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Frontiers in Oncology 2022To systematically evaluate the efficacy and safety of olaparib in the treatment of recurrent platinum-sensitive ovarian cancer.
OBJECTIVE
To systematically evaluate the efficacy and safety of olaparib in the treatment of recurrent platinum-sensitive ovarian cancer.
METHODS
The Cochrane Library, PubMed, Chinese Biomedical Literature Database, CNKI, VIP Database, Wanfang Science and Technology Database were searched for randomized controlled trials (RCTs) of olaparib in the treatment of recurrent platinum-sensitive ovarian cancer from the establishment of each database to January 2022. Two reviewers independently evaluated the quality of the literature, extracted the data, and cross-checked the methodological quality. Meta-analysis was performed using RevMan 5.4 software.
RESULTS
A total of 7 RCTs were included, including 2406 patients, There were 1497 patients in treatment groups and 909 patients in the control group. Meta-analysis results showed that in terms of effectiveness, the overall survival time of patients in the olaparib group [HR=1.24, 95%CI(1.06, 1.45), P=0.006]; in terms of safety, for all grades of adverse events (including nausea, fatigue, vomiting, diarrhea, abdominal pain, and headache), [HR=1.54, 95%CI(1.38, 1.71), P=0.0002], for grade 3 or higher adverse events (including nausea, fatigue, vomiting, diarrhea, abdominal pain, and headache), [HR=2.13, 95%CI(1.61, 2.81), P=0.003], there were significant differences compared with the control group, suggesting that the risk of adverse reactions in the experimental group was higher than that in the control group. Subgroup analysis showed that only abdominal pain, headache and vomiting were not statistically significant, and other adverse reactions were statistically significant.
CONCLUSION
Based on the existing clinical evidence, olaparib in the treatment of recurrent platinum-sensitive ovarian cancer has a longer overall survival than the control group. It is an ideal regimen, but the incidence of adverse reactions is high.
PubMed: 35299755
DOI: 10.3389/fonc.2022.858826 -
Pharmacological Research Oct 2021We aimed to evaluate comparative safety and tolerability of the approved PARP inhibitors in people with cancer. (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
We aimed to evaluate comparative safety and tolerability of the approved PARP inhibitors in people with cancer.
METHODS
Eligible studies included randomized controlled trials comparing an approved PARP inhibitor (fluzoparib, olaparib, rucaparib, niraparib, or talazoparib) with placebo or chemotherapy in cancer patients. Outcomes of interest included: serious adverse event (SAE), discontinuation due to adverse event (AE), interruption of treatment due to AE, dose reduction due to AE, and specific grade 1-5 AEs.
RESULTS
Ten trials including 3763 participants and six treatments (olaparib, rucaparib, niraparib, talazoparib, placebo, and protocol-specified single agent chemotherapy) were identified. SAE and discontinuation of treatment did not differ significantly among the four approved PARP inhibitors. Regarding interruption of treatment and dose reduction due to AE, statistically significant differences and statistically non-significant trend were observed. Talazoparib is associated with a higher risk of interruption of treatment and dose reduction (excluding rucaparib) due to AE as compared with the other drugs. Niraparib showed a trend of lower risk of AE related dose reduction as compared with the other drugs. Furthermore, there were significant differences in specific grade 1-5 AE among the four drugs.
CONCLUSION
The safety profile of the four approved PARP inhibitors is comparable in terms of SAE and AE-related discontinuation of treatment. Statistically significant differences in the AEs spectrum and AEs related dose interruption and dose reduction demonstrated the prompt identification of AE and dose personalization seem mandatory to obtain maximal benefit from PARP inhibitors.
Topics: Humans; Indazoles; Indoles; Neoplasms; Network Meta-Analysis; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 34389457
DOI: 10.1016/j.phrs.2021.105808 -
Oncotarget Feb 2016Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of small-molecule drugs suppressing PARP enzymes activity, inducing the death of cells deficient in homologous... (Review)
Review
Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of small-molecule drugs suppressing PARP enzymes activity, inducing the death of cells deficient in homologous recombination repair (HRR). HRR deficiency is common in tumor cells with BRCA gene mutation. Since their first clinical trial in 2003, PARP inhibitors have shown benefit in the treatment of HRR-deficient tumors. Recently, several randomized clinical trials (RCTs) have been conducted to investigate the potential benefit of administration of PARP inhibitors in cancer patients. However, the results remain controversial. To evaluate the efficiency and safety of PARP inhibitors in patients with cancer, we performed a comprehensive meta-analysis of RCTs. According to our study, PARP inhibitors could clearly improve progression-free survival (PFS), especially in patients with BRCA mutation. However, our study showed no significant difference in overall survival (OS) between the PARP inhibitors and controls, even in the BRCA mutation group. Little toxicity was reported in the rate of treatment correlated adverse events (AEs) in PARP inhibitor group compared with controls. In conclusion, PARP inhibitors do well in improving PFS with little toxicity, especially in patients with BRCA deficiency.
