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BMC Cancer Aug 2023Patients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast... (Meta-Analysis)
Meta-Analysis
Neoadjuvant immunotherapy and chemotherapy regimens for the treatment of high-risk, early-stage triple-negative breast cancer: a systematic review and network meta-analysis.
BACKGROUND
Patients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast cancer patients. Recently, neoadjuvant delivery of the programmed cell death protein-1 inhibitor pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was approved for patients with high-risk, early-stage TNBC, but this treatment regimen has not been evaluated in head-to-head trials with other neoadjuvant treatment regimens. Therefore, the objective of this study was to estimate the relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab versus other neoadjuvant treatments for early-stage TNBC through a systematic review and network meta-analysis (NMA).
METHODS
EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts, and clinical trial registries were searched for randomized controlled trials evaluating neoadjuvant treatments for early-stage TNBC. NMA was performed to estimate relative treatment effects among evaluated interventions.
RESULTS
Five trials met the inclusion criteria and were included in the NMA. The relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab was favorable to paclitaxel followed by anthracycline + cyclophosphamide in terms of pathologic complete response (pCR), event-free survival (EFS), and overall survival; paclitaxel + carboplatin followed by anthracycline + cyclophosphamide in terms of pCR and EFS; paclitaxel + bevacizumab followed by anthracycline + cyclophosphamide + bevacizumab in terms of pCR; and paclitaxel + carboplatin + veliparib followed by anthracycline + cyclophosphamide in terms of EFS.
CONCLUSIONS
Neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.
Topics: Humans; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Network Meta-Analysis; Bevacizumab; Carboplatin; Neoplasm Recurrence, Local; Immunotherapy; Adjuvants, Immunologic; Anthracyclines; Cyclophosphamide; Paclitaxel
PubMed: 37612624
DOI: 10.1186/s12885-023-11293-4 -
Cancer Research Communications Jun 2023Veliparib is a PARP inhibitor (PARPi) with activity in 1/2/-deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic...
PURPOSE
Veliparib is a PARP inhibitor (PARPi) with activity in 1/2/-deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi.
EXPERIMENTAL DESIGN
NCI 7977 was a multicohort phase I clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1-4 and 8-11 with irinotecan 100 mg/m days 3 and 10 in 21-day cycles.
RESULTS
Fifteen patients enrolled, 8 of 15 (53%) received ≥4 prior systemic treatments. At DL1, 1 of 6 patients experienced a dose-limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2 of 6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m and veliparib 50 mg twice daily was the MTD. No objective responses were observed, although 4 patients had progression-free survival >6 months.
CONCLUSIONS
The MTD of intermittent veliparib is 50 mg twice daily days 1-4 and 8-11 with weekly irinotecan 100 mg/m days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely.
SIGNIFICANCE
The combination of intermittent veliparib with weekly irinotecan was deemed too toxic for further development. 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.
Topics: Humans; Irinotecan; Neoplasms; Benzimidazoles; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 37377610
DOI: 10.1158/2767-9764.CRC-22-0485 -
Cancers Jun 2023Among ovarian cancer patients with mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib,... (Review)
Review
Prevalence of Homologous Recombination Deficiency in First-Line PARP Inhibitor Maintenance Clinical Trials and Further Implication of Personalized Treatment in Ovarian Cancer.
Among ovarian cancer patients with 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. mutation and HRD are currently indicated for PARP inhibitor maintenance treatment in ovarian cancer. HRD diagnostic tests examine various components, resulting in different HRD status definitions and, as a result, different treatment decisions. A number of HRD diagnostic tests exist, but test results provided by different companies may differ as they use different methods and different cutoffs. HRD prevalence difference was shown between PARP inhibitor maintenance trials. It is important to select an appropriate method that can present accurate HRD phenotypes to predict sensitivity to PARP inhibitors so that patients who are most likely to benefit from treatment are selected. 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.
PubMed: 37370704
DOI: 10.3390/cancers15123095 -
Nanomaterials (Basel, Switzerland) May 2023The development of a lipid nano-delivery system was attempted for three specific poly (ADP-ribose) polymerase 1 (PARP1) inhibitors: Veliparib, Rucaparib, and Niraparib....
