Poly (ADP-ribose) polymerase (PARP) inhibitor regimens for ovarian cancer in phase III randomized controlled trials: a network meta-analysis

2020 ◽  
Vol 30 (10) ◽  
pp. 1576-1582
Author(s):  
Han Gong ◽  
Dan Nie ◽  
Yue Huang ◽  
Zhengyu Li
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Brca Mutation ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Health Benefit ◽  
Phase Iii ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
The Cost

IntroductionWe 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.MethodsA 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.ResultsNetwork 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.ConclusionsThe 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.

Poly adenosine diphosphate ribose polymerase inhibitors maintenance in patients with ovarian cancer: A systematic review and meta-analysis of randomized controlled trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17081-e17081
Author(s):  
Thura WIN Htut ◽  
Aung Tun ◽  
Anita Sultan ◽  
Sriman Swarup ◽  
Myo Zaw ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
The Other ◽  
Phase Iii ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Platinum Based Chemotherapy

e17081 Background: Ovarian cancer is the deadliest of gynecologic cancers and many recur despite achieving a clinical response to initial platinum-based chemotherapy. The use of poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance has shown to improve survival in ovarian cancer. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 randomized controlled trials (RCT) which employed PARP inhibitors maintenance in ovarian cancer were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to some heterogeneity among studies. Results: Four phase III RCTs with a total of 1792 patients were eligible. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. The randomization ratio was 2:1 in all studies. Participants were sensitive to platinum-based chemotherapy, as newly diagnosed in SOLO-1 trial and had been previously on two such regimens in the other trials, with an objective response. Almost all patients in the SOLO-2 and SOLO-1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The pooled HR for PFS was statistically significant at 0.32 (95% CI: 0.27-0.38; P < 0.0001), including gBRCA cohort (HR, 0.28; 95% CI: 0.24-0.33; P < 0.0001) and non-gBRCA cohort (HR, 0.39; 95% CI: 0.32-0.48; P < 0.0001). Conclusions: Our meta-analysis demonstrated that the use of maintenance therapy with PARP inhibitors significantly improved PFS compared to placebo, regardless of the presence or absence of gBRCA mutation.

Risk of secondary hematologic malignancies in patients with ovarian cancer treated with PARP inhibitors: A combined meta-analysis of seven phase III randomized controlled trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12076-12076
Author(s):  
Thura Htut ◽  
Somedeb Ball ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Myat M. Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Hematologic Malignancies ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Control Group ◽  
Controlled Trials ◽  
Strand Breaks ◽  
Randomized Controlled

12076 Background: Ovarian cancer (OC) is a leading cause of death from gynecologic cancers in women worldwide. Poly adenosine diphosphate ribose polymerase (PARP) inhibitors prevent the repair of single-strand breaks and generate double-strand breaks in tumor cells and have recently shown survival benefits in OC. Yet, the impact on the risk of secondary hematologic malignancies (SHM) remains uncertain. We performed a combined meta-analysis of randomized controlled trials (RCT) to determine the risk of SHM in patients with advanced OC treated with PARP inhibitors. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2020 were queried. Phase III RCTs utilizing PARP inhibitors maintenance in advanced OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with I2 and Cochran's Q- statistic. Fixed effects model was applied. Results: A total of 4,445 patients with advanced OC from seven phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib or veliparib or olaparib +bevacizumab while the control arm utilized placebo or bevacizumab. Randomization ratio was 2:1 in all studies. The I2 statistic for heterogeneity was 0, suggesting some heterogeneity among RCTs. The overall SHM incidence was 0.80% in PARP inhibitors group vs 0.47% in control group (RR 1.45; 95% CI: 0.68 – 3.07, P = 0.34). In patients with newly diagnosed OC (n = 3,044), the incidence was 0.59% vs 0.09% in control group (RR 2.7; 95% CI: 0.7—10.37, P = 0.15). In recurrent OC subset (n = 1,401), 1.28% were reported in both study and control arms (RR 0.96; 95% CI: 0.38-2.46, P = 0.94). SHM was noted in 1.3% in the olaparib subgroup compared to 1% in the control with RR of 1.24 (95% CI: 0.46 –3.31, P = 0.67). SHM occurred in 0.7% in the niraparib subgroup compared to 0.47% in the control with RR of 1.28 (95% CI: 0.30-5.45, P = 0.74). Conclusions: Our study demonstrated that the risk of SHM was not significantly increased in patients who received PARP inhibitors compared to control arm, despite attaining survival benefits. Further studies and long term follow up are necessary to define the actual relation and definitive incidence.

scholarly journals Anti-Angiogenesis Maintenance Therapy in Newly Diagnosed and Relapsed Ovarian Cancer: A Meta-analysis of Phase III Randomized Controlled Trials

2021 ◽  
Vol 12 ◽  
Author(s):  
Yizi Wang ◽  
Shitai Zhang ◽  
Zixuan Song ◽  
Ling Ouyang ◽  
Yan Li
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
Controlled Trials ◽  
Newly Diagnosed ◽  
Randomized Controlled ◽  
Fatal Adverse Events

