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Cancers Oct 2020Three PARPis (olaparib, niraparib and rucaparib) are currently FDA-approved as maintenance therapy in newly diagnosed and recurrent ovarian cancer. However, thus far, no...
BACKGROUND
Three PARPis (olaparib, niraparib and rucaparib) are currently FDA-approved as maintenance therapy in newly diagnosed and recurrent ovarian cancer. However, thus far, no trial has compared the three approved PARPis in the overall population, in patients with mutations, or in those with wild-type .
METHODS
A frequentist network meta-analysis was used for indirect comparisons between the different PARPis with respect to progression free survival (PFS), overall survival (OS), and adverse events.
RESULTS
Overall, six randomized clinical trials involving 2,770 patients, were included in the analysis. Results from the indirect comparisons revealed no statistically significant differences between the three PARPis with respect to PFS or OS in the entire population and in patients with mutated and wild-type BRCA, separately. Niraparib showed a statistically significant increased risk for grade 3 and 4 thrombocytopenia (risk-difference [RD] from placebo: 0.3; 95% confidence interval [CI], 0.27‒0.34) and any grade neutropenia (RD from placebo: 0.22; 95% CI, 0.18‒0.25) as compared with the other PARPis.
CONCLUSION
No statistically significant difference was found between the three PARPis with respect to PFS or OS (overall and in subpopulations by status). There is, however, a statistical difference in toxicity as niraparib is associated with a greater risk for thrombocytopenia and neutropenia.
PubMed: 33081005
DOI: 10.3390/cancers12103026 -
International Journal of Gynecological... Oct 2020We aimed to evaluate poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) regimens in BRCA-mutated ovarian cancer for patients responsive to front-line platinum...
INTRODUCTION
We aimed to evaluate poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) regimens in BRCA-mutated ovarian cancer for patients responsive to front-line platinum (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) or platinum-sensitive relapsed (olaparib, rucaprib, niraparib) patients in phase III randomized controlled trials.
METHODS
A network meta-analysis was utilized to generate the direct and indirect comparisons. The primary outcomes for network meta-analysis were efficacy (hazard ratios for progression-free survival in BRCA mutation cohort) and toxicity (odds ratios for all grade 3-4 adverse events). The American Society of Clinical Oncology (ASCO) value framework was used to assess the cost-effectiveness of the PARPi regimens.
RESULTS
Network meta-analysis indicated no statistically significant differences in efficacy and toxicity among the assessed upfront or relapsed PARPi regimens (95% CI included 1). The ASCO value framework indicated that current PARPi regimens were similar in clinical benefits, toxicity, and net health benefit in the upfront (bevacizumab and olaparib, veliparib and chemotherapy, olaparib) and relapsed setting (olaparib, rucaprib, niraparib). The addition of bevacizumab to olaparib ($353.72) increased the cost per unit net health benefit for patients compared with olaparib monotherapy ($260.57). The upfront PARPi regimens had lower toxic scores than the regimens used at relapse.
CONCLUSIONS
The choice of PARPi regimens both in the upfront and relapsed setting should consider not only efficacy and toxicity but also costs in BRCA mutation patients. Current combining PARPi regimens are not recommended for such patients in the upfront setting from the cost-effective perspective. Upfront PARPi regimens are less toxic than those used at relapse.
Topics: Carcinoma, Ovarian Epithelial; Clinical Trials, Phase III as Topic; Female; Humans; Neoplasm Recurrence, Local; Network Meta-Analysis; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Randomized Controlled Trials as Topic
PubMed: 32817083
DOI: 10.1136/ijgc-2020-001373 -
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 -
Journal of Clinical Oncology : Official... Oct 2020To provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC).
PURPOSE
To provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC).
METHODS
Randomized, controlled, and open-labeled trials published from 2011 through 2020 were identified in a literature search. Guideline recommendations were based on the review of the evidence, US Food and Drug Administration approvals, and consensus when evidence was lacking.
RESULTS
The systematic review identified 17 eligible trials.
