Lynparza (olaparib)

P2, N=180, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | N=600 --> 180 | Unknown status --> Terminated; study design, change of standard of care, enrollment difficulties

Critically, this process is dependent on the tumor suppressors BRCA1 and BRCA2 and is associated with the BRCA2-dependent accumulation of RAD51 recombinase in chromatin. Our data identify nascent strand gaps that are induced by olaparib independently of replication fork reversal and/or PRIMPOL-mediated repriming and that are repaired by a BRCA2-dependent process that we propose is daughter-strand gap protection and/or repair occurring hundreds of kilobases behind DNA replication forks.

Four PARP inhibitors, olaparib, niraparib, rucaparib, are approved by the Food and Drug Administration (FDA) approved. Despite these advances, selective inhibitors for ARTs remain underexplored. Ongoing research focuses on overcoming PARP inhibitor resistance, improving biomarker-driven patient selection, and expanding therapeutic strategies that target ART-related pathways.

In the field of urological malignancies, the approval of olaparib for metastatic castration-resistant prostate cancer with BRCA1/2 mutations has led to the practical application of cancer genomic medicine in many cases. However, various challenges exist in its implementation and clinical utilization. This review outlines cancer genomic medicine in urological malignancies, focusing on the types and characteristics of genetic tests performed in clinical settings, as well as the accessibility of treatments based on their results.

However, the combination of SR-4835 with cisplatin or olaparib primarily exhibited an additive, not synergistic, effect. In summary, the present findings indicate that CDK12/13 inhibitor SR-4835 has potent anti-cancer effects accompanied by a BRCAness induction, but fails to achieve synergistic effects with cisplatin or olaparib in OC cells.

Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

P1, N=52, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2030 --> Dec 2026

P2/3, N=1000, Not yet recruiting, Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC.

Additionally, drug sensitivity prediction analysis demonstrated that MSTN expression was significantly associated with sensitivity to paclitaxel and VE-822, while TCF12 expression showed potential associations with sensitivity to cytarabine, olaparib, Wee1 inhibitor, paclitaxel, and VE-822. Immunofluorescence confirmed upregulated expression of MSTN and TCF12 in glioma tissues and their co-localization with macrophages. In conclusion, this study identified TAFCs as the central cells in the glioma microenvironment, with their signature genes MSTN and TCF12 representing candidate immunometabolic signatures associated with macrophage-mediated immunosuppression and metabolic reprogramming in glioma, suggesting their potential as biomarkers for patient stratification and as targets for immunometabolic therapies.

hMOB2 depletion sensitized A549 cells to olaparib and rucaparib, resulting in a marked reduction in long-term clonogenic survival. Sensitization required functional p53, as it was absent in p53-null cells but restored upon p53 re-expression. These findings suggest that hMOB2 contributes to PARP inhibitor responses in lung cancer cells and underscore the complexity of PARP inhibitor sensitivity beyond classical HR deficiency.

Furthermore, NXP800 antitumor properties were significantly augmented when NXP800 was coupled with the DNA-damaging agent doxorubicin or the PARP inhibitor olaparib. Our investigation indicates that NXP800 has significant antitumor activity and might represent a promising therapeutic agent for the treatment of human HCC.