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Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian carcinoma

Published:October 20, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.08.021

      Highlights

      • Clinical/molecular characteristics associated with exceptional benefit from rucaparib maintenance in ARIEL3 were explored.
      • 21% of patients in the rucaparib arm derived exceptional benefit (PFS ≥2 years) compared with only 2% in the placebo arm.
      • Clinical characteristics associated with exceptional outcomes on rucaparib were related to platinum sensitivity.
      • BRCA1, BRCA2, RAD51C, and RAD51D mutations were associated with exceptional benefit from rucaparib.
      • A diverse set of patients with high-grade ovarian carcinoma can derive exceptional benefit from rucaparib maintenance.

      Abstract

      Objective

      ARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib.

      Methods

      Patients were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were evaluated for association with exceptional benefit (progression-free survival ≥2 years) versus progression on first scan (short-term subgroup) and other efficacy outcomes.

      Results

      Rucaparib treatment was significantly associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001). Exceptional benefit was more frequent among patients with favorable baseline clinical characteristics and with carcinomas harboring molecular evidence of homologous recombination deficiency (HRD). A comparison between patients who derived exceptional benefit from rucaparib and those in the short-term subgroup revealed both clinical markers (no measurable disease at baseline, complete response to latest platinum, longer penultimate platinum-free interval) and molecular markers (BRCA1, BRCA2, RAD51C, and RAD51D alterations and genome-wide loss of heterozygosity) significantly associated with exceptional benefit.

      Conclusions

      Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics or molecular features associated with HRD. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of patients with recurrent high-grade ovarian carcinoma.

      Keywords

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