Abstract LB-A12: Results from the phase 3 study ARIEL3: mutations in non-<i>BRCA</i> homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma
Bibliographic record
Abstract
Abstract Background: High-grade ovarian carcinomas (HGOC) with a mutation in BRCA1/2 or other core homologous recombination repair (HRR) genes are sensitive to treatment with the PARP inhibitor rucaparib. To study whether HRR gene mutations confer sensitivity to rucaparib in the maintenance setting, we performed next-generation sequencing (NGS) on carcinomas from a double-blind, placebo-controlled, phase 3 study of rucaparib in patients with HGOC following response to platinum-based chemotherapy (ARIEL3, NCT01968213). Materials and Methods: Archival ovarian carcinoma specimens were required for all 564 patients who were randomized in ARIEL3 and were sequenced using Foundation Medicine’s NGS-based assay to identify deleterious mutations in a prespecified list of HRR genes (BRCA1/2 and 28 non-BRCA HRR genes, including ATM, BARD1, BRIP1, CHEK2, RAD51C, RAD51D, RAD54L, and FANC family genes). Patients were randomized 2:1 to receive oral rucaparib 600 mg twice daily or placebo. The randomization was stratified by HRR gene mutation status (BRCA, non-BRCA HRR, no mutation in BRCA or HRR gene), progression-free interval of the penultimate platinum-based regimen, and best response to most recent platinum regimen. The primary endpoint for ARIEL3 was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Exploratory analysis of confirmed response was conducted for the subgroup of patients with measurable disease at study entry. Results: Deleterious mutations in non-BRCA HRR genes were detected in ovarian carcinoma specimens from 7.6% (43/564) of randomized patients. In these patients, PFS was significantly longer with rucaparib than with placebo (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.50; P=0.0005), with a median PFS of 11.1 mo and 5.5 mo, respectively. This HR is similar to that found in women with carcinomas containing a BRCA1/2 mutation (0.23; 95% CI, 0.16-0.34). The most commonly found non-BRCA HRR gene mutations among the 28 patients in the rucaparib arm were RAD51C (n=6) and RAD51D (n=4) and among the 15 patients in the placebo arm were BRIP1 (n=5) and RAD51C (n=2). A diverse set of mutation types were detected, including frameshift insertions/deletions, homozygous deletions, and nonsense and splice site mutations. All 10 RAD51C/D mutations were homozygous within the carcinomas, indicating biallelic loss. Additionally, all RAD51C/D-mutant carcinomas exhibited high genomic loss of heterozygosity, which is a type of genomic scar characteristic of HRR deficiency. At the visit cutoff date (15 April 2017), only 2 of the 10 RAD51C/D cases in the rucaparib arm had disease progression; 7 had a PFS duration of at least 1 y (median PFS, 16.4 mo; range 5.4+ to 30.4+ mo). Three of the RAD51C/D cases were in the subgroup of patients who had measurable disease at baseline, and all achieved a confirmed response (1 complete response and 2 partial responses). In comparison, the 3 RAD51C/D cases in the placebo arm had a median PFS of 5.4 mo (range, 3.9 to 5.5 mo). Conclusions: Patients with recurrent platinum-sensitive HGOC harboring a deleterious mutation in non-BRCA HRR genes (including RAD51C/D) had significantly longer PFS with rucaparib maintenance treatment than with placebo. Citation Format: David M. O'Malley, Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Iain A. McNeish, Elizabeth M. Swisher, Clare L. Scott, Gottfried E. Konecny, Heidi Giordano, Terri Cameron, Lara Maloney, Sandra Goble, James Sun, Thomas C. Harding, Kevin K. Lin, Jonathan A. Ledermann. Results from the phase 3 study ARIEL3: mutations in non-BRCA homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A12.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".