Lynparza (olaparib)

Mechanistically, 5i increases DNA damage by inhibiting SYK-mediated CtIP phosphorylation and shows synergy with the PARP inhibitor Olaparib. These findings establish 5i as a promising therapeutic candidate and demonstrate the potential of SYK inhibition as a strategy to overcome HR-mediated resistance in TNBC.

Molecular studies were performed in axitinib (VEGFR inhibitor)-treated human aortic endothelial cells, and vascular studies were undertaken in isolated intact vessels from mice...This was accompanied by increased p53 acetylation; these effects were mitigated by olaparib or the SIRT1 activator SRT1720...In conclusion, inhibition of VEGFR signalling induces oxidative stress and PARP activation, leading to SIRT1 downregulation, endothelial dysfunction and vascular inflammation. Targeting PARP activation or enhancing SIRT1 activity might represent promising strategies to mitigate VEGF inhibitor-induced vascular complications.

Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model.

These TNBC cells were significantly more sensitive to cisplatin than wild-type TNBC cells, consistent with our clinical data. In conclusion, RAD51D-deficient tumors were shown to have a phenotype similar to that of BRCA1-deficient tumors, and further investigation of responses to DNA-damaging agents, particularly platinum-based chemotherapy, is warranted.

P2, N=96, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed

P2, N=120, Not yet recruiting, Shandong University

P1, N=159, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2028

In vitro, JPI-547 and olaparib more effectively reduced cell survival in PTEN-deficient cells, and combined treatment with olaparib and the TNKS inhibitor XAV-939 induced synergistic cytotoxicity with elevated DNA double-strand breaks. PTEN knockdown further showed enhanced vulnerability to combined targeting. These findings show that JPI-547 enhances antitumor efficacy in PTEN-deficient EC by disrupting DNA repair pathways and Wnt signalling, supporting dual PARP/TNKS inhibition as a potential therapeutic strategy and providing a rationale for further clinical evaluation.

Since the initial US Food Administration approval of olaparib in 2014, PARP inhibitors have shown efficacy across ovarian, breast, and prostate cancers, although differences in trial design and biomarker strategies have resulted in tumor-specific indications...Ongoing studies are evaluating rational combinations targeting complementary DNA damage response pathways (ATR/CHK1/WEE1, PI3K/AKT) and integrating immunotherapy or hormonal agents to extend benefit. Moving forward, harmonizing HRD testing across tumor types, accounting for germline, somatic, and liquid biopsy-derived alterations, and refining patient selection will be essential to maximize therapeutic efficacy and safely expand PARP inhibitor use beyond canonical BRCA-mutated cancers.

Our study establishes a pathogenic axis through which the clinically aggressive p53 DNA contact mutations drive genomic instability by dislodging BRCA2 from chromatin and disrupting R-loop homeostasis. These findings suggest a potential therapeutic avenue for treating cancers harboring high-risk p53 DNA contact mutations.

High-level evidence, including prospective interventional studies, supports exposure-guided dosing for imatinib and sunitinib, demonstrating improved molecular or clinical outcomes when predefined trough concentration targets are achieved. For alectinib, cabozantinib, trametinib, and lenvatinib, consistent exposure-response or exposure-toxicity relationships and pragmatic concentration thresholds support selective implementation, although randomized validation remains limited. For agents such as osimertinib, brigatinib, olaparib, and niraparib, monitoring appears most clinically relevant in toxicity-driven scenarios rather than for efficacy optimization. In contrast, lorlatinib currently lacks a clearly defined therapeutic window, limiting routine applicability...In conclusion, therapeutic drug monitoring and model-informed precision dosing are ready for selective clinical adoption in a subset of oral targeted therapies. Future prospective trials integrating pharmacometric tools with patient-centered outcomes are required to refine exposure targets and expand evidence-based implementation.

P2, N=60, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting