Abstract PR06: ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC)
Authors: Coleman Robert L. , Oza Amit M. , Lorusso Domenica , Aghajanian Carol , Oaknin Ana , Dean Andrew , Colombo Nicoletta , Weberpals Johanne I. , Clamp Andrew , Scambia Giovanni , Leary Alexandra , Holloway Robert W. , O’Malley David M. , Cameron Terri , Maloney Lara , Goble Sandra , Lin Kevin , Sun James , Giordano Heidi , Ledermann Jonathan A. 
Published: August 2018

Abstract
Background: Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the United States for treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with two or more chemotherapies. Rucaparib has also demonstrated antitumor activity in the treatment setting in patients (pts) with BRCA wild-type associated recurrent OC whose tumor has high genomic loss of heterozygosity (LOH). ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC.
Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All pts were required to have CA-125 less than the upper limit of normal. Pts were randomized 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested cohorts: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/LOH high); and (3) intent-to-treat (ITT) population. PFS was also assessed by blinded independent central review (BICR) (secondary endpoint) and LOH status in pts with BRCA wild type OC (exploratory endpoint). Adverse events (AEs) were summarized descriptively.
Results: ARIEL3 enrolled 564 pts (375, rucaparib; 189, placebo). Nearly 200 pts (n=196) had BRCA mutation-associated OC. Of these pts, 130 had a germline BRCA mutation (82 [21.9%], rucaparib; 48 [25.4%], placebo), 56 had a somatic BRCA mutation (40 [10.7%], rucaparib; 16 [8.5%], placebo), and 10 pts had tumors with germline and/or somatic BRCA status unknown (8 [2.1%], rucaparib; 2 [1.1%], placebo). Median investigator-assessed PFS in the BRCA-mutant cohort (130, rucaparib; 66 placebo) was 16.6 mo vs 5.4 mo (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34; P&lt;0.0001). In the HRD cohort (236, rucaparib; 118, placebo), median PFS was 13.6 mo vs 5.4 mo (HR, 0.32; 95% CI, 0.24-0.42; P&lt;0.0001), and in the ITT population, median PFS was 10.8 mo vs 5.4 mo (HR, 0.37; 95% CI, 0.30-0.45; P&lt;0.0001). Median PFS by BICR in the BRCA-mutant cohort was 26.8 mo vs 5.4 mo (HR, 0.20; 95% CI, 0.13-0.32; p&lt;0.0001). In the HRD cohort, median PFS by BICR was 22.9 mo vs 5.5 mo (HR, 0.34; 95% CI, 0.24-0.47; p&lt;0.0001), and in the ITT population, median PFS by BICR was 13.7 mo vs 5.4 mo (HR, 0.35; 95% CI, 0.28-0.45; p&lt;0.0001). In the safety population (372, rucaparib; 189, placebo), the most common treatment-emergent AEs (≥35% of pts in either arm) included nausea (75.3% and 36.5%), asthenia/fatigue (69.4% and 43.9%), dysgeusia (39.2% and 6.9%), anemia (37.4% and 5.8%), constipation (36.6% and 23.8%), and vomiting (36.6% and 14.8%). The most common grade 3 or higher treatment-emergent AEs were anemia (18.8% and 0.5%) and alanine/aspartate aminotransferase increase (10.5% and 0%). At the visit cutoff date (15 April 2017), 13.4% and 1.6% of pts discontinued maintenance treatment due to treatment-emergent AEs (excluding disease progression), and 1.6% and 1.1% of pts died due to treatment-emergent AEs (including disease progression).
Conclusion: Rucaparib significantly improved PFS vs placebo in pts with platinum-sensitive, recurrent OC in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Additionally, rucaparib significantly improved PFS vs placebo in pts with BRCA wild-type OC (LOH high and LOH low).
Clinical trial identification: NCT01968213.
This abstract is also being presented as Poster A47.
Citation Format: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, David M. O’Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann. ARIEL3: A phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC). [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR06.