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Gynaecological cancers

2444 - ARIEL3: A Phase 3, Randomised, Double-Blind Study of Rucaparib vs Placebo Following Response to Platinum-Based Chemotherapy for Recurrent Ovarian Carcinoma (OC)

Date

08 Sep 2017

Session

Gynaecological cancers

Topics

Cytotoxic Therapy;  Ovarian Cancer

Presenters

Jonathan Ledermann

Citation

Annals of Oncology (2017) 28 (suppl_5): v605-v649. 10.1093/annonc/mdx440

Authors

J. Ledermann1, A.M. Oza2, D. Lorusso3, C. Aghajanian4, A. Oaknin5, A. Dean6, N. Colombo7, J. Weberpals8, A. Clamp9, G. Scambia10, A. Leary11, R. Holloway12, D.M. O'Malley13, T. Cameron14, L. Maloney15, S. Goble16, K.K. Lin17, J. Sun18, H. Giordano14, R. Coleman19

Author affiliations

  • 1 Gynaecological Oncology, University College London Cancer Institute and UCL Hospitals, WC1E6BT - London/GB
  • 2 Division Of Medical Oncology And Hematology, Princess Margaret Cancer Centre, University Health Network, M5G 1Z5 - Toronto/CA
  • 3 Unità Di Ginecologia Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori and MITO, 20133 - Milan/IT
  • 4 Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 5 Medical Oncology Department, Vall d'Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 6 Department Of Oncology, St John of God Subiaco Hospital, Subiaco/AU
  • 7 7gynecologic Cancer Program, European Institute of Oncology and University of Milan-Bicocca, 20141 - Milan/IT
  • 8 Division Of Gynecologic Oncology, Ottawa Hospital Research Institute, K1H 8L6 - Ottawa/CA
  • 9 Department Of Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, Manchester/GB
  • 10 Gynecologic Oncology, Università Cattolica Roma, 00168 - Rome/IT
  • 11 Gynecological Unit, Gustave Roussy Cancer Center, INSERM U981, and Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), 94800 - Villejuif/FR
  • 12 Department Of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando/US
  • 13 Clinical Research Gynecologic Oncology, The Ohio State University, James Cancer Center, Columbus/US
  • 14 Clinical Science, Clovis Oncology, Inc., Boulder/US
  • 15 Clinical Science, Clovis Oncology, Inc., 80301 - Boulder/US
  • 16 Biostatistics, Clovis Oncology, Inc., Boulder/US
  • 17 Cancer Genomics, Clovis Oncology, Inc., Boulder/US
  • 18 Biomarker Development And Analysis, Foundation Medicine, Cambridge/US
  • 19 Department Of Gynecologic Oncology And Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 77030-3721 - Houston/US
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Abstract 2444

Background

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.

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 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).

Results

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:

LBA40_PR

Analysis PopulationRucaparib, nPlacebo, nPFS by Investigator Review (Primary Endpoint)PFS by BICR (Key Secondary Endpoint)
Hazard Ratio* (95% CI); P ValueMedian PFS, mo; P ValueHazard Ratio* (95% CI); P ValueMedian PFS, mo; P Value
Rucaparib vs PlaceboRucaparib vs Placebo
Primary Analyses
BRCA mutant130660.23 (0.16–0.34); P< 0.000116.6 vs 5.4; P< 0.00010.20 (0.13–0.32); P< 0.000126.8 vs 5.4; P< 0.0001
HRD (BRCA mutant or BRCA wild type/LOH high)2361180.32 (0.24–0.42); P< 0.000113.6 vs 5.4; P< 0.00010.34 (0.24–0.47); P< 0.000122.9 vs 5.5; P< 0.0001
Intent to treat3751890.37 (0.30–0.45); P< 0.000110.8 vs 5.4; P< 0.00010.35 (0.28–0.45); P< 0.000113.7 vs 5.4; P< 0.0001
Exploratory Analyses
BRCA wild type/LOH high106520.44 (0.29–0.66); P< 0.00019.7 vs 5.4; P< 0.00010.55 (0.35–0.89); P=0.013511.1 vs 5.6; P=0.0114
BRCA wild type/LOH low107540.58 (0.40–0.85); P=0.00496.7 vs 5.4; P=0.0040.47 (0.31–0.71); P=0.00038.2 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.

Conclusions

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

NCT01968213

Legal entity responsible for the study

Clovis Oncology, Inc.

Funding

Clovis Oncology, Inc.

Disclosure

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.

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