veliparib (ABT-888)

P1, N=18, Active, not recruiting, National Cancer Institute (NCI) | N=48 --> 18 | Trial completion date: Jul 2024 --> Dec 2025

P2, N=333, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Mar 2025 | Trial primary completion date: Oct 2024 --> Mar 2025

Subsequently, we conducted drug sensitivity analysis and immune checkpoint analysis, revealing that the majority of drugs are more sensitive to low-risk patients, while ABT-888, AS601245, and CCT007093 may have greater potential clinical benefits for high-risk patients. Immune checkpoint analysis showed significant differences in the expression of ADORA2A, BTLA, CD276, CD27, CD28, CD40LG, CD48, and TNFRSF14 between high-risk and low-risk patient groups, suggesting their potential as therapeutic targets for LUAD..

While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX3CR1, suggesting a potential therapeutic opportunity.

UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies.

P2, N=74, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Sep 2024 | Trial primary completion date: Jun 2025 --> Sep 2024

P1, N=44, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Apr 2017 --> Sep 2024

Rapid central pathology review and molecular testing for eligibility was feasible. The protocol therapy including radiation, veliparib and temozolomide was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy.

P2, N=38, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

This trial found that adding veliparib to adjuvant temozolomide did not significantly extend OS in patients with newly diagnosed, MGMT-hypermethylated glioblastoma. ClinicalTrials.gov Identifier: NCT02152982.

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.

P1, N=81, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

Furthermore, the veliparib/2HG liposomes demonstrated enhanced anti-tumor activity in both PARPi-resistant BRCA mutant cancer and BRCA wildtype cancer by synergistically enhancing the defect in DNA repair. Moreover, combination of veliparib and 2HG via liposomal co-delivery also augmented the function of cytotoxic T cells by activating the STING pathway and downregulating PD-L1 expression via 2HG-induced hypermethylation.

P1/2, N=88, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2024 --> Aug 2025

P1, N=44, Active, not recruiting, National Cancer Institute (NCI) | Completed --> Active, not recruiting | Trial completion date: Apr 2017 --> Aug 2025

The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.

We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. Combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.

Molecular docking analysis revealed ELF4 might be targeted by drugs/compounds, including Veliparib (ABT-888), Motesanib (AMG 706), and EHT 1864. Genomic analysis revealed that, in LGG, in the low ELF4 expression subgroup, IDH1 demonstrated a higher mutation rate, and TP53 and ATRX Chromatin Remodeler (ATRX) displayed the lower mutation rates, than the high ELF4 expression group. Our research suggests that ELF4 may contribute to the prognostic assessment of glioma and personalized medicine.

P1, N=121, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Aug 2025

C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX)...Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors...Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Eight randomized controlled trials (RCTs) were included in the systematic review comprising 3,021 patients evaluated efficacy and safety of PARP inhibitors: Olaparib, niraparib and veliparib with combinations of bevacizumab, carboplatin, cisplatin, cediranib, cyclophosphamide and paclitaxel. Niraparib and veliparib were notably associated with grade 3 or higher anaemia, neutropenia, and thrombocytopenia, olaparib caused fatigue and gastrointestinal disturbances while bevacizumab and cediranib caused hypertension. This review suggested combined PARP inhibitor and chemotherapy significantly prolonged progression-free survival especially in patients with BRCA mutation compared to chemotherapy and the combined therapy is safe.

Furthermore, drug sensitivity analysis showed that AZD.2281, Axitinib, AUY922, ABT.888, and ATRA were effective in high-risk MM patients. Our research shows that MMrisk is a potential biomarker which is helpful to identify the molecular characteristics of AML immunology.

P1, N=15, Completed, Northwestern University | Active, not recruiting --> Completed

Moreover, a low-Macrosig score indicates increased sensitivity to AZD.2281, A.443654, ABT.263, ABT.888, AG.014699 and ATRA, while a high Macrosig score indicates increased sensitivity to AZD6482, AKT inhibitor VIII, AS601245, AZ628, AZD.0530 and AZD6244. A novel scoring system was constructed to guide more effective prognostic evaluation and tailoring therapeutic regimens for HCC patients.

The polymer nanoformulation manifested pH-sensitive behaviour as a greater release of compound 8 was observed at 6.2 pH as compared to 7.4 pH mimicking physiological settings. The aforementioned findings indicate that the acidic pH of the tumour microenvironment might stimulate the nanomedicine release which in turn can attenuate the off-target effects precedentially claimed to be associated with HDAC inhibitors.

Veliparib shows the lowest PARP-Trapping effect but could hardly to be the warhead of PROTACs because of the strong steric hindrance...Furthermore, QSAR study showed that to develop novel compounds with high PARP1 binding affinity and low PARP-Trapping, we can choose the skeleton with substituent R1H, R2 = piperiazine, and R3 with large tPSA. And, if we want to develop the compounds with high PARP1 binding affinity and high PARP-Trapping which can possibly improve the lethality against tumor cells, we can choose the skeleton with substituent R1F, R2 = 3-methy-piperiazine, and R3 with large tPSA.

P2, N=123, Active, not recruiting, National Cancer Institute (NCI)

P2, N=25, Active, not recruiting, National Cancer Institute (NCI) | N=60 --> 25 | Trial completion date: Jun 2023 --> Dec 2024

P1, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1, N=12, Active, not recruiting, National Cancer Institute (NCI)

P1, N=94, Active, not recruiting, National Cancer Institute (NCI)

P1, N=66, Active, not recruiting, National Cancer Institute (NCI)

No abstract available

P3, N=509, Completed, AbbVie | Active, not recruiting --> Completed

P2, N=107, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=71, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Jun 2025

P1/2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown therapeutic success for patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) deficiency.1,2 Preclinical data suggest that PARP inhibitors may have efficacy in a wider population if combined with androgen receptor inhibition.3,4 One phase 2 trial for late-stage mCRPC supports this notion, finding that olaparib added to abiraterone/prednisone improved radiographic progression-free survival (PFS) versus abiraterone/prednisone alone in a population that was not biomarker preselected.5 However, another trial with abiraterone and veliparib did not show benefit.6.

Final OS data indicate that the PFS improvement shown in the primary analysis did not translate into an OS benefit. The long survival times observed in both arms suggest that combination therapy with paclitaxel and carboplatin provides clinical benefit in the population of patients with BRCA1/2-mutated metastatic breast cancer.

The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olaparib, Rucaparib) and investigational (Talazoparib, Niraparib, Veliparib) PARPi in mCRPC patients. PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2.

In newly diagnosed BRCAm-OC patients, olaparib (HR: 0.33; 95% confidence interval [CI]: 0.25, 0.43) and other PARPis [niraparib (HR: 0.40; 95% CI: 0.29, 0.55), rucaparib (HR: 0.40; 95% CI: 0.21, 0.76) and veliparib (HR: 0.44; 95% CI: 0.28, 0.69)] had a statistically significant effect on PFS versus placebo. All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women. CRD42021288932.

P2, N=64, Active, not recruiting, Steven J Isakoff, MD, PhD