A Phase II Multi-Center Open-Label Randomized Study of Capecitabine in Combination with Elacestrant versus Capecitabine Alone in Advanced Estrogen Receptor Positive Breast Cancer (CapEla)

Summary:

Endocrine therapy and targeted therapy such as CDK4/6 inhibitors and other inhibitors targeting the PI3K-AKT-mTOR pathway are highly effective in metastatic hormone receptor positive (HR+) breast cancer. However, nearly all patients will ultimately progress and transition to chemotherapy treatment. The investigators found that a specific type of endocrine therapy called a SERD (selective estrogen receptor degrader) had synergistic effects when combined with chemotherapy in cancer cells resistant to CDK4/6 inhibitor therapy. Since the ESR1 mutation is responsible for resistance and driving metastases, the investigators hypothesized that patients with the mutation may benefit the most from the combination. This was confirmed in a preclinical study as higher synergy scores were observed in cells with the ESR1 mutation. Additionally, two recent clinical trials provided evidence that combining endocrine therapy with an oral chemotherapy called capecitabine provided a benefit in patients HR+ breast cancer irrespective of the presence of an ESR1 mutation.

Since both the preclinical and clinical data showed increased efficacy of the combination, and the preclinical data showed increased efficacy of the combination in models expressing an ESR1 mutation, the investigators hypothesize the benefit from the addition of a SERD that targets the ESR1 mutation, such as elacestrant, may be superior in patients with mutant estrogen receptor positive (ER+) metastatic disease. This phase II study will assess the median progression-free survival (the length of time after starting treatment the cancer does not grow or spread) of elacestrant in combination with capecitabine versus capecitabine alone in patients with ER+, HER2-negative metastatic or locally recurrent invasive breast cancer with and without an ESR1 mutation who progressed on prior treatment with CDK4/6 inhibitors and other endocrine therapies. The proposed clinical trial will be the first randomized study to test the clinical benefit from the addition of an oral SERD in combination with capecitabine in patients who had progressed on a CDK4/6 inhibitor.

Trial Registration: ClinicalTrials.gov Identifier: NCT07222215