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Seminars in Oncology 2024PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors... (Review)
Review
PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways and exhibit remarkable efficacy in cancers with genetic deficiencies in the homologous recombination pathway responsible for mending DNA double-strand breaks. While all PARP inhibitors demonstrate potent and selective inhibition of PARP1 and PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another. This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types. Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review. 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.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Pharmacogenetics; Antineoplastic Agents; Neoplasms; Ovarian Neoplasms
PubMed: 37880048
DOI: 10.1053/j.seminoncol.2023.09.005 -
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 -
PeerJ 2023Lung cancer, originating from bronchial mucosa or lung glands, poses significant health risks due to its rising incidence and mortality. This study aimed to assess the... (Review)
Review Meta-Analysis
OBJECTIVE
Lung cancer, originating from bronchial mucosa or lung glands, poses significant health risks due to its rising incidence and mortality. This study aimed to assess the efficacy and safety of Veliparib combined with chemotherapy versus pharmacotherapy alone for lung cancer treatment, guiding clinical approaches for this severe disease.
METHODS
Comprehensive searches in PubMed, EMBASE, Cochrane, and Web of Science were conducted to identify randomized controlled trials (RCTs) comparing Veliparib combined with standard chemotherapy to chemotherapy alone in lung cancer treatment, up until December 28, 2022. Two reviewers meticulously selected literature based on inclusion and exclusion criteria. The Cochrane tool was used to assess the bias risk of the included studies, and meta-analysis was performed using Stata 15.0.
RESULTS
Five RCTs (1,010 participants) were included. The analysis results showed that only Veliparib combinedwith chemotherapy prolonged the progression-free survival (PFS) in small cell lung cancer (SCLC) patients [HR = 0.72, 95% CI = (0.57, 0.90)]. No significant differences were observed in overall survival (OS) and objective response rate (ORR). Veliparib and combined chemotherapy caused some side effects in patients with lung cancer, including leukopenia [RR = 2.12, 95% CI = (1.27, 3.55)], neutropenia [RR = 1.51, 95% CI = (1.01, 2.26)], anemia [RR = 1.71, 95% CI = (1.07, 3.07)], and thrombocytopenia [RR = 3.33, 95% CI = (1.19, 9.30)]. For non-small cell lung cancer (NSCLC) patients, there were no statistically significant differences in PFS, OS, or ORR between the experimental and control groups [HR = 0.97, 95% CI = (0.75, 1.27)].
CONCLUSION
The strategy of combining Veliparib with chemotherapy may, to some extent, prolong the PFS in lung cancer patients. However, this benefit is not observed in OS or ORR. Additionally, there are evident adverse reactions. Due to a limited number of the included studies, additional extensive multicenter RCTs are required to validate these results. PROSPERO registration number: CRD42023411510.
Topics: Humans; Antineoplastic Agents; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Benzimidazoles; Multicenter Studies as Topic
PubMed: 37965288
DOI: 10.7717/peerj.16402 -
Journal of Chemotherapy (Florence,... Nov 2023We conducted a meta-analysis to evaluate the efficacy and safety of veliparib in the treatment of advanced/metastatic breast cancer. Databases were searched for relevant... (Review)
Review
We conducted a meta-analysis to evaluate the efficacy and safety of veliparib in the treatment of advanced/metastatic breast cancer. Databases were searched for relevant studies till June 2023. Six RCTs involving 1912 patients were included. The pooled analysis provided evidence that veliparib-containing regimens could significantly improve the PFS (HR: 0.71; 95% CI: 0.61-0.83; < 0.0001), OS (HR: 0.87; 95% CI: 0.76-0.99; = 0.03), and ORR (RR: 1.52; 95% CI:1.06-2.18; = 0.02) than those of controls for treating advanced/metastatic breast cancer. Breast cancer patients with -mutation tended to have a better PFS than the -wildtype group, and patients with TNBC tended to associated with a longer PFS than the non-TNBC group. Veliparib could significantly increase the risk of anemia, leukopenia, neutropenia, diarrhea, stomatitis, fatigue, and peripheral neuropathy. Anemia and neutropenia should be well concerned. The veliparib-containing regimen was efficacious in treating advanced/metastatic breast cancer with a controllable safety factor.
PubMed: 37975589
DOI: 10.1080/1120009X.2023.2281760 -
PloS One 2023As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a...
BACKGROUND
As a poly-ADP ribose polymerase (PARP) inhibitor, veliparib has been identified as a potential therapeutic agent for lung cancer. The present study aimed to conduct a systematic review of clinical trials investigating the efficacy and safety of veliparib for treating lung cancer.
METHODS
PubMed, Scopus, the Web of Science, and Google Scholar were systematically searched up to October 30, 2022. Only randomized controlled trials (RCTs) evaluating the efficacy or safety of veliparib in the treatment of lung cancer patients were included. Studies were excluded if they were not RCTs, enrolled healthy participants or patients with conditions other than lung cancer, or investigated therapeutic approaches other than veliparib. The Cochrane risk-of-bias tool was used for quality assessment.
