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Pharmacological Research Sep 2021Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature,...
Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Resistance, Neoplasm; Glioblastoma; Humans
PubMed: 34302977
DOI: 10.1016/j.phrs.2021.105780 -
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 -
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 -
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 -
Clinical Genitourinary Cancer Apr 2024Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). The aim of the present... (Meta-Analysis)
Meta-Analysis Review
Poly (ADP-ribose) polymerase inhibitors (PARPi) represent an option in selected cases of metastatic castration-resistant prostate cancer (mCRPC). 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. Three databases were queried for studies analyzing oncological outcomes and adverse events of mCRPC patients receiving PARPi. Primary outcome was a PSA decline ≥ 50% from baseline. Secondary outcomes were objective response rate, progression-free survival (PFS), radiological PFS, overall survival (OS), conversion of circulating tumor cell count, and time to PSA progression. The number and rate of any grade adverse events (AEs), grade ≥ 3 AEs, and most common grade ≥ 3 AEs were registered. A subanalysis of outcomes per mutation type, prospective trials, and studies adopting combination therapies was performed. Overall, 31 studies were included in this systematic review, 28 of which are available for meta-analysis. The most frequently investigated drug was Olaparib. The most frequent mutation was BRCA2. A PSA decline rate of 43% (95% CI 0.32-0.54) was observed in the overall population. Mean OS was 15.9 (95% CI 12.9-19.0) months. In BRCA2 patients, PSA decline rate was 66% (95% CI 0.57-0.7) and OS 23.4 months (95% CI 22.8-24.1). Half of the patients suffered from grade 3 and 4 AEs (0.50 [95% CI 0.39-0.60]). Most common AEs were hematological, the most frequent being anemia (21.5%). 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.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Prostate-Specific Antigen; Prospective Studies; Mutation
PubMed: 38281877
DOI: 10.1016/j.clgc.2023.12.011 -
Hematology/oncology and Stem Cell... Apr 2023The PARP inhibitors (PARPis) olaparib and talazoparib are currently approved for the treatment of deleterious germline BRCA1/2-mutated (gBRCA+) metastatic breast cancer... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The PARP inhibitors (PARPis) olaparib and talazoparib are currently approved for the treatment of deleterious germline BRCA1/2-mutated (gBRCA+) metastatic breast cancer (MBC). These approvals were based on improvements in progression-free survival (PFS) observed in two randomized controlled trials (RCTs). Other PARPis, such as veliparib and niraparib, have also been studied. We conducted this meta-analysis of RCTs to assess the PFS and overall survival (OS) benefits of PARPis in gBRCA + MBC.
METHODS
We performed a systematic search for RCTs using the Cochrane Library, PubMed, Embase, and Web of Science databases up to March 2021. Only phase II and III RCTs evaluating PFS and OS for PARPis alone or in combination with chemotherapy (CT) and comparing the findings with standard CT were included in this meta-analysis. Pooled analysis of the hazard ratio (HR) was performed with RevMan v5.4 using a random effects method.
RESULTS
Five RCTs with a total of 1563 BRCA-mutated MBC patients were included in this meta-analysis. Temozolomide was used in the treatment arm in the BROCADE trial. Since temozolomide has limited effects on breast cancer, this arm was excluded from our meta-analysis. A statistically significant increase in PFS was observed in the PARPi group compared to the standard CT group (HR, 0.64; 95% CI, 0.56-0.74; P < 0.00001). However, the differences in OS did not reach statistical significance (HR, 0.89; 95% CI, 0.77-1.02; P = 0.09). Moreover, differences were not observed in the adverse event profile between the two groups (odds ratio, 1.18; 95% CI, 0.84-1.64; P = 0.33).
CONCLUSION
The results of our meta-analysis confirm the previously reported PFS benefit of PARPis over standard CT. PARPis lead to superior PFS in gBRCA + MBC when used alone or in combination with standard CT. The OS benefit is similar between PARPis and standard CT. Ongoing trials are evaluating the benefits of PARPis in early stage gBRCA + BC.
Topics: Female; Humans; BRCA1 Protein; Breast Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide; BRCA2 Protein
PubMed: 37023220
DOI: 10.56875/2589-0646.1033 -
Current Computer-aided Drug Design Sep 2023This study aims to evaluate the efficacy and safety of PARP inhibitor therapy in advanced ovarian cancer and identify the optimal treatment for the survival of patients.
AIMS
This study aims to evaluate the efficacy and safety of PARP inhibitor therapy in advanced ovarian cancer and identify the optimal treatment for the survival of patients.
BACKGROUND
The diversity of PARP inhibitors makes clinicians confused about the optimal strategy and the most effective BRCAm mutation-based regimen for the survival of patients with advanced ovarian cancer.
OBJECTIVES
The objective of this study is to compare the effects of various PARP inhibitors alone or in combination with other agents in advanced ovarian cancer.
METHODS
PubMed, Embase, Cochrane Library, and Web of Science were searched for relevant studies on PARP inhibitors for ovarian cancer. Bayesian network meta-analysis was performed using Stata 15.0 and R 4.0.4. The primary outcome was the overall PFS, and the secondary outcomes included OS, AE3, DISAE, and TFST.