Topics: Antineoplastic Agents; Humans; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Safety
PubMed: 26399274
DOI: 10.18632/oncotarget.5367 -
European Urology Oncology Oct 2020The goal of precision oncology is to use the underlying genomic characteristics of the patient and the cancer to select the optimal treatment at a given time. The recent...
CONTEXT
The goal of precision oncology is to use the underlying genomic characteristics of the patient and the cancer to select the optimal treatment at a given time. The recent Food and Drug Administration (FDA) approval of the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib for the treatment of advanced prostate cancer heralds the onset of precision medicine for this disease.
OBJECTIVE
To discuss the emerging role that PARP inhibitors may play as a personalised future treatment option in patients with prostate cancer, with a focus on patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumour cells harbour mutations resulting from deficient homologous recombination repair (HRR).
EVIDENCE ACQUISITION
To identify publications relevant to this review, a systematic literature search of PubMed was conducted for articles and proceedings of relevant major congresses, published between January 2010 and March 2020, reporting the use of PARP inhibitors in the treatment of cancers.
EVIDENCE SYNTHESIS
A total of 168 publications were identified, and 18 of these met the criteria for subsequent review. In addition, 15 phase 2 or on-going phase 3 (mCRPC) studies evaluating PARP inhibitors as monotherapy or in combination, which had not yet reported data, were identified through ClinicalTrials.gov. Emerging data suggest that the greatest efficacy with single-agent PARP inhibitors is seen in mCRPC patients with germline or somatic BRCA1/2 alterations (especially BRCA2 or biallelic mutations), with potential efficacy also observed in men with PALB2 and FANCA mutations.
CONCLUSIONS
PARP inhibitors have demonstrated efficacy in mCRPC, and similar to ovarian and breast cancers, the greatest effect is observed in patients with HRR deficiency. The PARP inhibitors olaparib and rucaparib are now FDA approved for mCRPC patients with HRR mutations and BRCA1/2 mutations, respectively. Furthermore, when PARP inhibition is combined with novel hormonal therapies, a treatment benefit may be observed regardless of the HRR deficiency status. Gaps in the knowledge and understanding around PARP inhibitor use in prostate cancer, including the most appropriate diagnostic testing method for identifying an HRR mutation, remain to be resolved.
PATIENT SUMMARY
The poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and rucaparib are now approved by the Food and Drug Administration for the treatment of advanced prostate cancer. Here, we reviewed the literature and proceedings from meeting presentations and published papers relevant to the use of PARP inhibitors in the treatment of prostate cancer. Testing methods for detecting homologous recombination repair gene mutations, as diagnostic tools to help identify patients most likely to benefit from PARP inhibitor treatment, are also discussed.
Topics: Clinical Trials as Topic; Humans; Indoles; Male; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant
PubMed: 32814685
DOI: 10.1016/j.euo.2020.07.005 -
Frontiers in Oncology 2021The present COVID-19 pandemic has tended toward normality. To provide convenient, safe, and effective home treatment programs for patients with recurrent ovarian cancer...
BACKGROUND
The present COVID-19 pandemic has tended toward normality. To provide convenient, safe, and effective home treatment programs for patients with recurrent ovarian cancer (ROC), the clinical efficacy and safety of poly (ADP-ribose) polymerase inhibitor (PARPi) (including olaparib, niraparib, and rucaparib) monotherapy as a maintenance treatment for platinum-sensitive ROC were systematically evaluated.
METHODS
Numerous electronic databases were systematically searched for randomized controlled trials (RCTs) of PARPi maintenance treatment for ROC that were published before June 2021. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was grade 3-4 adverse effects (AEs). After data extraction and the quality evaluation of the included studies, Bayesian network meta-analysis (NMA) was performed using R software. The ability of each treatment was ranked using the surface under the cumulative ranking (SUCRA) curve.
RESULTS
The analysis included five studies and 1390 patients. The NMA results demonstrated that compared with the placebo, olaparib and niraparib exhibited significant benefits in the gBRCA-mutated population, and respectively reduced the risk of death by 31% (HR = 0.69, 95% CI: 0.53-0.90) and 34% (HR = 0.66, 95% CI: 0.44-0.99). Olaparib, niraparib, and rucaparib were all found to be very effective in prolonging PFS in patients with ROC. All three PARPi treatments increased the number of grade 3-4 AEs in patients with ROC as compared with the placebo.