RECOMMENDATIONS
The guideline pertains to patients who are PARPi naïve. All patients with newly diagnosed, stage III-IV EOC whose disease is in complete or partial response to first-line, platinum-based chemotherapy with high-grade serous or endometrioid EOC should be offered PARPi maintenance therapy with niraparib. For patients with germline or somatic pathogenic or likely pathogenic variants in (g/s1) or (g/s2) genes should be treated with olaparib. The addition of olaparib to bevacizumab may be offered to patients with stage III-IV EOC with g/s2 and/or genomic instability and a partial or complete response to chemotherapy plus bevacizumab combination. Maintenance therapy (second line or more) with single-agent PARPi may be offered for patients with EOC who have not received a PARPi and have responded to platinum-based therapy regardless of mutation status. Treatment with a PARPi should be offered to patients with recurrent EOC that has not recurred within 6 months of platinum-based therapy, who have not received a PARPi and have a g/s, or whose tumor demonstrates genomic instability. PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Recommendations for managing specific adverse events are presented. Data to support reuse of PARPis in any setting are needed.Additional information is available at www.asco.org/gynecologic-cancer-guidelines.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Neoplasm Staging; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 32790492
DOI: 10.1200/JCO.20.01924 -
Frontiers in Oncology 2020PARP inhibitors are a novel targeted anti-cancer drug and a large number of clinical studies on PARP inhibitors have been accomplished. This updated meta-analysis was...
PARP inhibitors are a novel targeted anti-cancer drug and a large number of clinical studies on PARP inhibitors have been accomplished. This updated meta-analysis was conducted to evaluate the efficacy and safety of PARP inhibitors in advanced-stage epithelial ovarian cancer. Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus were searched to identify the eligible trials up to April 2020. ClinicalTrials.gov was also screened for additional unpublished trials. Data extraction and risk of bias assessment were performed by two independent investigators, respectively. The hazard ratios (HRs) and its 95% confidence intervals (CI) for time-to-event data of progression-free survival (PFS) and overall survival (OS), and the risk ratios (RRs) with 95% CI for dichotomous data of overall response rate (ORR) and occurrence of adverse events (AEs) were calculated by Review Manager 5.3 and Stata 12.0 software. A total of 12 trials with 5,347 patients were included in this meta-analysis. Compared with the control group, PARP inhibitors significantly improved PFS (HR, 0.51; 95% CI, 0.40-0.65; < 0.00001) and ORR (RR, 1.26; 95% CI, 1.11-1.43; = 0.0003). Specifically, PFS was improved regardless of genes mutations and homologous-recombination status. However, no difference was observed in OS between the PARP inhibitors group and the control group (95% CI, 0.73-1.01; = 0.06). PARP inhibitors were associated with a statistically significant higher risk of hematologic events and different PARP inhibitors had different toxicities profiles. PARP inhibitors are an effective and well-tolerated treatment for patients with advanced-stage epithelial ovarian cancer.
PubMed: 32719741
DOI: 10.3389/fonc.2020.00954 -
Journal of Oncology Pharmacy Practice :... Dec 2020The treatment landscape for ovarian cancer has shifted in recent years with the approval of poly ADP-ribose polymerase inhibitors in 2014. Most patients with ovarian...
OBJECTIVE
The treatment landscape for ovarian cancer has shifted in recent years with the approval of poly ADP-ribose polymerase inhibitors in 2014. Most patients with ovarian cancer have advanced disease at diagnosis. Understanding how treatments for advanced disease work in real-world settings must be assessed to provide care for these patients. Therefore, the objective of this study was to locate and assess real-world studies measuring the safety and effectiveness of poly ADP-ribose polymerase inhibitors and analyze the results. A targeted systematic literature review was conducted in April 2020 of PubMed/Medline. Inclusion criteria consisted of observational studies using real-world data of olaparib, rucaparib, or niraparib as an intervention in the treatment of ovarian cancer. In addition, studies needed to assess either clinical effectiveness or safety. Once studies were identified, we aimed to narratively describe the studies' patient population, intervention effectiveness, and/or safety. Our systematic review identified six studies assessing the real-world effectiveness and/or safety of poly ADP-ribose polymerase inhibitors, with five assessing olaparib, one assessing poly ADP-ribose polymerase inhibitors as a composite, and none assessing either niraparib or rucaparib. The median progression free survival in the real-world trials for olaparib ranged from 12.7 to 15.6 months. The median overall survival in the real-world trials for olaparib ranged from 30.9 to 35.4 months. Rates of treatment discontinuation due to adverse events for olaparib ranged from 4.4% to 12.5%.
