HRD

The observed results could prompt further investigation.

30 achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, 30 exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound 30 with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting.

Our findings suggest that HRR-related genetic abnormalities might be predictive of TTF in platinum-based chemotherapy for PC.

We observed that OC clinical and pathological characteristics of these patients from Tunisia were similar to those of Caucasian patients. We identified frequent CNA in this population that need to be confirmed in other sets from Africa.

P3, N=174, Active, not recruiting, The Netherlands Cancer Institute | Trial primary completion date: Oct 2024 --> Jul 2025

They have been evaluated both alone and in combination with radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy and other new drugs in newly diagnosed or recurrent glioma...In conclusion, early phase studies have shown promising anti-tumour activity of PARPi that should be confirmed in larger prospective and randomised trials. In addition, the development of novel PARPi with improved blood brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored.

Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.

HRD genomic instability tests and multigene panel assessments serve as synergistic tools in EOC clinical settings, proving essential for identifying patients likely to benefit from PARPi therapy. These tools also enhance the detection of HRR and MMR gene variants, aiding in preventive care. Further investigations into the genetic profiles of HRD-negative tumors are crucial for advancing cancer risk management and developing novel therapeutic avenues.

We emphasize the importance of long-term follow-up and real-world data coming from international registries to define the efficacy and safety of stopping PARPi at relapse at a pre-specified time. To this point, biomarkers able to identify the patients who will experience long-term remission with PARPi maintenance or develop early resistance are urgently needed to guide treatment decision and duration.

Pre-emptive treatment with antiemetics are required to manage early-phase NINV during niraparib maintenance therapy in patients with risk factors. Additional larger studies are needed to confirm these findings and to develop optimal preventive strategies for NINV.

This study provides insights into the effect of NACT on the tumor molecular landscape. While BRCA1/2 and HRD status remained stable, an increase in TIL proportion and changes in the mutational profiles were observed post-treatment.

We provide a personalized oncological approach to potentially improve the treatment of sarcoma patients. We encourage the evaluation of gene expression signatures to enhance the identification of patients who might benefit from DDR-based therapies.

Our preliminary results indicate excellent concordance using Illumina 500+HRD kit with DRAGEN pipeline with previous test results. The concordance appears slightly lower using NxClinical, however, not statistically significant in this small sample set. Of particular interest, our findings suggest that, to reduce the testing costs, the standard TSO500 panel without the additional HRD probe pool, followed by analysis with NxClinical software, may serve as a suitable initial screen.

The AVENIO CGP Assay demonstrated high agreement with 2 established CGP tests, F1CDx and PGDx, in variant reporting, and closely aligned with F1CDx in HRDsig analysis across various tissue types. These results highlight the assay's reliability and demonstrate its utility in translational research.

The analytical validation results demonstrate the high analytical concordance compared to an independent HRD biomarker, low false positive rate, high reproducibility, and robustness to interfering substances of HRDsig calling.

We developed a novel method to determine genomic instability for characterizing the consequences of HRD using OCA Plus, which was developed using CGP of cancer FFPE samples to aid research into precision oncology. By combining genomic instability assessment with DNA repair pathway analysis such as mutations in BRCA1/2 and other genes in HRR pathway, OCA Plus will support research into the mechanisms underlying HRD.

NGS, with its capacity for comprehensive genomic analysis, excels in detecting diverse genetic alterations, offering superior resolution compared to CMA. This study supports the use of the PGDx elio tissue complete panel as a compelling alternative to CMA, showcasing its accuracy in assessing the HRD phenotype. The observed high concordance rate further enhances its value in the clinical diagnostic setting.

Our AMP chemistry-based targeted panel and analysis method enable highly concordant HRD classifications with fewer reads than WGS and other NGS methods, and without requiring paired tumor-normal data or a panel of normals. The HRD module can be combined with any other VariantPlex panel content for simultaneous measurement of HRD, other genomic signatures, and variant calling.

The new Illumina TSO500 v2 assay features a simplified workflow with improved performance and reduced turnaround time. Driven by innovations in assay design and bioinformatics, these capabilities can accelerate the democratization of actionable cancer biomarker detection, from small variants and copy number variants to RNA variants and complex biomarker outputs like TMB, MSI, and GIS scores.

OCA Plus supports comprehensive detection of relevant copy number alterations in cancer FFPE samples. Combined with small variant profiling, detection of MSI, TMB, and HRD, OCA Plus facilitates comprehensive analysis of DNA structural changes in cancer that are relevant to precision oncology research.