Aim: Anti-angiogenesis agents have been added as maintenance therapy in ovarian cancer over the past decade. The aim of this meta-analysis was to analyze the efficacy of anti-angiogenesis therapy in newly diagnosed and relapsed ovarian cancer.Methods: PubMed, Embase, and Cochrane databases were searched for all phase III randomized controlled trials (RCTs) that assessed the efficacy and toxicity of anti-angiogenesis agents in ovarian cancer. Overall survival (OS) and progression-free survival (PFS) were used to evaluate the effectiveness of anti-angiogenesis therapy in ovarian cancer.Results: A total of 6097 patients with newly diagnosed ovarian cancer from 5 phase III RCTs and 2943 patients with relapsed ovarian cancer from 6 phase III RCTs were included in this meta-analysis. The pooled results showed that anti-angiogenesis maintenance therapy significantly improved PFS (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.76–0.93; p = 0.001), but not OS (HR, 0.98; 95% CI, 0.91–1.05; p = 0.49) compared with placebo in patients with newly diagnosed ovarian cancer. In patients with relapsed ovarian cancer, the pooled results showed a significant improvement on OS (HR, 0.89; 95% CI, 0.82–0.98; p = 0.02) and PFS (HR, 0.61; 95% CI, 0.52–0.72; p &lt; 0.001). The pooled results also showed that the anti-angiogenesis agents were associated with an increase in the occurrence of severe hypertension, neutropenia, diarrhea, thrombocytopenia, headache, and bleeding in ovarian cancer. However, infrequent fatal adverse events occurred in the anti-angiogenesis groups.Conclusions: Study results suggest that anti-angiogenesis agents were an effective therapy for newly diagnosed and relapsed ovarian cancer, especially for relapsed ovarian cancer. Anti-angiogenesis agents may be associated with some severe but not fatal adverse events.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42021283647

Incorporating Parp-inhibitors in Primary and Recurrent Ovarian Cancer: A Meta-analysis of 12 phase II/III randomized controlled trials

2020 ◽  
Vol 87 ◽  
pp. 102040 ◽  
Author(s):  
Ilary Ruscito ◽  
Filippo Bellati ◽  
Isabelle Ray-Coquard ◽  
Mansoor Raza Mirza ◽  
Andreas du Bois ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Phase Ii ◽  
Meta Analysis ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Controlled Trials ◽  
Randomized Controlled

Efficacy of Hypo-Methylating Agents in the Treatment of Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3632-3632
Author(s):  
Ambuj Kumar ◽  
Alan F. List ◽  
Rahul Mhaskar ◽  
Benjamin Djulbegovic
Keyword(s):  
Systematic Review ◽  
Supportive Care ◽  
Randomized Controlled Trials ◽  
Confidence Intervals ◽  
Meta Analysis ◽  
Phase Iii ◽  
P Value ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Methylating Agents

