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Hall 1
WELCOME (ID 793)
COMPREHENSIVE GENOMIC PROFILING OF LOW-GRADE SEROUS CANCERS AND ASSOCIATED CLINICAL OUTCOMES (ID 436)
- Beryl Manning-Geist (United States of America)
- Sushmita Gordhandas (United States of America)
- Arnaud F. Da Cruz Paula (United States of America)
- Britta Weigelt (United States of America)
- Ying Liu (United States of America)
- Herman Chui (United States of America)
- Rachel N. Grisham (United States of America)
Abstract
Objectives
The genetic landscape of low-grade serous carcinomas (LGSCs) is poorly described. We sought to characterize somatic mutational profiles of LGSCs and correlate findings with clinical outcomes.
Methods
Patients with LGSC (n=123) consented to an IRB-approved protocol of tumor-normal massively parallel sequencing that included 341-505 cancer-related genes. Clinical outcomes and frequency of genetic alterations, including somatic mutations and copy number alterations, were assessed and compared using the Fisher exact test.
Results
Among 123 sequenced tumors, median tumor mutational burden was low (1.8 mutations/Mb). Recurrent alterations included those affecting KRAS (32%), NRAS (11%), BRAF (10%), CDKN2A (9%), and ERBB2 (5%) (see figure). KRAS mutations were more frequent in patients ≥50 years of age at LGSC diagnosis than in patients <50 years of age (41% vs 23%, respectively; p<0.05); in those with platinum-sensitive vs. platinum-resistant disease (41% vs 19%, respectively; p=0.05); and in patients surviving ≥5 years compared with <5 years (39% vs 11%, respectively; p<0.05). BRAF mutations were more frequent in platinum-resistant compared with platinum-sensitive disease (19% vs 3%, respectively; p<0.05). CDKN2A alterations were associated with risk of recurrence, while none of the patients with CDKN2A-wildtype tumors developed recurrence (13% vs 0%, respectively; p<0.05). Recurrence was also associated with higher median fraction of genome altered (p<0.05).
Conclusions
The presence of KRAS mutations in LGSC may be associated with less aggressive phenotypes and older age at diagnosis. CDKN2A and BRAF alterations may be associated with recurrence and platinum resistance, respectively.
CLINICAL AND MOLECULAR CHARACTERISTICS OF ARIEL3 PATIENTS WHO DERIVED EXCEPTIONAL BENEFIT FROM RUCAPARIB MAINTENANCE TREATMENT FOR HIGH-GRADE OVARIAN CANCER (HGOC) (ID 233)
- Robert L. Coleman (United States of America)
- Amit M. Oza (Canada)
- Domenica Lorusso (Italy)
- Carol Aghajanian (United States of America)
- Ana Oaknin (Spain)
- Andrew Dean (Australia)
- Nicoletta Colombo (Italy)
- Johanne I. Weberpals (Canada)
- Andrew Clamp (United Kingdom)
- Giovanni Scambia (Italy)
- Alexandra Leary (France)
- Robert W. Holloway (United States of America)
- Margarita Amenedo Gancedo (Spain)
- Peter Fong (New Zealand)
- Jeffrey C. Goh (Australia)
- David O'Malley (United States of America)
- Lara Maloney (United States of America)
- Sandra Goble (United States of America)
- Tanya Kwan (United States of America)
- Jonathan A. Ledermann (United Kingdom)
Abstract
Objectives
ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of characteristics associated with exceptional benefit from rucaparib.
Methods
Patients were randomized 2:1 to rucaparib 600 mg BID or placebo. As of 31 Dec 2019 (data cutoff), 33/375 (9%) and 1/189 (0.5%) patients were still ongoing and receiving rucaparib or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between patients who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term subgroup) within each treatment arm.
Results
Of 564 patients, 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm showed exceptional benefit. Within the rucaparib arm, exceptional benefit patients had more favorable clinical prognostic factors at baseline versus the short-term subgroup (Table). Although BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 33/79 (42%) of these patients were BRCA wild type. Patterns of enrichment varied among other biomarkers. Overall trends were similar in the placebo arm.
Conclusions
Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest rucaparib can deliver exceptional benefit to a diverse set of patients with HGOC.
EFFICACY AND SAFETY OF NIRAPARIB MAINTENANCE TREATMENT IN PLATINUM-SENSITIVE RECURRENT OVARIAN CANCER AFTER SHORTER OR LONGER CHEMOTHERAPY: A POST HOC SUBGROUP ANALYSIS (ID 15)
- Yunong Gao (China)
- Xiaohua Wu (China)
- Jianqing Zhu (China)
- Rutie Yin (China)
- Jiaxin Yang (China)
- Jihong Liu (China)
- Jing Wang (China)
- Lingying Wu (China)
- Ziling Liu (China)
- Danbo Wang (China)
- Ge Lou (China)
- Hongying Yang (China)
- Qi Zhou (China)
- Beihua Kong (China)
- Yi Huang (China)
- Lipai Chen (China)
- Guiling Li (China)
- Ruifang An (China)
- Tao Tan (China)
- Juan Dong (China)
Abstract
Objectives
Traditionally ≥6 cycles of platinum-containing chemotherapy (Pt-chemo) are recommended for platinum-sensitive recurrent ovarian cancer (PSROC). PARP inhibitor maintenance treatment (MT) can be initiated upon clinical complete/partial response (CR/PR) after ≥4 cycles of chemotherapy. Shorter chemotherapy may improve patient experience without compromising efficacy. This study aims to compare the efficacy and safety of niraparib to placebo as MT administered after ≤4 or >4 cycles of Pt-chemo.
Methods
This is a post hoc analysis of the published NORA phase III study (NCT03705156). Adults with PSROC and CR/PR to most recent Pt-chemo were randomized 2:1 to niraparib or placebo. Primary endpoint was PFS by BICR. Subgroups comprised patients with ≤4 or >4 cycles of most recent Pt-chemo.
Results
Table 1 summarizes key baseline characteristics which were overall balanced between groups. Median (95% CI) PFS was 18.37 months (8.54–not estimable [NE], ≤4-cycle/niraparib) versus 3.88 months (3.68–7.43, ≤4-cycle/placebo; HR=0.36 [p=0.0016]), and was 18.33 months (10.28–NE, >4-cycle/niraparib) versus 5.49 months (3.71–5.75, >4-cycle/placebo; HR=0.33 [p<0.0001]) (Figure 1). Overall safety profiles were comparable between ≤4-cycle/niraparib and >4-cycle/niraparib, with similar percentages of patients experiencing neutrophil count decrease (60.4%; 58.1%), anemia (50.0%; 55.0%), and platelet count decrease (45.8%; 58.1%). Composition of grade ≥3 TEAEs was consistent with the overall NORA results.
Conclusions
Similar niraparib-versus-placebo PFS benefits were observed after ≤4-cycle or >4-cycle Pt-chemo in CR/PR patients. The efficacy and safety of niraparib MT after shorter Pt-chemo remain to be verified in larger samples.