Randomized open-label multicenter phase 2 trial comparing first-line olaparib versus CDK4/6 inhibitor plus endocrine therapy in patients with gBRCAmut-associated HR+/HER2-advanced breast cancer [BR21-08, OPERA trial]

초록

Background: In HR+/HER2- advanced breast cancer (ABC), CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) represent the current first-line standard. However, a subset of patients exhibit early resistance, and the impact of germline BRCA1/2 mutations (gBRCAmut) on treatment outcomes has not been fully evaluated. gBRCAmut tumors harbor homologous recombination deficiency and are potentially sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Although PARP inhibitors are established in gBRCAmut triple-negative BC, prospective data in gBRCAmut HR+/HER2- ABC are lacking. Methods: This open-label, multicenter, randomized phase II study (BR21-08, OPERA) enrolled patients with recurrent or metastatic HR+/HER2- ABC harboring germline BRCA1/2 mutations and no prior systemic therapy for advanced disease. Patients were randomized to olaparib (300 mg orally twice daily) or investigator’s choice of CDK4/6i plus ET. Upon progression, cross-over to the alternate regimen was allowed. The primary endpoint was progression-free survival on first-line therapy (PFS1). Based on an assumed HR of 0.375, 66 patients (33 per arm) were required to achieve 90% power with a two-sided alpha of 0.05. Results: As of September 2025, 10 patients were screened and 9 enrolled before early termination due to slow patient accrual. Median age was 50 years; 1 carried a gBRCA1 and 8 a gBRCA2 mutation. Six patients received CDK4/6i+ET (2 ribociclib, 2 abemaciclib, 2 palbociclib) and 3 received olaparib as first-line therapy. With median follow-up of 25.5 months, median PFS1 was 13.6 months in the control arm and 16.4 months in the olaparib arm. Two patients on abemaciclib remain on first-line therapy. Objective response rate (ORR) was 50% in the control arm (1 CR, 2 PR) and 33% in the olaparib arm (1 PR). Seven patients received second-line therapy: median PFS2 was 4.5 months for those receiving CDK4/6i+ET and 8.1 months for those receiving olaparib. The most common adverse event (AE) in the control arm during the 1st line therapy was neutropenia, with three grade ≥3 events, whereas nausea and anemia were most common in the olaparib arm, with no grade ≥3 events observed. Conclusion: In gBRCAmut HR+/HER2- ABC, first-line olaparib demonstrated numerically longer PFS and a favorable safety profile compared with CDK4/6i plus ET. These findings should be interpreted with caution given the small sample size.