Lynparza (olaparib)

P2, N=23, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Nov 2026

Sapacitabine with olaparib produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of response in some patients suggest possible combinatorial benefit. Further exploration of olaparib with different sapacitabine schedules or substitution of a PARP1-selective inhibitor to potentially decrease hematological toxicity is warranted.

We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout...Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.

Afterwards, the cytostatic and cytotoxic responses of these models to three targeted anti-PARP therapies, Olaparib, Rucaparib and Niraparib, were analyzed, revealing their sensitivity. These results demonstrated that our liquid overlay-based technique provides both a large cell culture panel, whatever the tissue type or pathological level, and an automated drug screening process that could lead to highly predictive efficacy results.

P2, N=176, Recruiting, Fondazione Ricerca Traslazionale | Trial primary completion date: May 2024 --> May 2026 | Trial completion date: Apr 2025 --> May 2027

Notably, when combined with the PARP inhibitor olaparib, the aptamer triggers synthetic lethality (SL) in a dose-dependent manner, an effect that is also preserved in 3D spheroid models. Our study showcases an aptamer-based approach for selectively targeting protein interactions within DNA repair pathways, introducing a promising avenue for SL-based treatments applicable to a wide range of cancers.

P2, N=0, Withdrawn, Gustave Roussy, Cancer Campus, Grand Paris | N=36 --> 0 | Recruiting --> Withdrawn

Functional assays in both T47D and MCF7 cells demonstrated that co-expression of N4BP2L2 restored HR activity and reduced olaparib sensitivity in EXO1-overexpressing cells. These findings suggest EXO1 overexpression serves as a marker of functional HR deficiency and a potential predictor of PARP inhibitor response, highlighting the EXO1-N4BP2L2 axis as a promising biomarker and therapeutic target, especially for guiding PARP inhibitor use beyond BRCA-mutated tumors.

PARPi selection differed by HRD status, with niraparib favored in HR-proficient and olaparib in HRD-positive tumors. No additional profiling was required for PARPi therapy recommendation, and no incidental findings beyond the scope of HRD testing were detected. Molecular profiling with F1CDx proved to be a technically feasible, clinically impactful, and time-efficient assay, demonstrating its value in supporting molecular-guided PARPi therapy recommendations in the routine care of HGSOC patients.

Mechanistically, SLC7A5 upregulates ERBB2 transcription through ELK1, and ERBB2 competes with CUL3 to prevent ACLY degradation. These findings suggest that targeting SLC7A5 may reverse olaparib resistance, offering new strategies for combination therapies and improving clinical outcomes in ovarian cancer treatment.

It demonstrates that targeting these lesions can yield outcomes that meet or exceed the benchmarks set by the NAPOLI-1 trial (liposomal irinotecan plus 5-fluorouracil and leucovorin), with a median overall survival of 6.2 months and progression-free survival of 3.1 months. Objective response rates reach 33% with adagrasib in KRAS G12C PDAC, 22% with olaparib maintenance in germline BRCA1/2 cancers, and over 50% with RET or NTRK inhibitors with fusion alterations; pembrolizumab produces durable benefit in the 1-3% of tumours that are MSI-H/dMMR. Emerging data highlight NRG1 fusions (overall response rate 42% with zenocutuzumab), HER2 amplification, MTAP deletion with PRMT5 dependency and variant-specific (MRTX1133) or pan-RAS (daraxonrasib) inhibitors as the next frontier...Taken together, these advances represent a substantive therapeutic progress in PDAC over the past decades, even though they currently apply to a minority of patients. These findings underscore the necessity of comprehensive next-generation sequencing for every patient with advanced disease, enabling identification of rare, yet clinically meaningful, targets and moving PDAC management towards a precision-oncology paradigm.

Some of the most prominent examples are Olaparib (IC50 = 5 nM), Rucaparib (IC50 = 7 nM), and Talazoparib (IC50 = 1 nM), which were optimized with docking scores between -9.0 to -9.3 kcal/mol and validated by in vitro and in vivo assays, achieving 60-80% inhibition of tumor growth in BRCA-mutated models and achieving up to 21-month improvement in progression-free survival in clinical trials of BRCA-mutated breast and ovarian cancer patients. Employing computation and experimental verification in a hybrid strategy have brought next-generation inhibitors to the clinic with accelerated development, higher efficacy, and personalized treatment for breast cancer patients. Future approaches, including AI-aided generative models and multi-omics integration, have the promise to further refine inhibitor design, paving the way for precision oncology.