RESULTS
The seven RCTs (n = 2188) showed that patients treated with a combination of veliparib and chemotherapy had a significantly higher risk of adverse events, when compared to the control arm. There was no statistically significant difference in overall survival (OS) between those treated with veliparib plus chemotherapy and those receiving the standard therapies. Only two trials demonstrated an improvement in progression-free survival (PFS), and only one study found an increase in objective response rate (ORR). Furthermore, adding veliparib to standard chemotherapy showed no benefit in extending the duration of response (DoR) in any of the studies.
CONCLUSIONS
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.
Topics: Humans; Benzimidazoles; Lung Neoplasms; Healthy Volunteers; Poly(ADP-ribose) Polymerases; Randomized Controlled Trials as Topic
PubMed: 37682974
DOI: 10.1371/journal.pone.0291044 -
Cancers Oct 2023Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based... (Review)
Review
BACKGROUND
Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events.
OBJECTIVE
To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer.
STUDY METHODOLOGY
A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities.
RESULTS
The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities.
CONCLUSION
PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.
PubMed: 37835597
DOI: 10.3390/cancers15194904 -
Research Square Oct 2023A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP]...
PURPOSE
A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma.
METHODS
Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed.
RESULTS
Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%).
CONCLUSIONS
Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.
PubMed: 37961385
DOI: 10.21203/rs.3.rs-3466927/v1 -
BMC Women's Health Jan 2024Both mitophagy and long non-coding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). We sought to explore the characteristics of mitophagy-related gene (MRG) and...
BACKGROUND
Both mitophagy and long non-coding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). We sought to explore the characteristics of mitophagy-related gene (MRG) and mitophagy-related lncRNAs (MRL) to facilitate treatment and prognosis of OC.
METHODS
The processed data were extracted from public databases (TCGA, GTEx, GEO and GeneCards). The highly synergistic lncRNA modules and MRLs were identified using weighted gene co-expression network analysis. Using LASSO Cox regression analysis, the MRL-model was first established based on TCGA and then validated with four external GEO datasets. The independent prognostic value of the MRL-model was evaluated by Multivariate Cox regression analysis. Characteristics of functional pathways, somatic mutations, immunity features, and anti-tumor therapy related to the MRL-model were evaluated using abundant algorithms, such as GSEA, ssGSEA, GSVA, maftools, CIBERSORT, xCELL, MCPcounter, ESTIMATE, TIDE, pRRophetic and so on.
RESULTS
We found 52 differentially expressed MRGs and 22 prognostic MRGs in OC. Enrichment analysis revealed that MRGs were involved in mitophagy. Nine prognostic MRLs were identified and eight optimal MRLs combinations were screened to establish the MRL-model. The MRL-model stratified patients into high- and low-risk groups and remained a prognostic factor (P < 0.05) with independent value (P < 0.05) in TCGA and GEO. We observed that OC patients in the high-risk group also had the unfavorable survival in consideration of clinicopathological parameters. The Nomogram was plotted to make the prediction results more intuitive and readable. The two risk groups were enriched in discrepant functional pathways (such as Wnt signaling pathway) and immunity features. Besides, patients in the low-risk group may be more sensitive to immunotherapy (P = 0.01). Several chemotherapeutic drugs (Paclitaxel, Veliparib, Rucaparib, Axitinib, Linsitinib, Saracatinib, Motesanib, Ponatinib, Imatinib and so on) were found with variant sensitivity between the two risk groups. The established ceRNA network indicated the underlying mechanisms of MRLs.
CONCLUSIONS
Our study revealed the roles of MRLs and MRL-model in expression, prognosis, chemotherapy, immunotherapy, and molecular mechanism of OC. Our findings were able to stratify OC patients with high risk, unfavorable prognosis and variant treatment sensitivity, thus improving clinical outcomes for OC patients.
Topics: Female; Humans; RNA, Long Noncoding; Mitophagy; Ovarian Neoplasms; Paclitaxel; Axitinib; Prognosis
PubMed: 38218807
DOI: 10.1186/s12905-023-02864-5 -
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 -
Cancer Investigation Mar 2024In this study, we investigate the veliparib‑induced toxicity in cancer patients. Databases were searched for RCTs treated with veliparib. We found veliparib could... (Meta-Analysis)
Meta-Analysis
In this study, we investigate the veliparib‑induced toxicity in cancer patients. Databases were searched for RCTs treated with veliparib. We found veliparib could increase the risk of hematologic and gastrointestinal toxicities. Anemia, neutropenia, thrombocytopenia, and nausea were the most common toxicities. Patients diagnosed with gastrointestinal tumors tend to have a higher risk of high-grade neutropenia; patients in the first-line setting tend to have a higher risk of high-grade anemia and neutropenia than those in the ≥ second line setting. Patients receiving higher dosage of veliparib tend to have a higher risk of all-grade anemia. Veliparib could also increase the risk of insomnia, myalgia, pneumonia, dyspnea, hyponatremia, and fatigue.
Topics: Humans; Benzimidazoles; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Anemia
PubMed: 38588003
DOI: 10.1080/07357907.2024.2338128