Exploratory analysis of percentage of genomic loss of heterozygosity (LOH) in patients with platinum-sensitive recurrent ovarian carcinoma (rOC) in ARIEL3.

Authors

Ana Oaknin

Ana Oaknin

Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

Ana Oaknin , Jonathan A. Ledermann , Amit M. Oza , Domenica Lorusso , Carol Aghajanian , Andrew Peter Dean , Nicoletta Colombo , Johanne I Weberpals , Andrew R. Clamp , Giovanni Scambia , Alexandra Leary , Robert W. Holloway , David M. O'Malley , Iain A. McNeish , Elizabeth M. Swisher , Teresa Cameron , Sandra Goble , James Sun , Kevin K. Lin , Robert L. Coleman

Organizations

Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, UCL Cancer Institute and UCL Hospitals, London, United Kingdom, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, Fondazione IRCCS Istituto Nazionale dei Tumori and MITO, Milan, Italy, Memorial Sloan Kettering Cancer Center, New York, NY, Saint John of God Subiaco Hospital, Subiaco, Australia, European Institute of Oncology and University of Milan-Bicocca, Milano, Italy, Ottawa Hospital Research Institute, Ottawa, ON, Canada, The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom, Università Cattolica Roma, Rome, Italy, Gustave Roussy Cancer Center, INSERM U981, and Groupe D'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Villejuif, France, Florida Hospital Cancer Institute, Orlando, FL, The Ohio State University, James Cancer Center, Columbus, OH, Imperial College London, London, United Kingdom, University of Washington, Seattle, WA, Clovis Oncology, Inc., Boulder, CO, Foundation Medicine, Cambridge, MA, The University of Texas MD Anderson Cancer Center, Houston, TX

Research Funding

Pharmaceutical/Biotech Company

Background: In ARIEL3, rucaparib significantly improved progression-free survival (PFS) vs placebo in all randomized patients, including patients with BRCA-mutant, BRCA wild-type/high-LOH (prespecified as ≥16% genomic LOH), or BRCA wild-type/low-LOH ( < 16% genomic LOH) rOC (Coleman et al. Lancet. 2017;390:1949-61). This exploratory analysis evaluated the optimal cutoff for percentage of (%) genomic LOH in BRCA wild-type rOC in ARIEL3. Methods: Genomic LOH of archival tumor tissue DNA was centrally assessed using Foundation Medicine’s next-generation sequencing-based assay (Cambridge, MA, USA). Treatment effect for investigator-assessed PFS (invPFS) was analyzed in BRCA wild-type rOC for the prespecified cutoff (16%) and across a range of cutoffs for % genomic LOH (5%–30%). Hazard ratios (HRs) were estimated using a stratified Cox proportional hazards model. Prognostic and predictive utility of % genomic LOH was assessed by comparing invPFS between and within the treatment arms. Results: In ARIEL3, 564 patients were randomized. Of the 368 patients with BRCA wild-type associated rOC, LOH was calculable for 319. Rucaparib significantly improved invPFS vs placebo between the 5% and 23% cutoffs for % genomic LOH. Using the prespecified cutoff (16%), the HR (rucaparib vs placebo) was 0.44 (95% confidence interval [CI], 0.29‒0.66; P< 0.0001) for patients with high-LOH rOC. To further assess the % genomic LOH cutoff, we compared patients with high- vs low-LOH rOC within the rucaparib arm and found a statistically significant benefit for invPFS at the prespecified cutoff of 16% (HR, 0.70; 95% CI, 0.50‒0.97; P= 0.0338). In the placebo arm, no statistically significant benefit was observed for invPFS in patients with high- vs low-LOH rOC at any cutoff tested. Conclusions: Rucaparib improved invPFS vs placebo across the range of cutoffs tested for % genomic LOH, including the prespecified cutoff of 16% for high LOH. The observance of significant differences between patients with high- vs low-LOH rOC in the rucaparib but not placebo arm suggests that genomic LOH is a predictive but likely not prognostic biomarker. Clinical trial information: NCT01968213

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Abstract Details

Meeting

2018 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Gynecologic Cancer

Track

Gynecologic Cancer

Sub Track

Ovarian Cancer

Clinical Trial Registration Number

NCT01968213

Citation

J Clin Oncol 36, 2018 (suppl; abstr 5545)

DOI

10.1200/JCO.2018.36.15_suppl.5545

Abstract #

5545

Poster Bd #

272

Abstract Disclosures