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Journal of Clinical Oncology : Official... May 2020Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline or (g+) mutation. Phase IB data from a trial that used cisplatin,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline or (g+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in g+ PDAC.
PATIENTS AND METHODS
Eligible patients had untreated g PDAC with measurable stage III to IV disease and Eastern Cooperative Oncology Group performance status of 0 to 1. Treatment for patients in arm A consisted of cisplatin 25 mg/m and gemcitabine 600 mg/m intravenously on days 3 and 10; treatment for patients in arm B was the same as that for patients in arm A, and arm A also received veliparib 80 mg orally twice per day on days 1 to 12 cycled every 3 weeks. The primary end point was RRs of arm A and arm B evaluated separately using a Simon two-stage design. Secondary end points were progression-free survival, DCR, OS, safety, and correlative analyses.
RESULTS
Fifty patients were evaluated by modified intention-to-treat analysis. The RR for arm A was 74.1% and 65.2% for arm B ( = .55); both arms exceeded the prespecified activity threshold. DCR was 100% for arm A and 78.3% for arm B ( = .02). Median progression-free survival was 10.1 months for arm A (95% CI, 6.7 to 11.5 months) and 9.7 months for arm B (95% CI, 4.2 to 13.6 months; = .73). Median OS for arm A was 15.5 months (95% CI, 12.2 to 24.3 months) and 16.4 months for arm B (95% CI, 11.7 to 23.4 months; = .6). Two-year OS rate for the entire cohort was 30.6% (95% CI, 17.8% to 44.4%), and 3-year OS rate was 17.8% (95% CI, 8.1% to 30.7%). Grade 3 to 4 hematologic toxicities for arm A versus arm B were 13 (48%) versus seven (30%) for neutropenia, 15 (55%) versus two (9%) for thrombocytopenia, and 14 (52%) versus eight (35%) for anemia.
CONCLUSION
Cisplatin and gemcitabine is an effective regimen in advanced g+ PDAC. Concurrent veliparib did not improve RR. These data establish cisplatin and gemcitabine as a standard approach in g/+ PDAC.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Benzimidazoles; Cisplatin; Constipation; Deoxycytidine; Fanconi Anemia Complementation Group N Protein; Female; Germ-Line Mutation; Humans; Hypertension; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Outcome Assessment, Health Care; Pancreatic Neoplasms; Gemcitabine
PubMed: 31976786
DOI: 10.1200/JCO.19.02931 -
OncoTargets and Therapy 2015Inhibition of poly(ADP-ribose) polymerase (PARP) is an attractive therapeutic strategy because of the importance of this pathway in restoring DNA damage. Small-molecule... (Review)
Review
Inhibition of poly(ADP-ribose) polymerase (PARP) is an attractive therapeutic strategy because of the importance of this pathway in restoring DNA damage. Small-molecule inhibitors of PARP appear most effective when used to treat tumors with underlying defects in DNA repair, or when combined with DNA-damaging agents. Veliparib is one of several recently developed oral inhibitors of PARP currently in clinical trials. This review summarizes the pharmacology, mechanisms of action, toxicity, and activity of veliparib seen in clinical trials to date. Also discussed are proposed mechanisms of resistance, potential biomarkers of activity, and issues regarding patient selection and combination therapies that may optimize use of this exciting new agent.
PubMed: 26251615
DOI: 10.2147/OTT.S69935 -
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 -
Expert Opinion on Investigational Drugs 2016Ovarian cancer represents the sixth most commonly diagnosed cancer among women, with an incidence of 6.1 cases per 100.000 women and a cumulative lifetime risk of 0.5%.... (Review)
Review
INTRODUCTION
Ovarian cancer represents the sixth most commonly diagnosed cancer among women, with an incidence of 6.1 cases per 100.000 women and a cumulative lifetime risk of 0.5%. Treatment is based on debulking surgery and platinum-based chemotherapy, with the potential combination with taxane. However, the recently available data on the genetic basis and aetiology of ovarian cancer has led to the development of new anticancer drugs. Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most promising new classes of targeted agents currently under investigation for the treatment of ovarian cancer. Veliparib is a small molecule that inhibits both PARP-1 and PARP-2 and was originally shown to be efficacious in BRCA-associated tumors.
AREAS COVERED
This manuscript reviews the Phase I and II studies investigating the use of veliparib in ovarian cancer. This article also provides and discusses the pharmacokinetics and pharmacodynamics of veliparib.
