Lynparza (olaparib)

We systematically deconstructed the molecular subtypes of primary GISTs by integrated genomic and transcriptomic analysis. A specific GIST subtype characterized by poor treatment responses and prognosis, marked by the activation of aerobic metabolism and HRD features, may be a potential candidate for PARP inhibitors.

These findings suggest that combining tumor-sensitizing therapies with selective T-cell activation may represent a broader strategy to overcome immune exclusion in solid tumors. Together, these results provide mechanistic rationale for clinical evaluation of olaparib in combination with STAR0602 in patients with mCRPC who have progressed on androgen deprivation therapy.

ATP significantly alleviates olaparib-induced hepatotoxicity by attenuating oxidative stress, suppressing inflammatory responses, restoring antioxidant defense mechanisms and significantly replenishing depleted hepatic ATP levels. These findings suggest that ATP may represent a promising therapeutic strategy for preventing PARP inhibitor-associated drug-induced liver injury.

Furthermore, G73-mediated RAD51 degradation synergizes with the PARP inhibitor olaparib, inducing synthetic lethality and re-sensitizing olaparib-resistant cancers to PARP inhibition. This fully small-molecule-based strategy presents a compelling strategy to overcome resistance to PARP inhibitors, expanding their therapeutic potential beyond patients with HR-deficient tumors.

Although PARP inhibitor olaparib has been approved for metastatic CRPC patients bearing BRCA1/2 mutations, its application is confined to this specific patient subpopulation...Their synergistic effect was confirmed in ex vivo explants from human PCa specimens. Our findings demonstrated CDK9 as a master regulator of BRCAness and proposed targeting CDK9 as a potential strategy to sensitize CRPC patients without BRCA1/2 mutations to PARP inhibition.

Screening identified elimusertib (ATR inhibitor), proteasome inhibitors (ixazomib, carfilzomib), and dinaciclib (Cdk1/2/5/9 inhibitor) as synergistic agents with olaparib. These results demonstrate that elimusertib is a very potent ATR inhibitor for combination with olaparib and provide mechanistic insight into this synergy through replication fork interference. Because this synergy spanned both HRD and HRP organoids, these findings support further preclinical optimization and well-designed clinical evaluation of the olaparib-elimusertib combination in HGSC, with attention to dose-finding, hematologic safety, and patient selection.

These data demonstrate that targeting HRD yields promising outcomes in stage III, HER2-negative, HRD breast cancer and that intensified chemotherapy with autologous stem cell rescue does not provide any advantage over state-of-the-art chemotherapy plus olaparib.

P=N/A, N=75, Not yet recruiting, AstraZeneca

Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles.

Yet, metastasis formation presented with a mixed outcome in mice with DPP9-deficient tumors. In summary, reduced DPP9 levels enhanced primary tumor growth but sensitized triple-negative breast tumors to a combination of irradiation and Olaparib.

After cytoreductive surgery, she received postoperative HIPEC followed by adjuvant chemotherapy nab-paclitaxel and carboplatin, then sequential maintenance therapy with bevacizumab followed by olaparib based on homologous recombination deficiency (HRD) positivity. The patient remained progression-free with good performance status at 24 months of follow-up. This hypothesis-generating case suggests that for selected patients with OCS, a multimodal approach incorporating aggressive cytoreductive surgery, postoperative HIPEC, and HRD-guided sequential maintenance therapy may warrant further investigation.

Here we focus on three mechanistically complementary drugs-sorafenib, cisplatin, and olaparib-because each converges, directly or indirectly, on the redox/LPO axis (system xc-/GPX4 modulation, mitochondrial ROS, and SLC7A11 regulation, respectively), modulating tumor cell responses by inducing PUFA oxidation, mitochondrial dysfunction, and membrane damage. Among regulated cell death modalities, ferroptosis is strictly dependent on lipid peroxidation, whereas apoptosis, necrosis, necroptosis, pyroptosis, and immunogenic cell death can be modulated by lipid peroxidation but do not universally require it. Collectively, these mechanisms indicate that lipid peroxidation is an important-though not exclusive-determinant of anticancer drug sensitivity and resistance, and that its dual, context-dependent role (tumor-suppressive at high flux, tumor-promoting under chronic, sub-lethal exposure) must be considered when designing LPO-based therapeutic strategies.