In oestrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, first-line treatment typically consists of a CDK4/6 inhibitor in combination endocrine therapy.1 Upon progression, second-line options often include endocrine therapy with or without targeted therapy.1 Vepdegestrant is an investigational oral proteolysis-targeting chimera (PROTAC) that induces targeted degradation of the ER via the ubiquitin-proteasome system. The phase III VERITAC-2 trial evaluated the efficacy and safety of vepdegestrant vs fulvestrant in patients who had previously received a CDK4/6 inhibitor plus endocrine therapy.2
The global, open-label, phase III VERITAC-2 trial enrolled patients with ER-positive, HER2-negative advanced breast cancer who had received one prior line of CDK4/6 inhibitor plus one line of endocrine therapy (and up to one additional line of endocrine therapy). The duration of the most recent endocrine therapy was ≥6 months, and patients could not have received a prior SERD (e.g., fulvestrant, elacestrant). Patients were randomised 1:1 to receive either vepdegestrant (orally) or fulvestrant (intramuscular injection). The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review, both in the ESR1-mutant subgroup and the overall intention-to-treat population.
A total of 624 patients were enrolled, of whom 43% had ESR1 mutations. Among the patients with ESR1 mutations, vepdegestrant significantly prolonged median PFS compared to fulvestrant (5.0 vs 2.1 months; HR[95% CI]: 0.58[0.43-0.78], p< 0.001). In the overall population, median PFS was 3.8 months with vepdegestrant compared to 3.6 months with fulvestrant (HR[95% CI]: 0.83[0.69-1.01], p= 0.07). Overall survival data were immature at the time of analysis.
Grade ≥3 adverse events occurred in 23.4% of patients receiving vepdegestrant and 17.6% of those receiving fulvestrant. Treatment discontinuation due to adverse events was relatively infrequent in both groups (2.9% vs 0.7%, respectively).
Vepdegestrant is the first PROTAC to be evaluated in a phase III study for advanced breast cancer. In VERITAC-2, vepdegestrant significantly improved PFS compared to fulvestrant in patients with ESR1-mutated, ER-positive, HER2-negative advanced breast cancer. The safety profile was manageable, with low rates of treatment discontinuation.
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