This prototype AMP-based next-generation sequencing method demonstrates a novel approach to quantification of GI, with a relatively small genomic footprint required to do so. The power of this method stems from its ability to monitor HRD at its source. By directly assigning DSBr events to their respective repair pathways, we can garner information about the DSBr pathways that are active in a tumor sample.

As evidence for multi-biomarker and complex genomic signatures grows in precision oncology, molecular pathology labs must evolve their sequencing capabilities with the latest innovation. The new AVENIO Tumor Tissue CGP Kit V2 demonstrates high performance and incorporates faster workflows, higher throughput, improved bioinformatics algorithms, and successful incorporation of a new HRD signature.

The FDA (US Food and Drug Administration) has approved olaparib as a front-line maintenance therapy in combination with bevacizumab for patients with newly diagnosed advanced ovarian, fallopian tube, or primary peritoneal cancer with HRD+ status. We have demonstrated that the TSO500-HRD assay can accurately determine HRD status in ovarian tumors.

The new TSO500 v2 assay with automated library prep on the NGS STAR MOA liquid handler was demonstrated to perform comparably to manual library prep and offers a high-throughput solution to enable comprehensive genomic profiling with a faster, more flexible workflow and easier-to-use reagent kit.

The TruSight Oncology 500 comprehensive solid tumor next-generation sequencing panel with HRD assay demonstrated a high degree of sensitivity and specificity for deployment in a clinical setting.

The new TSO500 v2 assay with automated library prep on the Biomek i7 workstation was demonstrated to perform comparably to manual library prep and offers a high-throughput solution to enable comprehensive genomic profiling with a faster, more flexible workflow and easier-to-use reagent kit.

TE-WGS enriches the genomic landscape accessible to clinicians, enhancing personalized treatment strategies in precision oncology through comprehensive and actionable genomic profiling.

Eight (16%) patients had dose adjustment, but none discontinued olaparib treatment due to AEs. We provide the first evidence that mono-olaparib could be a safe and effective maintenance treatment option for patients newly diagnosed with HRD-positive/BRCA wild-type ovarian cancer.

Furthermore, we have summarized recent studies on the combination of PARP inhibitors with a range of medications and discussed their clinical efficacy. The objective of this review is to enhance the comprehensiveness of information pertaining to this topic.

P2, N=104, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

The entire study population experienced long-term survival, with median OS well over five years. IACT compared to CDCT did not improve outcome in patients with OMBC harboring study-defined HRD. The optimal therapy for patients with OMBC requires further study.

We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker.

Furthermore, we derived a recurrence predictive index capable of predicting late recurrence, specifically in luminal subtypes, which plays a crucial role in guiding decisions on treatment durations for YBC patients. These findings improve the stratification and clinical implications for patients with YBC by contributing to the optimal adjuvant treatment and duration for favorable clinical outcomes.

The 100-gene expression signature identified in this study may serve as a valuable predictive biomarker for PARP inhibitor sensitivity in gastric cancer.

This study highlights the associations between HRD scores, clinical characteristics, and genomic mutations in ESCC, suggesting HRD as a potential prognostic biomarker. HRD assessment may aid in patient stratification and personalized treatment strategies, warranting further investigation to validate the therapeutic implications of HRD scores in ESCC.

In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed.

P1, N=216, Recruiting, IDEAYA Biosciences | N=68 --> 216 | Trial completion date: Sep 2025 --> May 2027 | Trial primary completion date: Jun 2025 --> Oct 2026

P=N/A, N=799, Active, not recruiting, University of Washington | Trial completion date: Aug 2024 --> Aug 2025

Adjuvant mFFX is effective and tolerable in resected PDAC in a non-trial setting, including for patients >70 years.

Here, we detailed the role of PARP-1 as a therapeutic target in CRC and studied the efficacy of novel PARPi compounds in wildtype (WT) and DNA repair-deficient CRC cell lines together with the chemotherapeutics irinotecan (IT), 5-fluorouracil (5-FU), and oxaliplatin (OXA). Finally, we provided evidence that all PARPi (olaparib > veliparib > X17613 > X17618) synergize with chemotherapeutic drugs (IT > OXA) in a BRCA2-dependent manner in CRC cells, whereas ATR deficiency had only a minor impact. Collectively, our study identified novel lead structures with potent PARP-1 inhibitory activity in CRC cells but low cytotoxicity due to the lack of PARP-1 trapping, which synergized with IT in homologous recombination deficiency.

Key drivers for selecting advanced ovarian cancer maintenance treatments include tumor mutational status as a key biomarker and clinician perception of the risk for early disease progression.

This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.