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