veliparib (ABT-888)

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

PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.

P1/2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Phase classification: P2 --> P1/2

Anemia and neutropenia should be well concerned. The veliparib-containing regimen was efficacious in treating advanced/metastatic breast cancer with a controllable safety factor.

We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone and in combination with was sufficient to significantly decrease tumor cell viability and self-renewal as measured by clonogenic survival assays (p < 0.01). 24 hours following these targeted treatments, 2 Gy of radiation was administered which resulted in a greater degree of decreased cell viability and self-renewal (p < 0.01), as well as in increased cell death. Together, this data suggests that inhibition of Smo, Gli1, and PARP1 either alone as single agents, or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.

P2; Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

5-FU+ABT-888 combination enhanced CRC-CSCs death by increasing DNA damage accumulation and simultaneously inhibiting the MMR pathway in MMR-proficient cells. But this study does not discuss whether the combination treatment will increase the sensitivity of MMR-deficient CSCs, for which further research will be performed in the future.

P3, N=1140, Terminated, AbbVie | Trial completion date: Oct 2026 --> Oct 2023 | Active, not recruiting --> Terminated; Business decision not related to patient safety

High-risk group of patients was more susceptible to A.443654, A.770041, ABT.888, AMG.706, and AZ628. Quantitative real-time polymerase chain reaction (qRT-PCR) exhibited that the expression levels of LINC01507, AC093278.2 were very high in all five ccRCC cell lines, AC084876.1 was upregulated in all ccRCC cell lines except 786-O, and the levels of AL118508.1 and DUXAP8 were upregulated in the Caki-1 cell line. This risk model may be promising for the clinical prediction of prognosis and immunotherapeutic responses in patients with ccRCC.

P1, N=81, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2023 --> Oct 2024

Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.

P2, N=363, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Sep 2023

No abstract available

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

We present a unique resource for examining radiosensitizing drug properties in 3D cultures. The observed radiosensitization patterns strongly argue for the use of larger panels of clinically relevant tumor models rather than a few non-representative cell lines. Our data highlight the urgent need for predictive biomarkers to guide IR/drug combinations, even for some DDR inhibitors.

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

Our data revealed that different PARPis were similarly effective in terms of PFS and OS. Moreover, we found that PARPi and platinum therapy were comparable in terms of PSA50 response rate and OS, highlighting that platinum is a valid treatment option for BRCA-positive mCRPC patients. However, prospective interventional studies comparing these agents are essential to provide a higher level of evidence.

Only a small number of studies have found veliparib to be effective, in terms of improved OS, PFS, and ORR, while the majority of studies found no benefit for veliparib over standard treatment.

PARP inhibitors are beneficial to the survival of patients with advanced ovarian cancer. The olaparibTR is the most effective for BRCAm patients, whereas olaparibANDAI and niraparibANDAI are preferable for non-BRCAm patients. Other: More high-quality studies are desired to investigate the efficacy and safety of PARP inhibitors in patients with other genetic performances.

Neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.

PARP inhibitors, of particular interest for clinical translation in this space, demonstrated relatively broad radiosensitization for talazoparib (62%) and olaparib (44%) but less so for veliparib (28%), which correlated with differential PARP trapping potentials. We present a unique resource for examining radiosensitizing drug properties in 3D cultures. The observed radiosensitization patterns strongly argue for the use of larger panels of clinically relevant tumor models rather than a few non-representative cell lines. Our data highlight the urgent need for predictive biomarkers to guide IR/drug combinations, even for some DDR inhibitors.

"pRRophetic" package screened five potential small molecule drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706). Finally, polymerase chain reaction (PCR) showed the expression of YTHN6-Methyladenosine RNA Binding Protein 1&lsqb;YTHDF1], TRNA Methyltransferase 61B &lsqb;TRMT61B], TRNA Methyltransferase 10C &lsqb;TRMT10C] and AlkB Homolog 1&lsqb;ALKBH1] in ccRCC cell lines. To sum up, the prognosis risk model we created not only has good predictive value, but also can provide guidance for accurately predicting the prognosis of ccRCC.

A novel scoring system based on macrophage subclusters was constructed, thereby guiding more effective prognostic evaluation and tailored potential drug agents strategies of HCC patients.

P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

Future PARPi combinations should focus on agents with nonoverlapping toxicities to improve tolerability. The treatment combination showed limited efficacy with prolonged stable disease observed in multiple heavily pretreated patients, but no objective responses were seen.

Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib, niraparib, veliparib, and rucaparib has been proven in a number of clinical trials. Additionally, in the subset data of the PARP inhibitor maintenance trials, there was a difference in HRD prevalence by race as higher HRD prevalence in Japanese and Chinese ovarian cancer patients was shown. Further large-scale investigations on racial differences in HRD prevalence are needed and this may contribute to changes in determining the treatment plan and personalized treatment in ovarian cancer patients.

P2, N=363, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2023 --> Mar 2024