CONCLUSIONS
The identified studies showed slightly higher, but comparable results for median progression free survival, median overall survival, and discontinuation due to adverse events compared to the respective randomized controlled trials.
Topics: Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Randomized Controlled Trials as Topic
PubMed: 32659172
DOI: 10.1177/1078155220940043 -
Cancer Treatment Reviews Jul 2020The second decade of 2000s is witnessing a new ovarian cancer (OC) paradigm shift thanks to the results recently obtained by a new class of targeted agents: the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The second decade of 2000s is witnessing a new ovarian cancer (OC) paradigm shift thanks to the results recently obtained by a new class of targeted agents: the Poly(ADP-ribose)polymerase (PARP)-Inhibitors (PARPi). Aim of this meta-analysis is to analyze available results obtained with PARPi, administered alone or in combination with chemo- and/or target-therapies in terms of efficacy and safety for the treatment of recurrent and primary advanced OC.
METHODS
On December 2019, all published phase II/III randomized clinical studies were systematically searched using the terms "[Parp-Inhibitor] AND [ovar*]". Twelve phase II/III randomized controlled trials were identified, with a total number of 5171 patients included.
RESULTS
Results demonstrated that PARPi account for a significant improvement of PFS in both recurrent and primary OC setting, independently from their administration schedule and independently from patients' BRCA mutational status. Moreover, patients harboring a Homologous Recombination Deficiency (HRD) positive testing primary or recurrent OC progress significantly later after PARPi administration/association. Results also reported that PARPi increase the occurrence of severe (G3-G4) anemia. Furthermore, severe fatigue occurred more frequently among patients subjected to PARPi combined with chemotherapy and to PARPi plus Bevacizumab. Finally, a significant increase in severe high blood pressure occurrence was observed when PARPi was added to antiangiogenetics, compared to PARPi alone but a significant decrease in G3-G4 hypertension occurrence was found in PARPi plus bevacizumab users compared to Bevacizumab alone.
CONCLUSIONS
PARPi are a valid option for the treatment of both primary and relapsed OC patients, with a relative low incidence of severe side effects.
Topics: Carcinoma, Ovarian Epithelial; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 32485510
DOI: 10.1016/j.ctrv.2020.102040 -
Prostate Cancer and Prostatic Diseases Dec 2020A great number of DNA-damage repair (DDR) pathways have been recognized to be frequently dysregulated in advanced stages of prostate cancer. DNA-repair defects in...
BACKGROUND
A great number of DNA-damage repair (DDR) pathways have been recognized to be frequently dysregulated in advanced stages of prostate cancer. DNA-repair defects in prostate cancer represents a clinically relevant disease subset. Tumors whose ability to repair double-strand DNA breaks by homologous recombination is compromised, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase (PARP).
METHODS
A systematic review of the literature has been conducted in January 2020 using PubMed Medline database in line with the recommendations from the PRISMA guidelines. The following string terms were used for searching clinical trial articles: castration resistant OR castrate resistance OR castration refractory AND prostate cancer AND PARP OR poly(ADP-ribose) polymerase inhibitor OR DNA-repair OR homologous recombination repair. On-going clinical trials with olaparib, niraparib, talazoparib, veliparib, and rucaparib in mCRPC were searched on the clinicalTrials.gov website.
