Emerging Oral SERD and PROTAC Treatment Options as Monotherapy and in Combination

PROTACs offer a novel mechanism of action distinct from oral SERDs through ubiquitination of the estrogen receptor. Vepdegestrant demonstrated clinical activity with improved median progression-free survival compared with physician’s choice of endocrine therapy as single-agent treatment. However, direct comparisons between studies such as Emerald (oral SERDs) and PROTAC trials must account for population differences, including varying degrees of prior treatment exposure and CDK4/6 inhibitor history.

The optimal sequencing of SERDs vs PROTACs remains undefined, creating uncertainty about whether to initiate with one class and progress to another or vice versa. Vepdegestrant shows promise as an additional therapeutic option for patients with ESR1 mutations, potentially useful at subsequent lines of therapy depending on disease progression patterns and extent. The benefit profile appears limited to patients with ESR1 mutations, similar to oral SERDs.

Combination strategies represent the future direction for both oral SERDs and PROTACs, addressing the limitation that 40% of patients experience progression regardless of novel endocrine agent type, with 60% experiencing benefits lasting no more than 6 months. The ELEVATE trial exemplifies this approach, studying various combinations with elacestrant, including CDK4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors. These combination approaches aim to overcome resistance mechanisms and improve treatment durability across broader patient populations beyond those with specific ESR1 mutations.