EXPERT OPINION
It is still being discussed whether PARP inhibitors should be used in a front-line or relapsed setting, alone or in combination with cytotoxic chemotherapy or as maintenance treatment. In terms of veliparib, further investigations are needed to explore its full potential in ovarian cancer. It is hoped that the ongoing phase 3 trials will help to further elucidate it potential as a treatment option.
Topics: Antineoplastic Agents; Benzimidazoles; Drug Design; Female; Humans; Molecular Targeted Therapy; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 26807493
DOI: 10.1517/13543784.2016.1146677 -
Biochemical and Biophysical Research... Jan 2020Overexpression of ATP-binding cassette (ABC) transporter is one of the most important factors taking responsibility for the progress of multidrug resistance (MDR) in...
Overexpression of ATP-binding cassette (ABC) transporter is one of the most important factors taking responsibility for the progress of multidrug resistance (MDR) in multiple cancers. In this study, we investigated that veliparib, a PARP inhibitor which is in clinical development, could overcome ABCB1-mediated MDR in liver cancer cells. Veliparib could significantly enhance the cytotoxic effects of a series of conventional chemotherapeutic drugs in ABCB1-overexpression liver cancer cells. Mechanism study showed that veliparib could significantly enhance the accumulation of doxorubicin in ABCB1-overexpression liver cancer cells, without down-regulating the expression level of ABCB1. Finally, veliparib could significantly inhibit the ATPase activity of ABCB1 transporter. This study could provide information that combine veliparib with other chemotherapeutic drugs may benefit liver cancer patients.
Topics: ATP Binding Cassette Transporter, Subfamily B; Antineoplastic Agents; Benzimidazoles; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Liver Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 31679697
DOI: 10.1016/j.bbrc.2019.10.141 -
International Journal of Clinical... Jan 2023The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. (Randomized Controlled Trial)
Randomized Controlled Trial
Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial.
BACKGROUND
The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma.
METHODS
Patients with previously untreated stage III-IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients.
RESULTS
Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18-1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy.
CONCLUSIONS
Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.
Topics: Humans; Female; Carboplatin; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Ovarian Neoplasms; Paclitaxel; Anemia; Thrombocytopenia
PubMed: 36534262
DOI: 10.1007/s10147-022-02258-x -
Recent Patents on Anti-cancer Drug... 2018Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis... (Review)
Review
BACKGROUND
Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients.
OBJECTIVES
The study aimed to highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis.
METHODS
We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google. com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer.
RESULTS
Olaparib, Niraparib and Rucaparib are already approved for the treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease).
CONCLUSION
PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 29512470
DOI: 10.2174/1574892813666180305165256 -
Targeted Oncology May 2021Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins... (Review)
Review
Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.
Topics: Breast Neoplasms; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 33710534
DOI: 10.1007/s11523-021-00796-4 -
Cancer Research Nov 2012Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single-strand breaks (SSB). However,...
Small-molecule inhibitors of PARP are thought to mediate their antitumor effects as catalytic inhibitors that block repair of DNA single-strand breaks (SSB). However, the mechanism of action of PARP inhibitors with regard to their effects in cancer cells is not fully understood. In this study, we show that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA. Trapped PARP-DNA complexes were more cytotoxic than unrepaired SSBs caused by PARP inactivation, arguing that PARP inhibitors act in part as poisons that trap PARP enzyme on DNA. Moreover, the potency in trapping PARP differed markedly among inhibitors with niraparib (MK-4827) > olaparib (AZD-2281) >> veliparib (ABT-888), a pattern not correlated with the catalytic inhibitory properties for each drug. We also analyzed repair pathways for PARP-DNA complexes using 30 genetically altered avian DT40 cell lines with preestablished deletions in specific DNA repair genes. This analysis revealed that, in addition to homologous recombination, postreplication repair, the Fanconi anemia pathway, polymerase β, and FEN1 are critical for repairing trapped PARP-DNA complexes. In summary, our study provides a new mechanistic foundation for the rational application of PARP inhibitors in cancer therapy.
Topics: Animals; Antineoplastic Agents; Birds; Cell Line; DNA Repair; Enzyme Inhibitors; Gene Knockout Techniques; Humans; Immunoblotting; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; RNA, Small Interfering; Transfection
PubMed: 23118055
DOI: 10.1158/0008-5472.CAN-12-2753