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Cell Death & Disease Oct 2022PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to...
PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to progression-free survival, especially in patients either carrying BRCA1/2 mutations or harboring defects in the homologous recombination repair system. Yet, it remains uncertain which PARPi to apply and how to predict responders when platinum sensitivity is unknown. To shed light on the predictive power of genes previously suggested to be associated with PARPi response, we systematically reviewed the literature and identified 79 publications investigating a total of 93 genes. The top candidate genes were further tested using a comprehensive CRISPR-Cas9 mutagenesis screening in combination with olaparib treatment. Therefore, we generated six constitutive Cas9 EOC cell lines and profiled 33 genes in a CRISPR-Cas9 cell competition assay using non-essential (AAVS1) and essential (RPA3 and PCNA) genes for cell fitness as negative and positive controls, respectively. We identified only ATM, MUS81, NBN, BRCA2, and RAD51B as predictive markers for olaparib response. As the major survival benefit of PARPi treatment was reported in platinum-sensitive tumors, we next assessed nine top candidate genes in combination with three PARPi and carboplatin. Interestingly, we observed similar dropout rates in a gene and compound independent manner, supporting the strong correlation of cancer cell response to compounds that rely on DNA repair for their effectiveness. In addition, we report on CDK12 as a common vulnerability for EOC cell survival and proliferation without altering the olaparib response, highlighting its potential as a therapeutic target in EOC.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Carcinoma, Ovarian Epithelial; Carboplatin; CRISPR-Cas Systems; Early Detection of Cancer; Phthalazines; Ovarian Neoplasms; Genes, Overlapping
PubMed: 36307400
DOI: 10.1038/s41419-022-05347-x -
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 -
Current Oncology (Toronto, Ont.) Dec 2023Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for... (Review)
Review
Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, ClinicalTrials.gov and ASCO-GU annual meeting abstracts up to March 2023 to identify potential phase III trials reporting the use of combining PARP inhibitors with NHT in the first-line setting for mCRPC. A total of four phase III trials met the criteria for subsequent review. Emerging data suggested that the radiographic progression-free survival (rPFS) was significantly longer in the PARP inhibitor combined with NHT group versus the placebo plus NHT group for the first-line setting of biomarker-unselected mCRPC patients, especially for patients with homologous recombination repair (HRR) mutation (HRR m), and with the greatest benefit for BRCA1/2 mutation (BRCA1/2 m) populations. Final overall survival (OS) data of the PROpel trial indicated a significant improvement in median OS for mCRPC patients with HRR m and BRCA1/2 m receiving olaparib + abiraterone. Prior taxane-based chemotherapy might not influence the efficacy of the combination. Compared with the current standard-of-care therapies, combining NHT with PARP inhibitors could achieve a significant survival benefit in the first-line setting for mCRPC patients with HRR and BRCA1/2 mutations.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; BRCA1 Protein; Ribose; BRCA2 Protein; Antineoplastic Agents
PubMed: 38132385
DOI: 10.3390/curroncol30120751 -
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 -
Frontiers in Oncology 2022This study aims to compare the efficacy and safety of different poly (ADP-ribose) polymerase (PARP) inhibitors in patients with ovarian cancer through a network...
OBJECTIVE
This study aims to compare the efficacy and safety of different poly (ADP-ribose) polymerase (PARP) inhibitors in patients with ovarian cancer through a network meta-analysis to support clinical treatment choices.
METHODS
The Cochrane Library, PubMed, Embase, Science Citation Index, China National Knowledge Infrastructure (CNKI), Wanfang Data, Chongqing VIP (CQVIP), and Chinese BioMedical Literature Database (CBM) were searched with a cutoff date of 14 January 2021. ClinicalTrials.gov was also checked for supplementary data. Phase II or III randomized controlled trials that compared a PARP inhibitor with a placebo in patients with relapsed or newly diagnosed advanced ovarian cancer were included. The hazard ratios (HRs) for progression-free survival and overall survival and odds ratios (ORs) for grade 3 or higher adverse events were analyzed. The network meta-analysis was conducted in a Bayesian framework based on the Markov Chain Monte Carlo model in the R gemtc package (version 4.0.3).
RESULTS
Eight eligible articles reporting six trials with a total of 2,801 patients were incorporated in this network meta-analysis. Three trials compared olaparib with placebo. Two trials compared niraparib with placebo. One trial compared rucaparib with placebo. The network meta-analysis failed to show significant differences in progression-free survival among the three PARP inhibitors: HR of 0.64, 95% confidence interval of 0.3 to 1.42 for olaparib versus niraparib, and olaparib versus rucaparib (0.86; 0.33 to 2.33). The comparison between niraparib and rucaparib also did not express a statistical difference (1.34; 0.47 to 3.72). Subgroup analysis bybreast cancer susceptibility gene (BRCA) status showed no obvious difference in progression-free survival among the three PARP inhibitors regardless of BRCA mutation status. Olaparib had fewer grade 3 or higher adverse events than niraparib (OR, 0.27; 95% confidence interval, 0.13 to 0.55) and rucaparib (0.34; 0.14 to 0.86). However, the analysis failed to show a significant difference between niraparib and rucaparib (1.27; 0.49 to 3.27).
CONCLUSION
Current evidence indicates that there is no significant difference observed in efficacy among olaparib, niraparib, and rucaparib. However, olaparib might have fewer grade 3 or higher adverse events.
PubMed: 35756600
DOI: 10.3389/fonc.2022.815265 -
The Cochrane Database of Systematic... May 2015Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ovarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has spread throughout the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy.PARP (poly (ADP-ribose) polymerase) inhibitors, are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer, with respect to survival, side effects and quality of life.
OBJECTIVES
To determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer (EOC).
SEARCH METHODS
We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to May 2014), EMBASE (1990 to May 2014), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.
SELECTION CRITERIA
Women with histologically proven EOC who were randomised to treatment groups in trials that either compared PARP inhibitors with no treatment, or PARP inhibitors versus conventional chemotherapy, or PARP inhibitors together with conventional chemotherapy versus conventional chemotherapy alone.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data, where possible. Outcomes included survival, quality of life and toxicity.
MAIN RESULTS
We included four RCTs involving 599 women with EOC. Data for veliparib were limited and of low quality, due to small numbers (75 women total). Olaparib, on average, improved progression-free survival (PFS) when added to conventional treatment and when used as maintenance treatment in women with platinum-sensitive disease compared with placebo (hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.29 to 0.60; 426 participants ; two studies), but did not improve overall survival (OS) (HR 1.05, 95% CI 0.79 to 1.39; 426 participants; two studies). We graded this evidence as moderate quality using the GRADE approach. Olaparib was associated with more severe adverse events (G3/4) during the maintenance phase compared with controls (risk ratio (RR) 1.74, 95% CI 1.22 to 2.49; 385 participants, two studies; moderate quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies.
AUTHORS' CONCLUSIONS
PARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease. Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC. More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease.
Topics: Adult; Antineoplastic Agents; Benzimidazoles; DNA Repair; Disease-Free Survival; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 25991068
DOI: 10.1002/14651858.CD007929.pub3 -
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 -
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 -
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 -
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