Rucaparib has antitumour activity in BRCA-mutant or BRCA wild-type/genomic loss of heterozygosity (LOH) high associated OC. ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC.
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 responses required CA-125 to be less than the upper limit of normal. Pts were randomised 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 groups: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (BRCA mutant or BRCA wild-type/LOH high); and (3) intent-to-treat population. PFS was also assessed by blinded independent central review (key secondary endpoint) and LOH status in pts with BRCA wild-type OC (exploratory endpoint).
Data are presented for the rucaparib and placebo groups, respectively. ARIEL3 enrolled 564 pts (375 and 189 in each group). PFS data are summarised in the Table. The most common grade 3 or higher treatment-emergent AEs were anaemia (18.8% and 0.5%) and alanine/aspartate aminotransferase increase (10.5% and 0%). At the visit cutoff date (15 Apr 2017), 13.4% and 1.6% of pts discontinued due to treatment-emergent AEs (excluding disease progression); 1.6% and 1.1% of pts died due to AEs (including disease progression).Table:
|Analysis Population||Rucaparib, n||Placebo, n||PFS by Investigator Review (Primary Endpoint)||PFS by BICR (Key Secondary Endpoint)|
|Hazard Ratio* (95% CI); P Value||Median PFS, mo; P Value†||Hazard Ratio* (95% CI); P Value||Median PFS, mo; P Value†|
|Rucaparib vs Placebo||Rucaparib vs Placebo|
|BRCA mutant||130||66||0.23 (0.16–0.34); P< 0.0001||16.6 vs 5.4; P< 0.0001||0.20 (0.13–0.32); P< 0.0001||26.8 vs 5.4; P< 0.0001|
|HRD (BRCA mutant or BRCA wild type/LOH high)||236||118||0.32 (0.24–0.42); P< 0.0001||13.6 vs 5.4; P< 0.0001||0.34 (0.24–0.47); P< 0.0001||22.9 vs 5.5; P< 0.0001|
|Intent to treat‡||375||189||0.37 (0.30–0.45); P< 0.0001||10.8 vs 5.4; P< 0.0001||0.35 (0.28–0.45); P< 0.0001||13.7 vs 5.4; P< 0.0001|
|BRCA wild type/LOH high||106||52||0.44 (0.29–0.66); P< 0.0001||9.7 vs 5.4; P< 0.0001||0.55 (0.35–0.89); P=0.0135||11.1 vs 5.6; P=0.0114|
|BRCA wild type/LOH low||107||54||0.58 (0.40–0.85); P=0.0049||6.7 vs 5.4; P=0.004||0.47 (0.31–0.71); P=0.0003||8.2 vs 5.3; P=0.0002|
BICR, blinded independent central review. HRD, homologous recombination deficient.*
Estimated with a Cox proportional hazards model.†
Stratified log-rank P value.‡
Includes pts with BRCA-mutant (130, rucaparib; 66, placebo), BRCA wild-type/genomic LOH high (106, rucaparib; 52, placebo), BRCA wild-type/genomic LOH low (107, rucaparib; 54, placebo), or BRCA wild-type/genomic LOH indeterminate (32, rucaparib; 17, placebo) OC.
Rucaparib significantly improved PFS vs placebo in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Improvement in PFS was observed in non-nested subgroups of pts with BRCA wild-type OC (both LOH high and LOH low).
Clinical trial identification
Legal entity responsible for the study
Clovis Oncology, Inc.
Clovis Oncology, Inc.
J. Ledermann: Advisory Role: Clovis Oncology. A.M. Oza: Consulting or Advisory Role: Amgen, Verastem, Clovis Oncology, Immunovaccine Travel, Accommodations, Expenses: AstraZeneca Honoraria: WebRx. D. Lorusso: Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Roche, PharmaMar Travel, Accommodations, Expenses: Roche, PharmaMar. A. Oaknin: Consulting or Advisory Role: PharmaMar, Clovis Oncology, Roche, AstraZeneca N. Colombo: Advisory board: Roche, AstraZeneca, Tasaro, Pharmamar, Clovis, Advaxis J. Weberpals: Research support: Abbvie, AstraZeneca. A. Leary: Advisory board: Clovis Oncology, Pfizer, Pharmamar, Gamamabs, Merus. R. Holloway: Speaker’s Bureau honoraria: Astra Zeneca, Clovis, Tesaro. D.M. O\'Malley: Research support: Clovis Oncology Advisory Board: Janssen, Eisai. T. Cameron, L. Maloney, S. Goble, K.K. Lin, H. Giordano: Employment: Clovis Oncology Stock and Other Ownership Interests: Clovis Oncology. J. Sun: Stock and Other Ownership Interests: Foundation Medicine. R. Coleman: Research support: AstraZeneca, Roche/Genentech, Janssen, Oncomed, Millennium, Esperance, Abbvie. All other authors have declared no conflicts of interest.