NCT07242352

Marker - Adjusted Therapy Comparing Adjuvant Elacestrant With Standard Endocrine Treatment in Genomically and/or Clinically High-risk ER+/HER2- eBC

Dynamic Marker - Adjusted Therapy Comparing Adjuvant Elacestrant With Standard Endocrine Treatment in Genomically and/or Clinically High-risk ER+/HER2- Early Breast Cancer (ADAPTela)

• Status: Not Yet Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 1,520 (estimated)
• Sponsor: West German Study Group · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

In this clinical trial, the Sponsor plans to investigate whether patients with HR+/HER2- eBC identified during routine clinical assessments and treatments as having intermediate to high-risk (based on Oncotype DX® or similar tests and on response assessment to 2-6 weeks of preoperative ET) achieve a survival benefit from an initial 5-years use of elacestrant (with or without a CDK 4/6 inhibitor) followed by SoC ET for further 0-2.5 years in comparison to at least 5 up to 7.5 years SoC ET therapy (+/- CDK4/6 inhibitor). Based on several studies in the metastatic setting, it is reasonable to assume that the adjuvant use of elacestrant with or without CDK 4/6 inhibitors will prevent or delay the activation of mechanisms conferring resistance to ET (e.g., ESR1 mutations).

Detailed description

Patients with hormone-receptor positive/HER2-negative (HR+/HER2-) early breast cancer (eBC) remain at risk of recurrence for many years after diagnosis. Current guidelines provide treatment recommendations depending on stage, histological grade, and menopausal status. However, patients with a high-risk HR+/HER2- eBC are at need for more efficacious treatment. Several new strategies are currently investigated in patients diagnosed with high-risk HR+/HER2- eBC, including extending the duration of adjuvant endocrine therapy (ET), addition of ovarian function suppression (OFS) in case of premenopausal patients, and intensification of adjuvant ET by use of new therapies, such as cyclin-dependent kinase (CDK) 4/6 inhibitors. Moreover, development of algorithms incorporating not only clinical variables, but also key tumor biological variables such as Oncotype DX®/Recurrence Score (RS) or Mammaprint®, and possibly dynamic variables such as ET-response measured by Ki-67 after 2-6 weeks of preoperative standard endocrine induction therapy, could be of immense importance for risk estimation and subsequently optimization of therapy in intermediate to high-risk patients. Several retrospective studies have shown that Oncotype DX® or other genomic tests are informative regarding prediction of treatment benefit in HR+/HER2- eBC. Therefore, use of RS instead of mostly relying on histological grade provides stronger prognostic and predictive information. Further, characterization of ET-response has shown to provide important prognostic information in early HR+/HER2- eBC beyond clinical and genomic markers, as shown in the WSG-ADAPT-HR+/HER2-, ALLIANCE, and POETIC trials. The endocrine response has therefore become part of the ESMO guidelines as a prognostic factor. The combination of classical prognostic markers with genomic assessments (e.g., Oncotype DX®) and endocrine response seems to be the most promising tool for identification of patients with significant relapse risk despite of standard ET and/or chemotherapy. Remarkably in the 5-year analysis of the WSG-ADAPT-HR+/HER2- trial, ET-responders with RS \>25 were shown to have more favorable survival than ET-non-responders, despite of higher pCR-rates in a subset of neoadjuvant chemotherapy (NACT)-treated patients. Therefore, patients with high genomic or clinical risk and/or ET-non responders with RS \>25 with intermediate clinical risk are at need for alternative, more efficacious treatment approaches. Optimal ET treatment in patients with intermediate-risk stage I-II disease but enhanced relapse risk remains unclear despite of the significant positive impact of Ribociclib on iDFS in stage II-patients demonstrated in NATALEE (NCT03701334). The ADAPTcycle trial, based on the positive results for CDK 4/6 inhibitors in the adjuvant setting as shown in the MonarchE and NATALEE trials \[12\], is currently investigating whether replacing chemotherapy by an ET-CDK 4/6 based approach could be a better option for particular subgroups which are identified by combination of clinical and genomic risk and ET-responder status. Moreover, the ongoing ADAPTlate trial investigates the impact of abemaciclib if added to standard ET in intermediate to high-risk HR+/HER2- eBC given immediately or within the first 2-6 years after completion of primary therapy. Elacestrant is a novel, nonsteroidal, oral, selective oestrogen receptor degrader (SERD) that inhibits oestradiol-dependent gene transcription downstream of ER, including its mutated receptor variants, which is associated with endocrine resistance as demonstrated in phase I-trials \[13\]. Therefore, adjuvant use of SERDs may be beneficial in preventing ET resistance mechanisms. In the phase III-trial EMERALD (NCT03778931), elacestrant improved PFS vs SoC in patients with metastatic HR+/HER2- breast cancer previously treated with ET in combination with a CDK4/6 inhibitor, especially in those harboring an ESR1-mutation. Also, according to EMBER-3 data in the metastatic setting, the use of SERDs in combination with standard CDK 4/6 inhibitors in patients with stage II-disease may be particularly effective across mutational profiles. Interestingly, other SERDs were shown to yield a PFS benefit specificity in subgroups with mutated ESR1 variants and appear to require a combination with CDK 4/6 inhibitors to improve survival in wild-type ESR1 receptors, as demonstrated in the EMBER-3 trial. Elacestrant is also under investigation in eBC. The phase I trial ELIPSE (NCT04797728) in postmenopausal women with early-stage (stage cT1-3, N0), ER-positive, HER2-negative breast cancer investigates 400 mg of elacestrant daily for four weeks in the neoadjuvant setting. The trial's primary outcome is proliferation arrest, defined as a Ki-67 level of ≤ 2.7%, in the surgical specimens collected after the end of trial treatment. Furthermore, the EORTC-2129-BCG (TREAT ctDNA, NCT05512364) is a phase III trial in pre- and postmenopausal women and men with high-risk early-stage ER-positive, HER2-negative breast cancer, and circulating tumor DNA (ctDNA) relapse. ctDNA-positive patients identified during the eligibility assessment, with no evidence of distant metastasis, will be randomized to receive either SoC endocrine treatment or elacestrant; the trial's primary endpoint is distant metastasis-free survival. However, this trial focuses on the populations at a high risk of recurrence, that is, stage IIB or stage III disease and completion of adjuvant chemotherapy or patients with at least four cycles of neoadjuvant chemotherapy and residual tumor at surgery of ≥ 1cm (≥ypT1c) or axillary node-positive (ypN+). Therefore, the information provided by the EORTC-2129-BCG trial on the activity of elacestrant in patients with intermediate-risk stage I-II disease will be limited.

Conditions

• Breast Cancer
• HR+/HER2- Breast Cancer

Interventions

Type	Name	Description
DRUG	Elacestrant	Elacestrant, a tetrahydronaphthalene compound, is a potent, selective, and orally active oestrogen receptor-α (ERα) antagonist and degrader.
DRUG	Standard-of-care endocrine treatment	SoC ET comprises all endocrine treatments authorized for the condition under review. The choice is made upon investigator´s discretion.

Timeline

• Start date: 2026-01-31
• Primary completion: 2033-09-30
• Completion: 2033-09-30
• First posted: 2025-11-21
• Last updated: 2025-11-21