Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis.
2015; Lippincott Williams & Wilkins; Volume: 33; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2015.33.15_suppl.5508
ISSN1527-7755
AutoresIain A. McNeish, Amit M. Oza, Robert L. Coleman, Clare L. Scott, Gottfried E. Konecny, Anna V. Tinker, David M. O’Malley, James D. Brenton, Rebecca Kristeleit, Katherine M. Bell‐McGuinn, Ana Oaknin, Alexandra Léary, Kevin Lin, Mitch Raponi, Heidi Giordano, Sandra Goble, Lindsey Rolfe, Roman Yelensky, Andrew R. Allen, Elizabeth M. Swisher,
Tópico(s)CRISPR and Genetic Engineering
Resumo5508 Background: At least 50% of high-grade serous ovarian cancers (OC) may have homologous recombination deficiency (HRD). Germline BRCA1 and BRCA2 mutations (gBRCAmut) account for ~1/3. Identification of BRCAwt HRD tumors likely to respond to a PARP inhibitor remains challenging. ARIEL2 prospectively tested a novel next generation sequencing-based HRD assay and algorithm to predict rucaparib sensitivity by assessing tumor BRCA status and genome-wide loss of heterozygosity (LOH). Methods: ARIEL2 enrolled pts with platinum-sensitive, recurrent, high-grade serous or endometrioid OC. The primary objective was to evaluate clinical activity of 600 mg BID rucaparib in 3 pre-defined HRD subgroups: tumor BRCAmut, BRCAwt/LOHhigh and BRCAwt/LOHlow. Known gBRCAmut pt enrollment was limited. Tumor HRD status was assessed in pre-treatment biopsies and archival tumor. Response was assessed by RECIST and GCIG CA-125 criteria. Results: In 206 treated pts: median age=64 [range 31-86]; 64% ECOG=0; 96% high-grade serous; 46% with ≥2 prior regimens. Treatment-related AEs in ≥15% of pts were GI symptoms (nausea, dysgeusia, ↓ appetite, vomiting, constipation, diarrhea), fatigue, ↓ Hgb, and transient ALT/AST elevations with no other evidence of liver dysfunction. Efficacy data for 135 pts indicate RECIST + CA125 ORRs of 69%, 39%, and 11% in BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow pts, respectively (Table 1, p<0.0001, Cochran-Armitage trend test). Responses occurred in both gBRCAmut (14/19, 74%) and somatic BRCAmut (10/16, 63%) tumors. Only 15/161 (9%) BRCAwt tumors had a loss-of-function mutation or homozygous deletion in a HR gene; 4/15 (27%) alterations were in RAD51C. All 4 tumors were LOHhighand responded to rucaparib, suggesting a potential HRD mechanism. Importantly, matched archival and screening tumor analysis revealed an increase in genomic LOH over time in a subset of tumors. Conclusions: ARIEL2 data indicate a tumor HRD assay and algorithm combining BRCA analysis and genomic LOH identifies OC pts likely to respond to rucaparib. Clinical trial information: NCT01891344.Response by HRD status. HRD Subgroup # of Pts RECIST, % RECIST & CA-125, % BRCAmut 35 66 69 BRCAwt/LOHhigh 56 32 39 BRCAwt/LOHlow 44 11 11
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