RESULTS
From this research 176 articles were identified. After title screening and abstract reading, five papers and four abstract were considered for the systematic review. Thirty-two clinical trials were also identified: from these 16 trials which did not include mCRPC patients or only prostate cancer patients, trials not yet recruiting and trials including radio-metabolic treatments were excluded. Sixteen trials were included and discussed in the paper.
CONCLUSIONS
Olaparib has been the first agent showing a benefit in terms of rPFS and ORR alone or in combination with abiraterone plus prednisone in patients with DDR deficiency prostate cancer. Also rucaparib showed a benefit in terms of PSA response rate and ORR in patients with BRCA2 and BRCA1 mutation in a phase-II study. Other phase-III clinical trials are evaluating niraparib and talazoparib, alone or in combination with AR signaling inhibitors.
Topics: BRCA1 Protein; BRCA2 Protein; Clinical Trials as Topic; Humans; Male; Mutation; Neoplasm Metastasis; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome
PubMed: 32367009
DOI: 10.1038/s41391-020-0233-3 -
Anticancer Research Feb 2020We performed a systematic review and meta-analysis to investigate the safety of maintenance with olaparib after platinum-based chemotherapy in cancer patients. (Meta-Analysis)
Meta-Analysis
BACKGROUND/AIM
We performed a systematic review and meta-analysis to investigate the safety of maintenance with olaparib after platinum-based chemotherapy in cancer patients.
MATERIALS AND METHODS
Eligible studies included randomized controlled trials (RCTs) regarding the clinical role of olaparib maintenance therapy versus placebo in BRCA-mutated, advanced cancers. Safety profile from each selected study was investigated for all-grade and G3-G4 haematological and non-haematological adverse drug events (ADEs).
RESULTS
Four RTCs that involved 1099 patients were included in the analysis. Overall incidences of all-grade and G3-4 ADEs in olaparib group were 97.6% and 41%, respectively. Patients treated with maintenance olaparib showed higher risk of all-grade and G3-G4 anaemia, all-grade neutropenia and thrombocytopenia. Moreover, all-grade and G3-G4 fatigue, all-grade vomiting, diarrhoea, nausea and decreased appetite were more common in the olaparib group compared to placebo.
CONCLUSION
Despite an increased risk and incidence of several haematological and non-haematological toxicities, olaparib is a relatively safe agent for the treatment of advanced solid tumors. Prompt identification of ADEs is mandatory to avoid therapy discontinuation and optimize treatment.
Topics: Antineoplastic Agents; Humans; Neoplasms; Phthalazines; Piperazines; Placebos; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 32014900
DOI: 10.21873/anticanres.13989 -
Critical Reviews in Oncology/hematology Nov 2019Although paclitaxel plus ramucirumab has been recommended as the preferred second-line strategy, other regimens also display potentially comparable efficacies. Record... (Meta-Analysis)
Meta-Analysis
Although paclitaxel plus ramucirumab has been recommended as the preferred second-line strategy, other regimens also display potentially comparable efficacies. Record retrieval was conducted in PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Embase, ASCO and ESMO meeting libraries. Randomized controlled trials featuring comparisons between different systemic treatments among previously treated patients with advanced gastric cancer were eligible for our systematic review. Network calculation were based on random-effects model and the relative ranking of each regimen was numerically indicated by P-score (CRD42018104672). Concerning second-line regimens, "paclitaxel plus olaparib" and "paclitaxel plus ramucirumab" dominated the overall survival ranking while "paclitaxel plus ramucirumab" additionally topped the hierarchy for progression-free survival. Among refractory or third-line only cases, apatinib reigned the hierarchy by significantly and insignificantly surpassing placebo and nivolumab respectively. In conclusion, paclitaxel plus ramucirumab is the optimal second-line regimen. Both apatinib and nivolumab could be potentially recommended as refractory regimens.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Network Meta-Analysis; Nivolumab; Paclitaxel; Pyridines; Randomized Controlled Trials as Topic; Salvage Therapy; Stomach Neoplasms; Ramucirumab
PubMed: 31449984
DOI: 10.1016/j.critrevonc.2019.08.001