Real-world clinical outcomes and prognostic factors of olaparib maintenance in Korean patients with primary or recurrent high-grade ovarian cancer with exploratory analysis of location of <i>BRCA1</i> and <i>BRCA2</i> mutations.
Authors: Junhwan Kim, So-Yeon Park, Ju-Hyun Kim, Shin-Wha Lee, Jeong-Yeol Park, Dae-Shik Suh, Jong-Hyeok Kim, Yong-Man Kim, Dae-Yeon Kim
Journal: Journal of Clinical Oncology (2024)

e17561 Background: Olaparib is approved for first-line (1L) and second or subsequent-line (2L+) maintenance therapy in BRCA-mutated ovarian cancer (OC). However, the correlation between location of BRCA mutation and benefit of olaparib maintenance therapy has not been thoroughly investigated. We aimed to analyze real-world clinical outcomes and identify prognostic factors for olaparib maintenance therapy in Korean patients with BRCA-mutated OC, focusing on BRCA mutation sites. Methods: This retrospective cohort study included Korean patients with BRCA-mutated OC who received olaparib as 1L or 2L+ at the single center between January 2015 and April 2023. Survival outcomes and toxicity were correlated with BRCA mutation location summaries and patient characteristics by maintenance therapy line. Results: For the 1L group (n = 70), 2-year PFS and 3-year OS were 75.5% (95% CI, 56.4–87.1) and 98.5% (95% CI, 90.0–99.8). For the 2L+ group (n = 83), 2-year PFS and 3-year OS were 54.8% (95% CI, 56.4–87.1) and 87.3% (95% CI, 76.7–93.3). Primary stage (IV vs. ≤ III) was a prognostic factor for PFS in the 1L group (adjusted hazard ratio [aHR], 5.74; 95% CI, 1.23–26.73; P = 0.026). Notably, Korean-specific pathogenic variant p.Leu1780Pro BRCA1 mutation carriers (n= 8) showed significantly worse PFS than non-carriers (n = 32) in the 1L group (Log-rank P = 0.014). For the 2L+ group, platinum-free interval ≥ 12 months was a good prognostic factor for both PFS (aHR, 0.42; 95% CI, 0.23–0.75) and OS (aHR, 0.31; 95% CI, 0.11–0.91). Additionally, somatic BRCA1 mutation was a poor prognostic factor for PFS in the 2L+ group (hazard ratio [HR], 3.39; 95% CI, 1.22–9.38; P = 0.029). In the 1L group, the longer interval between the last chemotherapy and maintenance therapy was associated with the lower risk of hematologic toxicity induced by olaparib (odd ratio [OR], 0.75; 95% CI 0.57–0.99; P = 0.04). In addition, age ≥ 65 years (OR, 3.33; 95% CI, 1.05–10.63; P = 0.04) and the dose reduction of the last chemotherapy (OR, 3.80; 95% CI, 1.02–14.18; P = 0.047) were associated with a higher risk of hematologic toxicity in the 1L group. In the 2L+ group, germline BRCA1 (OR, 0.36; 95% CI, 0.14–0.92; P = 0.03) and BRCA2 (OR, 7.47; 95% CI, 1.96–28.39; P = 0.003) mutations showed contrariwise risks for hematologic toxicity. Drug discontinuation due to toxicity was 1.4% and 6.0% in the 1L and the 2L+ groups and no acute myeloid leukemia/myelodysplastic syndrome cases were observed. Conclusions: Olaparib maintenance therapy was effective and tolerable in Korean patients with BRCA-mutated OC. Prognostic factors for survival outcomes and risk factors of hematologic toxicity in olaparib maintenance therapy were different between 1L and 2L+. The prognostic significance of Korean-specific p.Leu1780Pro BRCA1 mutation on olaparib should be further researched.