veliparib (ABT-888)

P1/2, N=88, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2026 --> Mar 2027

P2, N=97, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

Twenty-five treatment nodes were formed, with paclitaxel (P) or docetaxel (D) + anthracycline - based (A) chemotherapy as the main comparator. Compared with PA-based + cyclophosphamide, higher pCR rates were observed with PA-based + carboplatin + pembrolizumab + cyclophosphamide (OR 3,04) and PA - based + carboplatin + veliparib + cyclophosphamide (OR 2,67). When DA-based + cyclophosphamide was the comparator, DA-based + cyclophosphamide + bevacizumab (OR 1,67) increased pCR. The SUCRA ranked PA-based + carboplatin + pembrolizumab, paclitaxel + carboplatin + atezolizumab, and DA-based + lobaplatin as most effective. Platinum agents, PARP inhibitors, and immune checkpoint inhibitors were associated with higher pCR rates in early-stage TNBC. CRD42025640277.

P1, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

P2/3, N=447, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026

P1, N=94, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

P2, N=25, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026

P1/2, N=53, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026

The OGA inhibitor PUGNAc suppressed hyperresection due to PARP1 knockout while PARP inhibitor veliparib exacerbated defects in OGT- or EZH2-deficient cells. Our results highlight the potential of targeting cancer-associated metabolic reprogramming to overwhelm HR repair and drive resection stress. Combining PARP inhibition with blockade of O-GlcNAcylation or EZH2 may offer a strategy to radiosensitize proliferating, HR-proficient cancers while sparing non-cycling normal tissues.

Compared with chemotherapy with placebo, veliparib added to chemotherapy and continued as maintenance had significant patient-centered benefits in terms of quality-adjusted progression-free survival and on-treatment quality-adjusted time without symptoms of disease or toxicity for the overall, homologous recombination-deficient, and BRCA mutation patient populations.

We also identified and characterised a PARP1 mutation resulting in loss of the enzymatic inhibition and trapping activity of the PARP1-selective inhibitor, saruparib. However, the same mutation increased the trapping ability of other PARPi, namely veliparib and olaparib, without enhancing their enzymatic inhibition activity, a change that led to an increase in efficacy in this BRCA1m model. Together, these data suggest that PARP1 trapping, and not only its enzymatic inhibition, is a key driver for PARPi effectiveness in BRCA1m cancer cells.

The "immune+/replication+" showed sensitivity to pembrolizumab (OR = 10.192, p < 0.001) and veliparib/carboplatin (OR = 5.184, p = 0.006), while "immune-/replication-" responded poorly to pembrolizumab (OR = 0.086, p < 0.001). Additionally, "immune+/replication-" had the best distant recurrence-free survival (DRFS), whereas "immune-/replication+" had the worst (log-rank p = 6 × 10-4, HR = 5.45). By linking imaging heterogeneity directly to molecular subtypes and therapeutic response, this framework provides a robust, non-invasive surrogate for genomic profiling and a strategic tool for personalized neoadjuvant therapy selection.