In a significant shift for hormone-sensitive breast cancer care, the US Food and Drug Administration approved Etcamah (camizestrant) on 4 September for certain patients with estrogen receptor-positive breast cancer whose tumors develop resistance mutations during treatment. The approval is the first based on a circulating tumor DNA blood test used to identify emerging changes in the ESR1 gene.
The test can reveal resistance while it is still detectable in the bloodstream, before progression becomes visible on standard imaging. Doctors can then replace the existing endocrine treatment with Etcamah rather than waiting for the tumor to show measurable growth.
Detecting resistance before visible progression
ER-positive breast cancers account for approximately ~70% of patients and commonly respond to hormone-directed treatment. Standard approaches include drugs that inhibit estrogen-receptor signaling or block estrogen production. For advanced or metastatic ER-positive, HER2-negative disease, these treatments are often combined with a CDK4/6 inhibitor.
However, about 40% of patients receiving endocrine therapy with a CDK4/6 inhibitor eventually develop resistance. Mutations in ESR1 can leave the estrogen receptor active even when estrogen is absent, allowing cancer cells to continue growing.
The established treatment after resistance is often Faslodex (fulvestrant), an injectable estrogen-receptor antagonist and selective estrogen-receptor degrader. The source describes limitations including its intramuscular delivery, pharmacokinetics and weak activity after CDK4/6 inhibitor treatment.
Results from the SERENA-6 trial
Etcamah is an oral, next-generation selective estrogen-receptor degrader and complete estrogen-receptor antagonist. Its development tested whether changing endocrine therapy at the moment an ESR1 mutation appeared could preserve the benefit of continuing CDK4/6 inhibition.
The FDA and European Medicines Agency approvals rely on SERENA-6, a trial involving more than 3,000 patients receiving first-line treatment with an aromatase inhibitor and a CDK4/6 inhibitor for ER-positive, HER2-negative advanced breast cancer.
When an ESR1 mutation emerged, patients who switched from the aromatase inhibitor to Etcamah had progression-free survival of 16.8 months, an increase of more than 7 months compared with patients who continued the aromatase inhibitor. Second progression-free survival, measuring time to progression after a subsequent treatment, also increased by over 6 months.
A broader wave of oral ER-targeted drugs
Etcamah is part of a growing group of oral therapies developed to improve on fulvestrant. Veppanu (vepdegestrant), approved in May 2026, uses a PROTAC mechanism: one part binds the estrogen receptor and another recruits an E3 ligase from the ubiquitin–proteasome system, promoting protein degradation. In a subgroup of about 270 patients with ESR1 mutations, it delayed disease progression or death by about 3 months compared with standard care.
Other drugs, including Orserdu (elacestrant) and Inluriyo (imlunestrant), also showed their clearest benefits in patients with ESR1 mutations. Their approvals were restricted to that subgroup after broader trial populations did not show the same degree of benefit.
Trials moving treatment earlier
Further studies are testing whether these therapies can be used before resistance mutations appear. AstraZeneca’s SERENA-4 trial is expected to report later this year in patients who have not previously received drug therapy for advanced disease. The CAMBRIA-1 and CAMBRIA-2 trials are examining Etcamah in early breast cancer, with results expected next year.
Other investigational approaches include complete estrogen-receptor antagonists that block transcriptional regions called AF2 and AF1, while also promoting receptor destabilization. The source also describes research suggesting that some drugs may restrict estrogen-receptor movement inside the nucleus before degradation occurs.
Despite these advances, the article notes that resistance biology remains complex and clinicians still need better tests to identify which patients will respond to estrogen-receptor inhibitors. Assays measuring receptor activity, rather than only receptor expression or mutation status, are beginning to emerge.
Original source: nature.com
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