RESULTS
Fifteen studies involving 5,788 participants were included. The Bayesian network metaanalysis results showed that olaparibANDAI was the most beneficial in prolonging overall PFS and non-BRCAm PFS, followed by niraparibANDAI. However, for BRCAm patients, olaparibTR might be the most effective, followed by niraparibANDAI. Olaparib was the most effective for the OS of BRCAm patients. AI, olaparibANDAI, and veliparibTR were more likely to induce grade 3 or higher adverse events. AI and olaparibANDAI were more likely to cause DISAE.
CONCLUSION
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.
PubMed: 37691198
DOI: 10.2174/1573409920666230907093331 -
BMC Cancer Jan 2023To analyze the incidence and risk of hypertension associated with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in cancer patients and provide... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To analyze the incidence and risk of hypertension associated with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in cancer patients and provide reference for clinicians.
METHODS
We used R software to conduct a meta-analysis of phase II/III randomized controlled trials (RCT) on PARP inhibitors for cancer treatment published in PubMed, Embase, Clinical Trials, Cochrane Library and Web of Science from inception to July 29th, 2022.
RESULTS
We included 32 RCTs with 10,654 participants for this meta-analysis. For total PARP inhibitors, the incidence and risk ratio of all-grade hypertension were 12% and 1.22 (95% CI: 0.91-1.65, P = 0.19, I = 81%), and the incidence and risk ratio of grade 3-4 hypertension were 4% and 1.24 (95% CI: 0.74-2.08, P = 0.42, I = 68%). Compared with the control group, the niraparib group, olaparib 800 mg/day group, and olaparib plus cediranib group increased the risk of any grade and grade 3-4 hypertension, while the veliparib group and rucaparib group did not increase the risk of any grade and grade 3-4 hypertension, and olaparib 200 mg-600 mg/day group (exclude olaparib plus cediranib regime) reduced the risk of any grade and grade 3-4 hypertension.
CONCLUSION
Olaparib 200-600 mg/day (excluding olaparib plus cediranib regimen) may be the most suitable PARP inhibitor for cancer patients with high risk of hypertension, followed by veliparib and rucaparib. Niraparib, olaparib 800 mg/day and olaparib combined with cediranib may increase the risk of developing hypertension in cancer patients, clinicians should strengthen the monitoring of blood pressure in cancer patients and give medication in severe cases.
Topics: Humans; Antineoplastic Agents; Hypertension; Incidence; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Neoplasms
PubMed: 36717798
DOI: 10.1186/s12885-023-10571-5 -
European Urology Oncology Jun 2024Testing for mutations in Breast Cancer Gene 1/2 (BRCA) has emerged as a novel decision-making tool for clinicians. Patients with metastatic castration-resistant prostate... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis.
CONTEXT
Testing for mutations in Breast Cancer Gene 1/2 (BRCA) has emerged as a novel decision-making tool for clinicians. Patients with metastatic castration-resistant prostate cancer (mCRPC) harboring pathogenic BRCA mutations can benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) and platinum treatments, whereas the impact of the mutation on sensitivity to cabazitaxel and prostate-specific membrane antigen (PSMA)-ligand therapy is currently unknown.
OBJECTIVE
To assess the efficacy of PARPi, platinum, cabazitaxel, and PSMA-ligand therapies in BRCA-positive mCRPC.
EVIDENCE ACQUISITION
Databases were queried in February 2022. We performed data synthesis by using both proportional and individual patient data. For prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) evaluation, we pooled event rates with 95% confidence intervals (CIs). Progression-free (PFS) and overall (OS) survival analyses with individual patient data were performed with the mixed-effect Cox proportional hazard model and single-arm random-effect analysis, providing pooled medians.
EVIDENCE SYNTHESIS
We included 23 eligible studies with 901 BRCA-positive mCRPC patients. PSA50 response rates for PARPi and platinum were 69% (CI: 53-82%), and 74% (CI: 49-90%), respectively. Analyses of OS data showed no difference between PARPi and platinum treatments (hazard ratio: 0.86; CI: 0.49-1.52; p = 0.6). The single-arm OS and PFS analyses revealed similarities among different PARPis; pooled PFS and OS medians were 9.7 mo (CI: 8.1-12.5) and 17.4 mo (CI: 12.7-20.1), respectively.
CONCLUSIONS
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.
PATIENT SUMMARY
In this report, we found that different poly (ADP-ribose) polymerase inhibitors had similar efficacy, and platinum was a valid treatment option in BRCA-positive metastatic castration-resistant prostate cancer patients.
Topics: Humans; Prostatic Neoplasms, Castration-Resistant; Poly(ADP-ribose) Polymerase Inhibitors; Male; Treatment Outcome; BRCA2 Protein; Antineoplastic Agents; Neoplasm Metastasis; BRCA1 Protein
PubMed: 37722977
DOI: 10.1016/j.euo.2023.09.001