Treating Recurrent or Metastatic Breast Cancer with Vepdegestrant, an Estrogen Receptor Degrader
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on August 25th, 2025
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A majority of breast cancer tumors exhibit estrogen receptors on their surface while not having the receptor for human epidermal growth factor (HER2). To target this form of cancer, endocrine therapy is used in conjunction with CDK4/6 inhibitors, but treatment resistance poses a challenge for the management of disease progression. With funding from Pfizer, a study was conducted to examine the usage of vepdegestran in advanced breast cancer.
The phase 3 clinical trial included 624 participants who had been diagnosed with recurrent local or metastatic breast cancer that cannot be surgically removed or treated with radiation. The study exclusively enrolled patients who had tumors with estrogen receptor expression but without HER2. The participants had previously been treated with CDK4/6 inhibitor therapy plus endocrine therapy, most in the form of palbociclib and aromatase inhibitor.
The patients were randomly assigned to be treated with either fulvestrant or vepdegestran. The former was injected intramuscularly at a dose of 500 mg every 28 days. While vepdegestran can be taken orally, at a daily dose of 200 mg. Both medications specifically target the estrogen receptor with fulvestrant works as an antagonist that blocks downstream signaling and leads to degradation of the receptor. Vepdegestran lacks the antagonistic property and directly marks the estrogen receptor for degradation by proteasome.
The researchers found that there is no significant difference in the progression-free survival time between patients treated with fulvestrant and vepdegestran. However, vepdegestran significantly reduced disease progression and increased survival in patients with ESR1 mutation to the estrogen receptor. Researchers hypothesized that receptors with the ESR1 mutation exhibited an enhanced sensitivity to estrogen, while non-mutated disease is driven by other alternative pathways. Side effects analyses found that vepdegestran is less tolerable and leads to more treatment discontinuation.
The phase 3 clinical trial included 624 participants who had been diagnosed with recurrent local or metastatic breast cancer that cannot be surgically removed or treated with radiation. The study exclusively enrolled patients who had tumors with estrogen receptor expression but without HER2. The participants had previously been treated with CDK4/6 inhibitor therapy plus endocrine therapy, most in the form of palbociclib and aromatase inhibitor.
The patients were randomly assigned to be treated with either fulvestrant or vepdegestran. The former was injected intramuscularly at a dose of 500 mg every 28 days. While vepdegestran can be taken orally, at a daily dose of 200 mg. Both medications specifically target the estrogen receptor with fulvestrant works as an antagonist that blocks downstream signaling and leads to degradation of the receptor. Vepdegestran lacks the antagonistic property and directly marks the estrogen receptor for degradation by proteasome.
The researchers found that there is no significant difference in the progression-free survival time between patients treated with fulvestrant and vepdegestran. However, vepdegestran significantly reduced disease progression and increased survival in patients with ESR1 mutation to the estrogen receptor. Researchers hypothesized that receptors with the ESR1 mutation exhibited an enhanced sensitivity to estrogen, while non-mutated disease is driven by other alternative pathways. Side effects analyses found that vepdegestran is less tolerable and leads to more treatment discontinuation.