninferiority boundary of 0.40,” said Dr Elisabetta Munzone from the European Institute of Oncology, Milan, Italy, at ESMO Breast Cancer 2026.

In the age-related exploratory analysis, older premenopausal women had substantial reductions in Ki67 across all three regimens, with giredestrant monotherapy conferring the most pronounced suppression (GMP change per 1-year older age, –6 percent; r=–0.43). For GT and AT, the corresponding GMP changes were +2 percent and –2.7 percent. “These results suggest that age contributed to the variability of the antiproliferative effect [of giredestrant],” Munzone said.

Overall, grade 3 adverse events (AEs) were rare (3.5 percent). No grade 4–5 AEs were reported. There were three serious AEs: one grade 2 thromboembolic event post-surgery and reconstruction in the GT group, and two ovarian cysts in the giredestrant monotherapy group.

Discussant Dr Erica Mayer from the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, US, noted in the press release that oral SERDs may raise oestradiol levels, and this could be associated with side effects, such as ovarian cysts. “We await the oestradiol levels from the study to better understand the impact of SERD exposure.”

Clinical challenges

The incidence of breast cancer in young women is increasing (mostly ER+ disease). Moreover, the improvements with standard of care (ovarian function suppression [OFS] + tamoxifen or aromatase inhibitor [AI]) are confounded by endocrine-related toxicities, Munzone noted. “In premenopausal women, intact ovarian function limits AI efficacy without OFS.”

“However, OFS can be quite challenging, as its toxicity may impact patients’ quality of life and threaten adherence and clinical outcomes,” Mayer pointed out.

“Hence, there is a need for endocrine therapies that are active in a premenopausal hormonal environment … Oral SERDs have the potential to reduce or avoid OFS-related toxicity,” Munzone said.

Oral SERDs have shown potent antiproliferative activity in preclinical and clinical settings. [Ann Oncol 2025;36 (Suppl 2):S1561-S1562; Ann Oncol 2026;37:532-543; Lancet Oncol 2023;24:1029-1041]

In PREcoopERA, 231 patients (median age 45 years) were randomized 2:2:1 to receive 28 days of pre-operative treatment with oral giredestrant 30 mg daily either alone or in combination with intramuscular triptorelin 3.75 mg on day 1, or anastrozole 1 mg + triptorelin. On day 29, participants underwent re-biopsy/surgery to assess proliferation.

Approximately 53 percent of participants had Ki67 (local) ≥20 percent, and almost 20 percent had node-positive disease.

“Our findings suggest that giredestrant is biologically active in premenopausal women with or without triptorelin,” Munzone said.

“[The results] add to our understanding of how we can optimally provide endocrine therapy to younger patients with ER+/HER2– breast cancer, a population with unique needs and medical considerations,” noted Mayer. She called for larger trials on prolonged SERD monotherapy in this patient population to validate efficacy, safety, and any preferred population.