The development of a lipid nano-delivery system was attempted for three specific poly (ADP-ribose) polymerase 1 (PARP1) inhibitors: Veliparib, Rucaparib, and Niraparib. Simple lipid and dual lipid formulations with 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1'-glycerol) sodium salt (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC) were developed and tested following the thin-film method. DPPG-encapsulating inhibitors presented the best fit in terms of encapsulation efficiency (>40%, translates into concentrations as high as 100 µM), zeta potential values (below -30 mV), and population distribution (single population profile). The particle size of the main population of interest was ~130 nm in diameter. Kinetic release studies showed that DPPG-encapsulating PARP1 inhibitors present slower drug release rates than liposome control samples, and complex drug release mechanisms were identified. DPPG + Veliparib/Niraparib presented a combination of diffusion-controlled and non-Fickian diffusion, while anomalous and super case II transport was verified for DPPG + Rucaparib. Spectroscopic analysis revealed that PARP1 inhibitors interact with the DPPG lipid membrane, promoting membrane water displacement from hydration centers. A preferential membrane interaction with lipid carbonyl groups was observed through hydrogen bonding, where the inhibitors' protonated amine groups may be the major players in the PARP1 inhibitor encapsulation mode.
PubMed: 37242030
DOI: 10.3390/nano13101613 -
ACS Medicinal Chemistry Letters May 2023Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and...
Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.
PubMed: 37197461
DOI: 10.1021/acsmedchemlett.3c00065 -
Journal of Ovarian Research Apr 2023Ovarian cancer (OV), the most fatal gynecological malignance worldwide, has high recurrence rates and poor prognosis. Recently, emerging evidence supports that...
Ovarian cancer (OV), the most fatal gynecological malignance worldwide, has high recurrence rates and poor prognosis. Recently, emerging evidence supports that autophagy, a highly regulated multi-step self-digestive process, plays an essential role in OV progression. Accordingly, we filtered 52 potential autophagy-related genes (ATGs) among the 6197 differentially expressed genes (DEGs) identified in TCGA-OV samples (n = 372) and normal controls (n = 180). Based on the LASSO-Cox analysis, we distinguished a 2-gene prognostic signature, namely FOXO1 and CASP8, with promising prognostic value (p-value < 0.001). Together with corresponding clinical features, we constructed a nomogram model for 1-year, 2-year, and 3-year survival, which was validated in both in training (TCGA-OV, p-value < 0.001) and validation (ICGC-OV, p-value = 0.030) cohorts. Interestingly, we evaluated the immune infiltration landscape through the CIBERSORT algorithm, which indicated the upregulation of 5 immune cells, including CD8 + T cells, Tregs, and Macrophages M2, and high expression of critical immune checkpoints (CTLA4, HAVCR2, PDCD1LG2, and TIGIT) in high-risk group. Stepwise, high-risk group exhibited better sensitivity towards chemotherapies of Bleomycin, Sorafenib, Veliparib, and Vinblastine, though less sensitive to immunotherapy. Especially, based on the IHC of tissue microarrays among 125 patients in our institution, we demonstrated that aberrant upregulation of FOXO1 in OV was related to metastasis and poor prognosis. Moreover, FOXO1 could significantly promote tumor invasiveness, migration, and proliferation in OV cell lines, which was assessed through the Transwell, wound-healing, and CCK-8 assay, respectively. Briefly, the autophagy-related signature was a reliable tool to evaluate immune responses and predict prognosis in the realm of OV precision medicine.
Topics: Humans; Female; Prognosis; Autophagy; Ovarian Neoplasms; Nomograms; Algorithms; Tumor Microenvironment
PubMed: 37120633
DOI: 10.1186/s13048-023-01167-5 -
DNA Repair Jun 2023Laser micro-irradiation across the nucleus rapidly generates localized chromatin-associated DNA lesions permitting analysis of repair protein recruitment in living...