CONCLUSIONS
Overall, olaparib and niraparib maintenance treatment can significantly prolong the OS of patients with gBRCA mutations. Furthermore, the three investigated PARPi monotherapy maintenance treatments can prolong PFS regardless of BRCA mutation status. Although the incidence of AEs in the treatment groups was found to be significantly higher than that in the placebo group, the patients in the treatment group tolerated the treatment. Home oral PARPi treatment can balance tumor treatment and pandemic prevention and control, and is the most convenient, safe, and effective home treatment method available against the background of the current COVID-19 pandemic.
SYSTEMATIC REVIEW REGISTRATION
https://inplasy.com/inplasy-2021-6-0033/.
PubMed: 34900739
DOI: 10.3389/fonc.2021.785102 -
Journal of Ovarian Research Feb 2024Ovarian cancer is the eighth leading cause of cancer-related death among women, characterized by late diagnosis and a high relapse rate. In randomized controlled trials,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ovarian cancer is the eighth leading cause of cancer-related death among women, characterized by late diagnosis and a high relapse rate. In randomized controlled trials, we aimed to evaluate the efficacy and safety of PARP inhibitors (PARPi) in treating advanced ovarian cancer.
METHODS
This review was registered on PROSPERO (CRD42021283150), included all phase II and phase III randomized controlled trials (RCTs) assessing the effect of PARPi on ovarian cancer until the 13th of April, 2022. The main outcomes were progression- free survival (PFS), overall survival (OS), and adverse events (AEs). Pooled hazard ratios (HRs), and risk ratios (RRs) were calculated with 95% confidence intervals (95% CI). The random-effects model was applied in all analyses.
RESULTS
In the meta-analysis, 16 eligible RCTs were included, with a total of 5,815 patients. In recurrent ovarian cancer, PARPi maintenance therapy showed a significant PFS benefit over placebo in the total population (HR 0.34, CI 0.29-0.40), BRCA mutant (HR 0.24, CI 0.18-0.31), germline BRCA mutant (HR 0.23, CI 0.18-0.30), and BRCA wild-type cases (HR 0.50, CI 0.39-0.65). PARPi monotherapy also improved PFS (HR 0.62, CI 0.51-0.76) compared with chemotherapy in BRCAm patients with recurrent ovarian cancer. The use of PARPi maintenance therapy resulted in an improvement in PFS over placebo in newly-diagnosed cancers in the overall population (HR 0.46, CI 0.30-0.71) and the BRCAm population (HR 0.36, CI 0.29-0.44). Although the risk of severe AEs was increased by PARPi therapy compared to placebo in most settings investigated, these side effects were controllable with dose modification, and treatment discontinuation was required in the minority of cases.
CONCLUSIONS
PARPis are an effective therapeutic option for newly-diagnosed and recurrent ovarian cancer. Despite a minor increase in the frequency of serious adverse effects, they are generally well tolerated.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Antineoplastic Agents; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
PubMed: 38409030
DOI: 10.1186/s13048-024-01362-y -
World Journal of Oncology Dec 2023The emergence of olaparib, a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor to treat metastatic castration-resistant prostate cancer (mCRPC),...
BACKGROUND
The emergence of olaparib, a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor to treat metastatic castration-resistant prostate cancer (mCRPC), created a measurable clinical question on whether the agent positively influences the treatment outcomes and acceptable safety factors. The objective was to elaborate on the efficacy and safety of olaparib-added regimens in treating mCRPC patients as compared to the established guideline.
METHODS
The literature search was performed on several scientific databases, e.g., PubMed, Cochrane, and ScienceDirect, by applying the Boolean Term method. Statistical and risk of bias (RoB) analyses were calculated through RevMan 5.4.1. to investigate our outcomes, i.e., progression-free survival (PFS) and overall survival (OS) with the reported adverse effects (AEs). These outcomes were presented in hazard ratio (HR) and risk ratio (RR).
RESULTS
Three trials consisting of 1,325 individuals with comparable baseline characteristics were investigated. The meta-analysis showed that introducing olaparib into the regimens significantly improved the PFS (HR 0.59 (0.48 - 0.73); P < 0.05), which disclosed even better outcomes among mutated homologous recombinant repair (HRR) and ataxia-telangiectasia mutated (ATM) gene (HR 0.43 (0.30 - 0.62); P < 0.05) in 95% confidence interval (CI). Furthermore, similar outcomes were observed in OS analysis (HR 0.81 (0.67 - 0.99); P < 0.05), despite olaparib group disclosed higher AEs rate with insignificant difference in mortality rate.