Abstract Background: With the FDA approval of two hypomethylating agents (HA) for the treatment of myelodysplastic syndromes (MDS), both azacitidine (AZA-C) and decitabine have shown widespread usage. These agents improved response rates (RR) in phase III registration trials, however, overall survival (OS) was not significantly improved. Furthermore, head to head comparison of AZA-C versus decitabine is lacking. We performed a systematic review of randomized controlled trials (RCTs) to assess the efficacy of AZA-C and decitabine versus supportive care (SC), and AZA-C versus decitabine for the treatment of MDS. Methods: A comprehensive literature search of MEDLINE, EMBASE and Cochrane library database was undertaken to identify all phase III randomized controlled trials (RCT) published through July 2008. Meetings abstracts from ASCO, ASH and European Society for Hematology were searched for the years 2006–2007. Data extraction and meta-analysis on benefits and harms of HA for MDS was performed as per the methods recommended by the Cochrane Collaboration. Indirect comparison of AZA-C versus decitabine was conducted according to the methods developed by Bucher et al and Glenny et al and were extended to calculate hazard ratios (HR). We created the following chain of inference: we first pooled RCTs that compared AZA-C with SC, and decitabine versus SC. We then compared the pooled estimates to obtain the unbiased estimate in treatment differences between decitabine and AZA-C. Results: We found 4 RCTs assessing the efficacy of HA for the treatment of MDS. Two RCTs compared AZA-C versus SC, and 2 compared decitabine versus SC. The results from 1 trial describing the effects of decitabine versus SC were reported as a press release stating that OS was not significant between two arms, however, data were not available for this analysis. The results for all comparisons are summarized in the table below. Meta-analysis of RCTs comparing HA versus SC showed significantly better OS, EFS, and RR in favor of HA without a significant increase in treatment-related mortality (TRM). Comparison of AZA-C versus SC also showed significantly better OS, EFS and RR favoring AZA-C without significant risk of TRM. In one RCT comparing decitabine versus SC, RR was significantly superior in the decitabine arm. However, there was no difference in OS, EFS and TRM between decitabine and SC. Evaluation of decitabine versus AZA-C showed significantly better OS and RR favoring AZA-C, whereas EFS and TRM were similar. Conclusion: This first systematic review on the efficacy of HA versus SC shows that OS, EFS and RR are superior with HA without significant TRM. Additionally, use of AZA-C is associated with significantly improved OS and RR compared to decitabine. In order to definitively confirm these findings, a prospective RCT comparing AZA-C and decitabine is warranted. Results from this systematic review on the efficacy of AZA-C and decitabine should be considered the threshold against which efficacy of future agents in MDS should be tested. Outcome Comparisons Hypo-methylating agents versus supportive care (3 RCTs; N=719) Conclusion Azacitidine versus supportive care (2 RCTs; N= 549) Conclusion Decitabine versus supportive care (1 RCT; N=170) Conclusion Azacitadine versus Decitabine (Indirect comparison) Conclusion Overall Survival Hazard ratio (HR)(95% Confidence Intervals) P-value HR=0.79 (0.67, 0.95) p=0.01 Hypo- methylating agents better HR=0.62 (0.48, 0.78) p=0.00 Azacitidine better HR=1.064 (0.82, 1.38) p=0.636 No difference HR=0.579 (0.41, 0.82) p=0.002 Azacitidine better Event-free survival Hazard ratio (HR) (95% Confidence Intervals) P-value HR=0.59 (0.46, 0.75) p=0.00 Hypo- methylating agents better HR=0.58 (0.44, 0.76) p=0.00 Azacitidine better HR=0.64 (0.35, 1.19) p=0.16 No difference HR=0.89 (0.46, 1.80) p=0.753 No difference Response rate Risk ratio (RR) (95% Confidence Intervals) P-value RR=1.28 (1.19, 1.37) p=0.00 Hypo- methylating agents better RR=1.37 (1.25, 1.52) p=0.00 Azacitidine better RR=1.2 (1.08, 1.31) p=0.00 Decitabine better RR=1.15 (1.0, 1.314) p=0.05 Azacitidine better Treatment-related mortality Risk ratio (RR) (95% Confidence Intervals) P-value RR=0.69 (0.36, 1.32) p=0.264 No difference RR=2.79 (0.12, 67.64) p=0.528 No difference RR=0.65 (0.34, 1.26) p=0.203 No difference RR=4.29 (0.16, 111.1) p=0.381 No difference

Maintenance Therapies for Multiple Myeloma (MM): A Network Meta-Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 236-236
Author(s):  
Helen Mahony ◽  
Ambuj Kumar ◽  
Rahul Mhaskar ◽  
Branko Miladinovic ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
Novel Agents ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Randomized Controlled ◽  
American Society ◽  
Novel Agent

Abstract Abstract 236 Background: There is little consensus on which maintenance therapy clinicians should choose for their patients. Since 1999, the three novel agents of bortezomib, lenalidomide, and thalidomide have been approved for use among patients with MM. These agents have been increasingly used as maintenance therapy. To date, only two randomized controlled trials of maintenance therapy have examined the efficacy of these novel agents head-to-head. Here, we conduct a network meta-analysis of bortezomib, lenalidomide, and thalidomide to determine which of these novel agents could potentially increase overall survival (OS) and progression-free survival (PFS). Methods: A comprehensive literature search of MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and meetings abstracts from American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology and European Hematology Association was undertaken to identify all phase III randomized controlled trials (RCTs) of maintenance therapy published until July 2012. We applied the Bayesian mixed treatment comparison (MTC) method under the random-effects model. The indirect comparisons were constructed from trials that have one treatment in common. For each included RCT, we calculated the hazard ratio (HR) and its corresponding standard error and used this to calculate the indirect estimates of HR and corresponding credible intervals (CrI). We also ranked the treatments according to the probability of best treatment and calculated the surface underneath the cumulative ranking curve (SUCRA). All analyses were conducted in WinBUGS 1.4.3 and Stata 11.2. Results: The network, number of trials for each comparison, and number of patients enrolled is shown in Figure 1. The network for OS was based on 12 RCTs enrolling 5542 patients and the network for PFS was constructed from 13 RCTs and 5784 patients. The MTC networks were consistent for both OS and PFS. For both OS and PFS, two comparisons were produced (Figure 2). For OS, the analysis showed that none of the treatments were superior. For PFS, lenalidomide was superior to thalidomide (HR = 0.58, 95% CrI [0.37, 0.94]). The estimates of SUCRA and rank probabilities (Figure 3) suggested that for OS bortezomib was best followed by lenalidomide and thalidomide. For PFS, lenalidomide was best followed by bortezomib and thalidomide. Conclusion: Using the MTC method, we found no evidence that any of the novel agents are superior to one another in terms of OS. Lenalidomide was the only novel agent which was superior to another active therapy (thalidomide). While these results provide preliminary evidence to which novel agent may be more beneficial as maintenance therapy, definitive conclusions cannot be reached until large, well designed RCTs evaluating these therapies head-to-head are conducted. Disclosures: No relevant conflicts of interest to declare.

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