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e17599 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in cells with homologous recombination deficiency (HRD). PARPi treatment revolutionized management of patients with cancer, particularly in types where HRD is common, such as ovarian and breast cancer. However, challenges in the implementation of available methods currently limit adoption of HRD testing in the clinics. Here we present the analytical performance evaluation of the Genomic Integrity Index (GII) (SOPHiA GENETICs SA). Methods: GII is a deep-learning based solution for identification of HRD positive tumors from low-pass whole genome sequencing (lpWGS) data (X1 fold coverage). The analytical performance of the GII was evaluated as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement with the HRD status determined by Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.; US FDA-approved). We generated whole genome sequencing libraries for DNA extracted from 139 ovarian cancer Formalin-Fixed Paraffin- Embedded samples, in 4 independent clinical laboratories. We sequenced to the equivalent of 1X coverage (̃10 million reads, 150 base paired end reads, Illumina) and performed HRD classification data using GII using manufacturer’s recommended thresholds. Results: The GII demonstrated high analytical concordance with Myriad myChoice CDx with 91.7% PPA, 95.5% NPA and 94.5% OPA (Table). The HRD status obtained by GII from a subset of positive and negative samples was 100% reproducible (n = 4) between runs. Conclusions: The HRD status obtained by GII is highly concordant with that obtained from standard method, supporting that GII allows accurate and reproducible detection of HRD from lpWGS data. LpWGS is amongst the most cost-effective and easy to implement genome profiling methods, making it uniquely suited for clinical applications. [Table: see text]

TPS1116 Background: PARP inhibitors have documented clinical activity in patients with HER2 negative breast cancer (BC) and a germline pathogenic variant (PV) in BRCA1 or BRCA2. Defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI) have been associated with preclinical cellular sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested synergy between immune checkpoint blockade and PARP inhibitors. Indeed, tumors with deficiency in HRR have higher mutagenic potential and produce a larger number of neoantigens. Around 60% of BC with a germline PV in BRCA1/ 2 are ER+/HER2- tumors, and the ER-pathway remains a key target of their therapy. The combination of PARP inhibitors with endocrine therapy has shown to be superior to monotherapy. Methods: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab in ER+/HER2- metastatic or locally advanced BC with somatic or germline PV in BRCA1, BRCA2 or other genes implicated in the HRR pathway (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes ( AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor NGS. Further an amendment in May 2021, patients with only alterations in these other actionable genes can no longer be included. Patients must have received 1 prior line of endocrine therapy for their metastatic BC, including CDK4/6 inhibitor and maximum of 1 line of chemotherapy in the metastatic setting. Patients receive olaparib (twice daily at 300 mg), fulvestrant (2 intramuscular injections of 250 mg every 28 days) and durvalumab (1500 mg intravenous every 4 weeks). The primary objective is to evaluate the progression-free survival rate at 24 weeks. Secondary endpoints include safety, overall survival, objective response rate, in the overall population and in the germline BRCA mutated population. With an optimum two-stage Simon design, α = 2.5%, β = 5%, p0 (probability of inefficiency maximum) = 50%, p1 (probability of minimum efficiency) = 65%, it is necessary to include 158 patients. The strategy could be considered sufficiently effective if there are at least 87 patients without progression at 24 weeks. Given the lack of safety data from this association, a safety run-in phase including 6 patients has been completed without DLT. As of December 31, 2021, 266 patients have been screened of whom 102 have been treated. The first interim analysis occured in November 2021 after the inclusion of 64 evaluable patients. IDMC suggested that the trial continue as planned. Clinical trial information: NCT04053322.

5558Background: To investigate clinical factors predictive for prolonged progression-free survival (PFS) in ovarian cancer (OC) patients carrying BRCA mutations and receiving olaparib as a maintena...