PURPOSE ATHENA (ClinicalTrials.gov identifier: NCT03522246 ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo. METHODS Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

Exosomes are endosome-derived membrane vesicles that contain proteins, lipids, and nucleic acids. The exosomal transcriptome mediates intercellular communication, and represents an understudied reservoir of novel biomarkers for human diseases. Next-generation sequencing enables complex quantitative characterization of exosomal RNAs from diverse sources. However, detailed protocols describing exosome purification for preparation of exosomal RNA-sequence (RNA-Seq) libraries are lacking. Here we compared methods for isolation of exosomes and extraction of exosomal RNA from human cell-free serum, as well as strategies for attaining equal representation of samples within pooled RNA-Seq libraries. We compared commercial precipitation with ultracentrifugation for exosome purification and confirmed the presence of exosomes via both transmission electron microscopy and immunoblotting. Exosomal RNA extraction was compared using four different RNA purification methods. We determined the minimal starting volume of serum required for exosome preparation and showed that high quality exosomal RNA can be isolated from sera stored for over a decade. Finally, RNA-Seq libraries were successfully prepared with exosomal RNAs extracted from human cell-free serum, cataloguing both coding and non-coding exosomal transcripts. This method provides researchers with strategic options to prepare RNA-Seq libraries and compare RNA-Seq data quantitatively from minimal volumes of fresh and archival human cell-free serum for disease biomarker discovery.

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6050 Background: Niraparib is approved at a fixed starting dose (FSD) of 300 mg QD for maintenance treatment of patients (pts) with recurrent ovarian cancer (OC) achieving a complete or partial response to platinum-based chemotherapy based in the ENGOT-OV16/NOVA study. A post-hoc analysis of NOVA showed baseline bodyweight (BW) and platelet count (PC) were predictive for hematologic toxicities and dose reductions. Following this analysis, the PRIMA/ENGOT-OV26/GOG-3012 study was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen. Methods: This double-blind, placebo-controlled, phase III study randomized 733 pts with newly diagnosed advanced OC with a complete or partial response to first-line (1L) platinum-based chemotherapy. The protocol was amended to change the dose from 300 mg FSD for all patients to an ISD regimen: 200 mg QD in pts with BW <77 kg and/or PC <150,000/µL or 300 mg QD in pts with BW ≥77 kg and PC ≥150,000/µL. Exposure, efficacy, and safety data were compared between patients treated with FSD vs ISD. Results: Efficacy in the ISD subgroup was comparable to the FSD subgroup relative to placebo (Table). An interaction test showed no treatment difference between ISD and FSD at the pre-specified 0.10 significance level ( p=0.30). Medians for dose intensity and relative dose intensity in pts who received niraparib were similar. The overall safety profile among pts in the niraparib arm (n=484), including grade ≥3 hematologic toxicities, improved with the ISD. Conclusions: The ISD in the 1L maintenance setting provides comparable efficacy to the FSD while reducing the risk of hematologic toxicities. No new safety signals were identified. Clinical trial information: NCT02655016. [Table: see text]