CONCLUSION
The efficacy and safety of olaparib-added regimens in mCRPC patients need to be explored more extensively in trials because they are beneficial, particularly among -mutated individuals.
PubMed: 38022404
DOI: 10.14740/wjon1685 -
Frontiers in Pharmacology 2023Metastatic castration-resistant prostate cancer (mCRPC) presents significant treatment selection challenges due to limited therapeutic options. This study aimed to...
Metastatic castration-resistant prostate cancer (mCRPC) presents significant treatment selection challenges due to limited therapeutic options. This study aimed to comprehensively assess the efficacy of multiple treatment regimens for mCRPC through a network meta-analysis (NMA) of randomized controlled trials (RCTs). A systematically comprehensive search for randomized controlled trials (RCTs) was performed in Pubmed, Cochrane Library, Embase, and Web of Science databases. The network meta-analysis was employed to compare the overall survival (OS), progression-free survival (PFS), and radiographic progression-free survival (rPFS) among different interventions at specific time points. This study was prospectively registered with PROSPERO (CRD42023422823). A total of 29 RCTs, involving 12,706 patients and investigating 16 interventions, were included in the analysis. Chempretarget ((capivasertib or cabozantinib) + docetaxel + prednisone)) and PARP (Olaparib or rucaparib) inhibitors emerged as interventions that significantly improved survival outcomes compared to first-line treatment in mCRPC patients. Chempretarget demonstrated superior overall survival starting from the 12th month, while PARP inhibitors showed a clear advantage in progression-free survival within the 3-18 months range. Notably, chempre ((Docetaxel or Cabazitaxel) + prednisone) exhibited favorable performance in radiographic progression-free survival during the 3-18 month period. Our findings underscore the efficacy of chempretarget, PARP inhibitors, and chempre in enhancing survival outcomes for mCRPC patients. Further head-to-head comparisons are warranted to validate these results. These findings carry important implications for treatment decision-making in mCRPC and may guide the development of more effective therapeutic strategies.
PubMed: 38074136
DOI: 10.3389/fphar.2023.1290990 -
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 -
Critical Reviews in Oncology/hematology Jan 2024Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Carboplatin is still the cornerstone of the first-line treatment in advanced Epithelial Ovarian Cancer (aEOC) management and the clinical response to platinum-derived agents remains the major predictor of long-term outcomes.
PATIENT AND METHODS
We aimed to identify the best treatment of the aEOC in terms of efficacy and safety, considering all treatment phases. A systematic literature search has been done to compare all treatments in aEOC population. Randomized trials with available survival and safety data published in the 2011-2022 timeframe were enclosed. Only trials reporting the BRCA or HRD (Homologous Recombination Deficiency) status were considered.
DATA EXTRACTION AND SYNTHESIS
A ranking of treatment schedules on the progression-free survival (PFS) endpoint was performed. The random-effect model was used to elaborate and extract data. The Network Meta-Analysis (NMA) by Bayesian model was performed by STATA v17. Data on PFS were extracted in terms of Hazard ratio with relative confidence intervals.
RESULTS
This NMA involved 18 trials for a total of 9105 patients. Within 12 treatment groups, we performed 3 different sensitivity analyses including "all comers" Intention to Treat (ITT) population, BRCA-mutated (BRCAm), and HRD subgroups, respectively. Considering the SUCRA-reported cumulative PFS probabilities, we showed that in the ITT population, the inferred best treatment was niraparib plus bevacizumab with a SUCRA of 96.7. In the BRCAm subgroup, the best SUCRA was for olaparib plus chemotherapy (96,9). The HRD population showed an inferred best treatment for niraparib plus bevacizumab (SUCRA 98,4). Moreover, we reported a cumulative summary of PARPi toxicity, in which different 3-4 grade toxicity profiles were observed, despite the PARPi "class effect" in terms of efficacy.
CONCLUSIONS
Considering all aEOC subgroups, the best therapeutical option was identified as PARPi plus chemotherapy and/or antiangiogenetic agents, suggesting the relevance of combinatory approaches based on molecular profile. This work underlines the potential value of "chemo-free" regimens to prolong the platinum-free interval (PFI).
Topics: Humans; Female; Bevacizumab; Poly(ADP-ribose) Polymerase Inhibitors; Network Meta-Analysis; Bayes Theorem; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
PubMed: 38065404
DOI: 10.1016/j.critrevonc.2023.104229