Laser micro-irradiation across the nucleus rapidly generates localized chromatin-associated DNA lesions permitting analysis of repair protein recruitment in living cells. Recruitment of three fluorescently-tagged base excision repair factors [DNA polymerase β (pol β), XRCC1 and PARP1], known to interact with one another, was compared in gene-deleted mouse embryonic fibroblasts and in those expressing the endogenous factor. A low energy micro-irradiation (LEMI) forming direct single-strand breaks and a moderate energy (MEMI) protocol that additionally creates oxidized bases were compared. Quantitative characterization of repair factor recruitment and sensitivity to clinical PARP inhibitors (PARPi) was dependent on the micro-irradiation protocol. PARP1 recruitment was biphasic and generally occurred prior to pol β and XRCC1. After LEMI, but not after MEMI, pol β and XRCC1 recruitment was abolished by the PARPi veliparib. Consistent with this, pol β and XRCC1 recruitment following LEMI was considerably slower in PARP1-deficient cells. Surprisingly, the recruitment half-times and amplitudes for pol β were less affected by PARPi than were XRCC1 after MEMI suggesting there is a XRCC1-independent component for pol β recruitment. After LEMI, but not MEMI, pol β dissociation was more rapid than that of XRCC1. Unexpectedly, PARP1 dissociation was slowed in the absence of XRCC1 as well with a PARPi after LEMI but not MEMI, suggesting that XRCC1 facilitates PARP1 dissociation from specific DNA lesions. XRCC1-deficient cells showed pronounced hypersensitivity to the PARPi talazoparib correlating with its known cytotoxic PARP1 trapping activity. In contrast to DNA methylating agents, PARPi only minimally sensitized pol β and XRCC1-deficient cells to oxidative DNA damage suggesting differential binding of PARP1 to alternate repair intermediates. In summary, pol β, XRCC1, and PARP1 display recruitment kinetics that exhibit correlated and unique properties that depend on the DNA lesion and PARP activity revealing that there are multiple avenues utilized in the repair of chromatin-associated DNA.
Topics: Animals; Mice; Fibroblasts; DNA Repair; DNA Damage; X-ray Repair Cross Complementing Protein 1; Poly (ADP-Ribose) Polymerase-1; DNA; Poly(ADP-ribose) Polymerases; Chromatin; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 37028218
DOI: 10.1016/j.dnarep.2023.103486 -
The Oncologist May 2023Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors,...
BACKGROUND
Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination.
METHODS
A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles.
RESULTS
Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose-limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1).
CONCLUSION
The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).
Topics: Humans; Irinotecan; Poly(ADP-ribose) Polymerase Inhibitors; Neoplasms; Antineoplastic Agents; Topoisomerase I Inhibitors; Poly(ADP-ribose) Polymerases; Diarrhea; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37010988
DOI: 10.1093/oncolo/oyad023 -
Oncology Letters Apr 2023Poly (ADP ribose) polymerase (PARP) inhibitors are novel targeted anticancer agents that have been widely used in patients with cancer, particularly in patients with... (Review)
Review
Poly (ADP ribose) polymerase (PARP) inhibitors are novel targeted anticancer agents that have been widely used in patients with cancer, particularly in patients with breast-related cancer antigen 1/2 mutations. PARP inhibitors are administered orally and have been associated with improved efficacy and toxicity profiles when compared to conventional chemotherapy agents; this improvement is convenient and results in good compliance among patients with cancer. However, as PARP inhibitors are administered long-term and frequently concomitantly with other therapeutic agents, the risk of drug-drug interactions (DDIs) is increasing. Transporters are widely expressed in numerous types of tissue, where they have crucial roles in the membrane transport of several drugs. An alteration in the activity and expression of transporters may change the drug pharmacokinetics (PKs) and cause DDIs. As the five PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib and veliparib) are transporter substrates, inhibitors or inducers, the potential transporter-mediated DDIs with the use of PARP inhibitors should be taken into consideration when co-administered with other agents. The present review focused on recent findings on transporter-mediated DDIs with PARP inhibitors to provide specific recommendations for reducing the occurrence of undesired DDIs.
PubMed: 36936025
DOI: 10.3892/ol.2023.13747 -
Breast Cancer Research and Treatment Apr 2023Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly...
A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).
BACKGROUND
Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).
METHODS
Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1.
RESULTS
Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%.
CONCLUSION
Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.
Topics: Humans; Female; Carboplatin; Paclitaxel; Breast Neoplasms; Triple Negative Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Anemia
PubMed: 36853577
DOI: 10.1007/s10549-023-06889-0